Journal articles on the topic 'Prostaglandins Antagonists'
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Vanner, S., M. M. Jiang, and A. Surprenant. "Mucosal stimulation evokes vasodilation in submucosal arterioles by neuronal and nonneuronal mechanisms." American Journal of Physiology-Gastrointestinal and Liver Physiology 264, no. 2 (February 1, 1993): G202—G212. http://dx.doi.org/10.1152/ajpgi.1993.264.2.g202.
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The effects of mechanical stimulation of intestinal mucosa on submucosal arterioles of guinea pig ileum were examined using video microscopy of in vitro preparations consisting of submucosal plexus with adjacently attached mucosa. Mucosal stimulation did not alter the diameter of relaxed vessels but dilated arterioles preconstricted with phenylephrine or the prostaglandin analogue U-46619. Tetrodotoxin (TTX) or muscarinic receptor antagonists inhibited the vasodilation evoked by mucosal stimulation in 60% of preparations examined from normal and extrinsically denervated animals. The TTX-sensitive vasodilation to mucosa stimulation was partially inhibited by the 5-hydroxytryptamine3 (5-HT3) receptor antagonist ICS 205930. The TTX-insensitive vasodilation was largely prevented when the histamine receptor antagonists cimetidine and pyrilamine and the prostaglandin synthesis inhibitor indomethacin were applied. This study has demonstrated a reflex vasodilation to mucosal stimulation in an isolated submucosal plexus preparation that involves both neuronal and nonneuronal pathways. The neuronal pathway converges on cholinergic vasodilator neurons in the submucosal ganglia. The nonneuronal pathway involves the release of 5-HT, histamine, and prostaglandins from mucosal elements; 5-HT excites cholinergic vasodilator neurons, whereas histamine and prostaglandins dilate submucosal arterioles directly.
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Banks, R. O., and E. D. Jacobson. "Renal vasodilation with ureteral occlusion and prostaglandins: attenuation by histamine H1 antagonists." American Journal of Physiology-Renal Physiology 249, no. 6 (December 1, 1985): F851—F857. http://dx.doi.org/10.1152/ajprenal.1985.249.6.f851.
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We evaluated the effects of histamine receptor antagonists on the renal vasodilatory responses to ureteral occlusion (UO), to the intrarenal infusion of prostaglandins E2, I2, A2, D2 and E1, and to bradykinin. We also determined the effects of meclofenamic acid, a cyclooxygenase inhibitor, on histamine-induced renal vasodilation and the effects of 2-methylhistamine (2-MeH), and H1 agonist, on glomerular filtration rate (GFR) and renal blood flow (RBF). Experiments were performed on adult mongrel dogs anesthetized with pentobarbital sodium. RBF was measured with an electromagnetic flow probe. Neither UO-induced nor prostaglandin- (PG) induced renal vasodilation was affected by infusion of the histamine H2 receptor antagonist cimetidine into the renal artery at 10(-5) M/min. On the other hand, renal artery infusion of the H1 receptor antagonist chlorpheniramine (CP) at 10(-5) M/min blocked UO-induced renal vasodilation [RBF increased 34 +/- 4% (SE) prior to but only 2 +/- 2% during infusion of CP) and markedly attenuated PGI2-, PGA2-, and PGE2-induced increases in RBF (CP inhibited 64 +/- 9% of the PGE2-induced renal vasodilation). CP had less effect on the renal vasodilation associated with infusion of PGD2 or PGE1 and had no effect on the vasodilation induced by bradykinin. Infusion of exogenous histamine (1 micrograms X kg-1 X min-1) into the renal artery prior to ureteral occlusion resulted in a typical H1 + H2-mediated vasodilatory response (RBF increased 53 +/- 7%).(ABSTRACT TRUNCATED AT 250 WORDS)
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Lonardoni, Maria Valdrinez Campana, Momtchillo Russo, and Sonia Jancar. "Essential Role of Platelet-Activating Factor in Control of Leishmania (Leishmania)amazonensis Infection." Infection and Immunity 68, no. 11 (November 1, 2000): 6355–61. http://dx.doi.org/10.1128/iai.68.11.6355-6361.2000.
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ABSTRACT In the present study we investigated the role of platelet-activating factor (PAF) and prostaglandins in experimental Leishmania (Leishmania)amazonensis infection and the relationship between these mediators and nitric oxide (NO) production. Mouse peritoneal macrophages elicited with thioglicolate were infected with leishmania amastigotes, and the infection index determined 48 h later. The course of infection was monitored for 5 weeks in mice infected in the footpad with promastigotes by measuring the footpad swelling and parasite load in regional lymph nodes and spleen. The addition of PAF to C57BL/6 mouse macrophages significantly inhibited parasite growth and induced NO production. Treatment of macrophages with a selective PAF antagonist, WEB2086, increased the infection, indicating that endogenously produced PAF regulates macrophage ability to control leishmania infection. This effect of PAF was abolished by addition of the inhibitor of NO synthesis, L-NAME, to the cultures. The addition of prostaglandin E2 significantly increased the infection and NO production. Treatment with cyclo-oxygenase inhibitor, indomethacin, reduced the infection and PAF-induced release of NO. Thus, the increased NO production induced by PAF seems to be mediated by prostaglandins. The more-selective inhibitors of cyclo-oxygenase 2, nimesulide and NS-398, had no significant effect. Thus, antileishmanial activity correlates better with the presence of PAF or absence of prostaglandins than with NO production. In vivo treatment with PAF antagonists significantly increased leishmania lesions, as well as the parasite load, in regional lymph nodes and spleens. These findings indicate that PAF is essential for the control of leishmania infection.
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Ye, Yao, Peng Lin, Junyan Zhu, Udo Jeschke, and Viktoria von Schönfeldt. "Multiple Roles of Prostaglandin E2 Receptors in Female Reproduction." Endocrines 1, no. 1 (May 6, 2020): 22–34. http://dx.doi.org/10.3390/endocrines1010003.
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Among prostaglandins, Prostaglandin E2 (PGE2) (PGE2) is considered especially important for decidualization, ovulation, implantation and pregnancy. Four major PGE2 receptor subtypes, EP1, EP2, EP3, EP4, as well as peroxisome proliferator-activated receptors (PPARs), mediate various PGE2 effects via their coupling to distinct signaling pathways. This review summarizes up-to-date literatures on the role of prostaglandin E2 receptors in female reproduction, which could provide a broad perspective to guide further research in this field. PGE2 plays an indispensable role in decidualization, ovulation, implantation and pregnancy. However, the precise mechanism of Prostaglandin E2 (EP) receptors in the female reproductive system is still limited. More investigations should be performed on the mechanism of EP receptors in the pathological states, and the possibility of EP agonists or antagonists clinically used in improving reproductive disorders.
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Ribeiro-Junior, Jerônimo Aparecido, Marcelo Franchin, Miriam Elias Cavallini, Carina Denny, Severino Matias de Alencar, Masaharu Ikegaki, and Pedro Luiz Rosalen. "Gastroprotective Effect of Geopropolis fromMelipona scutellarisIs Dependent on Production of Nitric Oxide and Prostaglandin." Evidence-Based Complementary and Alternative Medicine 2015 (2015): 1–5. http://dx.doi.org/10.1155/2015/459846.
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The aim of this study was to evaluate the gastroprotective activity of ethanolic extract of geopropolis (EEGP) fromMelipona scutellarisand to investigate the possible mechanisms of action. The gastroprotective activity of the EEGP was evaluated using model ulcer induced by ethanol. To elucidate the possible mechanisms of action, we investigated the involvement of the nonprotein sulfhydryl (NP-SH) groups, nitric oxide and prostaglandins. In addition, the antisecretory activity of EEGP was also evaluated by pylorus ligated model. The EEGP orally administrated (300 mg/kg) reduced the ulcerative lesions induced by the ethanol (P<0.05). Regarding the mechanism of action, the prior administration of nitric oxide and prostaglandins antagonists suppressed the activity of gastroprotective EEGP (P<0.05). On the other hand the gastroprotective activity of EEGP was kept in the group pretreated with the antagonist of the NP-SH groups; furthermore the antisecretory activity was not significant (P>0.05). These results support the alternative medicine use of geopropolis as gastroprotective and the activities observed show to be related to nitric oxide and prostaglandins production.
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Healy, DL. "Progesterone receptor antagonists and prostaglandins in human fertility regulation: a clinical review." Reproduction, Fertility and Development 2, no. 5 (1990): 477. http://dx.doi.org/10.1071/rd9900477.
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Progesterone receptor antagonists have been developed by substitutions at the 11-beta and 17 side-chain positions of the progestagen norethisterone. The most studied progesterone receptor antagonists are mifepristone (Mifegyne; Roussel-UCLAF; RU486) and ZK98734 and ZK98299 (Schering AG). These compounds bind avidly to the progesterone receptor and glucocorticoid receptor but have essentially no binding to the mineralocortocoid, oestrogen or androgen receptors. Mifepristone also binds avidly to albumin, resulting in a half-life of approximately 24 h after oral administration. Progesterone receptor antagonists can induce menstruation by a direct action upon the endometrium. They have also been shown to exert weak progesterone agonist actions in certain circumstances and to modulate pituitary hormone secretion by antagonizing the feedback actions of progesterone. Moreover, they release prostaglandin F2 alpha and E2 from human endometrium or early pregnancy decidua and reduce the metabolism of these eicosanoids. Clinically, progesterone receptor antagonists have been used in trials of menstrual regulation, abortion and induction of labour, and during treatment of breast or ovarian cancer, some forms of hypertension and meningioma. Progesterone receptor antagonists have been administered to approximately 70,000 women in 18 countries as medical abortifacients. They have been proven, especially when combined with prostaglandin analogues, to be as effective as surgical methods of termination of pregnancy. Progesterone receptor antagonists have focussed international attention on menstrual regulation, abortion and the rights of women to regulate their fertility.
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Healy, David L. "Prostaglandins and Progesterone Receptor Antagonists in Human Fertility Regulation." Australian and New Zealand Journal of Obstetrics and Gynaecology 34, no. 3 (June 1994): 357–60. http://dx.doi.org/10.1111/j.1479-828x.1994.tb01089.x.
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Knauss, T., and H. E. Abboud. "Effect of serotonin on prostaglandin synthesis in rat cultured mesangial cells." American Journal of Physiology-Renal Physiology 251, no. 5 (November 1, 1986): F844—F850. http://dx.doi.org/10.1152/ajprenal.1986.251.5.f844.
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Serotonin (5-hydroxytryptamine) (5-HT) is a potent vasoactive amine that reduces renal blood flow and glomerular filtration rate. Vasodilator prostaglandins (PGs) modulate the effects of several vasoconstrictors on the renal circulation. Since mesangial cells are smooth muscle-like cells that may regulate glomerular hemodynamics, we studied the effect of 5-HT on PGs synthesis in rat cultured mesangial cells. 5-HT (10(-6)-10(-3) M) resulted in progressive stimulation of prostaglandin E2 (PGE2) synthesis. Significant stimulation in response to 10(-4) M 5-HT started after 2 min of incubation and progressively increased for at least 30 min. This effect was structurally specific for the 5-HT receptor since indole-containing precursors and metabolites of 5-HT as well as the aminergic compounds, adenosine, and dopamine were without effect. Moreover, 5-HT receptor antagonists, but not histaminergic or beta-adrenergic antagonists, abolished 5-HT-stimulated PGE2 synthesis. 5-HT also stimulated prostacyclin (measured as 6-ketoprostaglandin F1 alpha) but not thromboxane synthesis in the same cell cultures. 5-HT-stimulated PGE2 synthesis was not affected by extracellular calcium depletion but was abolished by preincubating the cells with the intracellular calcium antagonist 8-(N,N-diethylamine)-octyl-3,4-5 trimethoxybenzoate (10(-5) M). These studies show that 5-HT stimulates PGE2 and prostacyclin (PGI2) synthesis in mesangial cells via a mechanism dependent on intracellular calcium. These vasodilator PGs may modulate the effect of 5-HT on renal and specifically glomerular hemodynamics.
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Gulla, Surendra, Dakshayani Lomada, Anusha Lade, Reddanna Pallu, and Madhava C. Reddy. "Role of Prostaglandins in Multiple Sclerosis." Current Pharmaceutical Design 26, no. 7 (March 25, 2020): 730–42. http://dx.doi.org/10.2174/1381612826666200107141328.
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: Multiple sclerosis (MS) is an autoimmune demyelinating disorder with chronic inflammation in the central nervous system, manifested by both physical and cognitive disability. Neuroinflammation and neurodegeneration are the phenomena that appear in the central nervous system associated with various neurodegenerative disorders, including MS, Alzheimer’s diseases, amyotrophic lateral sclerosis and Parkinson’s disease. Prostaglandins are one of the major mediators of inflammation that exhibit an important function in enhancing neuroinflammatory and neurodegenerative processes. These mediators would help understand the pathophysiology of MS as the combination of antagonists or agonists of prostaglandins receptors could be beneficial during the treatment of MS. The present review focuses on the role played by different prostaglandins and the enzymes which produced them in the etiopathogenesis of MS.
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Fattahi, Mohammad Javad, and Abbas Mirshafiey. "Prostaglandins and Rheumatoid Arthritis." Arthritis 2012 (November 7, 2012): 1–7. http://dx.doi.org/10.1155/2012/239310.
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Rheumatoid arthritis (RA) is a chronic, autoimmune, and complex inflammatory disease leading to bone and cartilage destruction, whose cause remains obscure. Accumulation of genetic susceptibility, environmental factors, and dysregulated immune responses are necessary for mounting this self-reacting disease. Inflamed joints are infiltrated by a heterogeneous population of cellular and soluble mediators of the immune system, such as T cells, B cells, macrophages, cytokines, and prostaglandins (PGs). Prostaglandins are lipid inflammatory mediators derived from the arachidonic acid by multienzymatic reactions. They both sustain homeostatic mechanisms and mediate pathogenic processes, including the inflammatory reaction. They play both beneficial and harmful roles during inflammation, according to their site of action and the etiology of the inflammatory response. With respect to the role of PGs in inflammation, they can be effective mediators in the pathophysiology of RA. Thus the use of agonists or antagonists of PG receptors may be considered as a new therapeutic protocol in RA. In this paper, we try to elucidate the role of PGs in the immunopathology of RA.
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Dixon, B. S., R. Breckon, J. Fortune, R. J. Vavrek, J. M. Stewart, R. Marzec-Calvert, and S. L. Linas. "Effects of kinins on cultured arterial smooth muscle." American Journal of Physiology-Cell Physiology 258, no. 2 (February 1, 1990): C299—C308. http://dx.doi.org/10.1152/ajpcell.1990.258.2.c299.
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The present study uses various kinin agonists and antagonists to examine the cellular mechanisms of bradykinin's actions on intracellular calcium, prostaglandins, and adenosine 3',5'-cyclic monophosphate (cAMP) accumulation in cultured arterial smooth muscle cells (casmc) obtained from rat mesenteric arteries. Exposure to bradykinin produced a rapid release of calcium (peak less than or equal to 20 s) from intracellular stores and an increase in prostaglandin (PG) E2 and cAMP production in casmc. Compared with bradykinin, the bradykinin B1-agonist [des-Arg9]BK produced only a small increase in intracellular calcium. The bradykinin-mediated increase in intracellular calcium was competitively blocked by the B2 receptor antagonist [D-Arg-O-Hyp3-Thi5,8-D-Phe7]BK (B4307) but not the B1-antagonist ([des-Arg9-Leu8]BK). In addition, the similarity of the dose-response curves for the bradykinin-mediated increase in Ca2+, PGE2, and cAMP (half-maximal stimulation of 12, 11, and 13 nM, respectively) and the ability of the B2-antagonist (B4307) to block each of these effects of bradykinin suggest that all three effects are mediated by the same bradykinin (B2) receptor. Further studies revealed that increases in intracellular calcium are necessary for the bradykinin-mediated increase in PGE2 formation and the subsequent PGE2-dependent formation of cAMP. Taken together, these results suggest that bradykinin acts via a B2-receptor on arterial smooth muscle cells to release calcium from intracellular stores, leading to increases in PGE2 production and the PGE2-dependent activation of adenylate cyclase.
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Yamane, K., and T. Kobayashi. "Endogenous AA metabolites and their possible role in tracheal smooth muscle tone in guinea pigs." Journal of Applied Physiology 69, no. 1 (July 1, 1990): 26–32. http://dx.doi.org/10.1152/jappl.1990.69.1.26.
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The effects of endogenous arachidonic acid (AA) metabolites on inherent tone and histamine-induced constriction were studied in guinea pig tracheal smooth muscle. Inhibitors of either cyclooxygenase (indomethacin) or lipoxygenase (AA 861) significantly diminished the inherent tone of the muscle. Antagonists of prostaglandins (SC 19220) or leukotrienes (FPL 55712) also diminished the inherent tone, whereas an inhibitor of thromboxane synthase (OKY 046) had no significant effect. These results show that the metabolites of the lipoxygenase pathway as well as prostaglandins also participate in the maintenance of inherent tone. To reexamine the previously reported augmentation of histamine constriction induced by the inhibitors and the antagonists, we compared the active tension of the muscle measured from the maximum relaxed level as the base line to eliminate the fluctuation of inherent tone. Such comparison revealed that the inhibitors and the antagonists have no augmentative effect on either the maximum response to histamine or the concentration required to produce 50% of maximum active tension and that there is functional synergism between the exogenously added histamine and the endogenously produced AA metabolites. Therefore the zero active tension is useful as a base line to compare the contractile response of a drug-treated preparation with that of a nontreated preparation.
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Vrachnis, Nikolaos, Fotodotis M. Malamas, Stavros Sifakis, Efthymios Deligeoroglou, and Zoe Iliodromiti. "The Oxytocin-Oxytocin Receptor System and Its Antagonists as Tocolytic Agents." International Journal of Endocrinology 2011 (2011): 1–8. http://dx.doi.org/10.1155/2011/350546.
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Oxytocin, a hormone involved in numerous physiologic processes, plays a central role in the mechanisms of parturition and lactation. It acts through its receptor, which belongs to the G-protein-coupled receptor superfamily, while Gq/phospholipase C (PLC)/inositol 1,4,5-triphosphate (InsP3) is the main pathway via which it exerts its action in the myometrium. Changes in receptor levels, receptor desensitization, and locally produced oxytocin are factors that influence the effect of oxytocin on uterine contractility in labor. Activation of oxytocin receptor causes myometrial contractions by increasing intracellular Ca+2and production of prostaglandins. Since oxytocin induces contractions, the inhibition of its action has been a target in the management of preterm labor. Atosiban is today the only oxytocin receptor antagonist that is available as a tocolytic. However, the quest for oxytocin receptor antagonists with a better pharmacological profile has led to the synthesis of peptide and nonpeptide molecules such as barusiban, retosiban, L-368,899, and SSR-126768A. Many of these oxytocin receptor antagonists are used only as pharmacological tools, while others have tocolytic action. In this paper, we summarize the action of oxytocin and its receptor and we present an overview of the clinical and experimental data of oxytocin antagonists and their tocolytic action.
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Conger, J. D., G. E. Kim, and J. B. Robinette. "Effects of ANG II, ETA, and TxA2 receptor antagonists on cyclosporin A renal vasoconstriction." American Journal of Physiology-Renal Physiology 267, no. 3 (September 1, 1994): F443—F449. http://dx.doi.org/10.1152/ajprenal.1994.267.3.f443.
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The renin-angiotensin system, endothelin (ET), and vasoconstrictor prostaglandins have been reported in separate studies to mediate the renal vasoconstrictor effect of cyclosporin A (CsA). However, direct comparison of the relative importance of these potential mediators has not been performed. In this study, the attenuating effects of comparable agonist-inhibiting doses of receptor antagonists for angiotensin II (ANG II), DuP-753 at 2.5 mg/kg, for ETA, BQ-123 at 0.5 mg/kg, and for thromboxane A2 (TxA2), SQ-29,548 at 1.6 mg.kg-1.h-1, or saline vehicle on acute CsA (20 mg/kg) renal vasoconstriction were compared in anesthetized Sprague-Dawley rats. All three receptor antagonists significantly limited the CsA-induced increase in renal vascular resistance; however, BQ-123 and SQ-29,548 were more effective than DuP-753. Because all three receptor antagonists demonstrated at least some attenuation of CsA-induced renal vasoconstriction, the potential role of acute CsA-related nitric oxide synthase (NOS) inhibition and nonspecific heterologous effects of specific receptor antagonists on other agonists were determined to exclude the possibilities that there was a general increased agonist sensitivity and that detection of a single or primary constrictor mediator was obscured by "crossover" receptor antagonist effects. CsA significantly reduced renal blood flow (39%) in the presence of the NOS inhibitor, N omega-nitro-L-arginine methyl ester, and there was negligible indication that receptor antagonists had nonspecific effects. It is concluded that CsA-induced renal vasoconstriction is complex and involves activation of multiple constrictor agonists independently or sequentially.
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Watanabe, Masatada, Mariko Noda, and Shizuo Nakajin. "Effect of epidermal growth factor and prostaglandin on the expression of aromatase (CYP19) in human adrenocortical carcinoma cell line NCI-H295R cells." Journal of Endocrinology 188, no. 1 (January 2006): 59–68. http://dx.doi.org/10.1677/joe.1.06214.
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We investigated the effects of epidermal growth factor (EGF) and prostaglandins (PG) on the expression of aromatase (CYP19) in human adrenocortical carcinoma cell line NCI-H295R cells. EGF significantly increased aromatase activity and CYP19 gene transcript in NCI-H295R cells. Exon PII was selected from among several tissue-specific exon I regions. Promoter II that abuts on exon PII was activated by EGF. PGE2 also significantly increased aromatase activity, CYP19 gene transcript, and promoter II activity. The results of experiments using protein kinase (PK) inhibitors suggest that the cAMP–PKA signaling pathway is involved in the up-regulation of aromatase expression by EGF. PGE2 activated promoter II activity in 4 h, while12 h was required for its activation by EGF. In addition, PGE2 was secreted from NCI-H295R cells in response to EGF. Selective agonists for prostaglandin receptors EP1 and EP2 significantly increased aromatase activity, which was decreased by the corresponding antagonists. Finally, antagonists for EP1 and EP2 inhibited the up-regulation of aromatase expression following EGF. These results suggest that PGE2 secondarily acts as an autocrine signal in the up-regulation of aromatase expression by EGF in NCI-H295R cells.
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&NA;. "Prostaglandins demonstrate no advantage over H2-antagonists in terms of safety." Reactions Weekly &NA;, no. 286 (February 1990): 2. http://dx.doi.org/10.2165/00128415-199002860-00003.
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Cong, Ping, Zuo-Liang Xiao, Piero Biancani, and Jose Behar. "Prostaglandins mediate tonic contraction of the guinea pig and human gallbladder." American Journal of Physiology-Gastrointestinal and Liver Physiology 292, no. 1 (January 2007): G409—G418. http://dx.doi.org/10.1152/ajpgi.00091.2006.
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The gallbladder (GB) maintains tonic contraction modulated by neurohormonal inputs but generated by myogenic mechanisms. The aim of these studies was to examine the role of prostaglandins in the genesis of GB myogenic tension. Muscle strips and cells were treated with prostaglandin agonists, antagonists, cyclooxygenase (COX) inhibitors, and small interference RNA (siRNA). The results show that PGE2, thromboxane A2 (TxA2), and PGF2α cause a dose-dependent contraction of muscle strips and cells. However, only TxA2 and PGE2 (E prostanoid 1 receptor type) antagonists induced a dose-dependent decrease in tonic tension. A COX-1 inhibitor decreased partially the tonic contraction and TxB2 (TxA2 stable metabolite) levels; a COX-2 inhibitor lowered the tonic contraction partially and reduced PGE2 levels. Both inhibitors and the nonselective COX inhibitor indomethacin abolished the tonic contraction. Transfection of human GB muscle strips with COX-1 siRNA partially lowered the tonic contraction and reduced COX-1 protein expression and TxB2 levels; COX-2 siRNA also partially reduced the tonic contraction, the protein expression of COX-2, and PGE2. Stretching muscle strips by 1, 2, 3, and 4 g increased the active tension, TxB2, and PGE2 levels; a COX-1 inhibitor prevented the increase in tension and TxB2; and a COX-2 inhibitor inhibited the expected rise in tonic contraction and PGE2. Indomethacin blocked the rise in tension and TxB2 and PGE2 levels. We conclude that PGE2 generated by COX-2 and TxA2 generated by COX-1 contributes to the maintenance of GB tonic contraction and that variations in tonic contraction are associated with concomitant changes in PGE2 and TxA2 levels.
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Kovacic-Milivojevic, Branka, Harold D. Schultz, and David G. Gardner. "Arachidonic acid metabolites regulate the secretion of atrial natriuretic peptide in cultured rat atrial cardiocytes." Canadian Journal of Physiology and Pharmacology 69, no. 10 (October 1, 1991): 1493–99. http://dx.doi.org/10.1139/y91-224.
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Prostaglandins F2α and E2 increase release of immunoreactive (irANP) in primary cultures of rat atrial cardiocytes. This effect is independent of cell density in the cultures and does not appear to operate through a cAMP-dependent mechanism. Studies that probed the PGF2α effect with a number of different pharmacological antagonists suggest that it is tied to a calmodulin-dependent step. This latter effect does not appear to be related to increased calcium entry through voltage-gated channels in the plasma membrane nor to mobilization of ryanodine-sensitive intracellular calcium pools. Inhibitors of the lipoxygenase pathway, a second avenue of arachidonate metabolism, resulted in a decrease in irANP release from cultured atrial or ventricular cardiocytes. Leukotriene C4, a lipoxygenase product, had a modest effect to promote irANP release over a 24-h period. However, pretreatment of anesthetized rats with nordihydroguarietic acid, a lipoxygenase inhibitor, had no effect on stretch-dependent release of irANP from the heart in vivo. These findings suggest that the prostaglandins represent the more important group of arachidonate metabolites in regulating irANP release physiologically.Key words: ANP secretion, prostaglandins, leukotrienes, cardiovascular homeostasis.
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Mene, P., G. R. Dubyak, H. E. Abboud, A. Scarpa, and M. J. Dunn. "Phospholipase C activation by prostaglandins and thromboxane A2 in cultured mesangial cells." American Journal of Physiology-Renal Physiology 255, no. 6 (December 1, 1988): F1059—F1069. http://dx.doi.org/10.1152/ajprenal.1988.255.6.f1059.
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Phospholipase C activation by prostaglandins (PG) and thromboxane A2 (TxA2) was studied in cultured rat and human glomerular mesangial cells, measuring accumulation of radiolabeled inositol phosphates and cytosolic free calcium ([Ca2+]i) with the fluorescent intracellular probe fura-2. Prostaglandin F2 alpha (PGF2 alpha) and TxA2 were found to be the major eicosanoids active on this signaling pathway in rat and human cells, respectively, whereas other PG had lesser or no effects. PGF2 alpha and TxA2 rapidly induced accumulation of inositol trisphosphate accompanied by a simultaneous transient rise of [Ca2+]i, followed by sustained elevation or, in human cells, by a distinct second increase of [Ca2+]i within 45 s. A minor initial accumulation of inositol monophosphate was followed by marked elevation greater than 5 min after the early responses. Responses to different eicosanoids were mediated by separate receptors, functionally characterized using receptor antagonists or heterologous desensitization during sequential applications. Protein kinase C activation by serum and phorbol esters potently inhibited inositol phosphate accumulation and/or [Ca2+]i transients, indicating a pathway for a negative feedback on PG-evoked intracellular signals. We conclude that receptor-mediated phospholipase C activation underlies the biological effects of certain eicosanoids on the glomerular mesangium.
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Penston, J. G., and K. G. Wormsley. "Histamine H2-Receptor Antagonists Versus Prostaglandins in the Treatment of Peptic Ulcer Disease." Drugs 37, no. 4 (April 1989): 391–401. http://dx.doi.org/10.2165/00003495-198937040-00001.
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Lonardoni, M. V. C., C. L. Barbieri, M. Russo, and S. Jancar. "Modulation ofLeishmania (L.) amazonensisGrowth in Cultured Mouse Macrophages by Prostaglandins and Platelet Activating Factor." Mediators of Inflammation 3, no. 2 (1994): 137–41. http://dx.doi.org/10.1155/s0962935194000177.
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The role of endogenously synthesized PAF and prostaglandins on the infection of mouse macrophages byLetsbmanta (L.) amazonensiswas investigated, as well as the possible correlation between the effects of these inflammatory mediators with nitric oxide production. It was found that pretreatment of macrophages with 10−5M of the PAF antagonists, BN-52021 or WEB-2086, increased macrophage infection by 17 and 59%, respectively. The cyclooxygenase inhibitor, indomethacin (10μg/ml), induced a significant inhibition which was reversed by addition of PGE (10-3 M) to the culture medium. These results suggested that the infection of macrophages by leisbmanla is inhibited by PAF and enhanced by prostaglandins and that these mediators are produced by macrophages during this infection. This was confirmed by addition of these mediators to the culture medium before infection; PAF (10−6, 10−9and 10−12M) reduced significantly the infection whereas PGE2(10−5M) induced a marked enhancement. This effect of exogenous PAF on macrophage infection was reversed by the two PAF antagonists used in this study as well as by the inhibitor of nitric oxide synthesis, L-arginine methyl ester (100 mM). Taken together the data suggest that endogenous production of PAF and PGE2exert opposing effects onLesbmana–macrophage interaction and that nitric oxide may be involved in the augmented destruction of parasites induced by PAF.
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Breyer, M. D., H. R. Jacobson, and R. M. Breyer. "Functional and molecular aspects of renal prostaglandin receptors." Journal of the American Society of Nephrology 7, no. 1 (January 1996): 8–17. http://dx.doi.org/10.1681/asn.v718.
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The diverse intrarenal effects of the prostaglandins (PG) are mediated by distinct guanine nucleotide regulatory protein (G-protein)-coupled receptors. The cDNA for these receptors have been cloned, their signal transduction mechanisms determined, and their intrarenal distribution mapped. PGE2, the major intrarenal prostaglandin, interacts with at least three distinct E-prostanoid (EP) receptors that are highly expressed in specific regions of the kidney. Each EP receptor not only selectively binds PGE2, but also preferentially couples to different signal transduction pathways, including: stimulation of cAMP generation, via Gq (EP2 and EP4 receptors); inhibition of cAMP generation, via Gi (EP3 receptors); and activation of phosphatidylinositol hydrolysis (EP1 receptor), via one of the Gq family members. Activation of each these EP receptors is responsible for a distinct renal effect of PGE2, including its well-described renal hemodynamic and transport effects along the nephron. Other intrarenal prostanoid receptors include the PGF2 alpha receptor (FP), the thromboxane A2 receptor (TP) and the prostacyclin receptor (IP). Knowledge about localization of these receptors and their affinities for receptor-selective agonists and antagonists should aid in the understanding of renal disease and the development of therapeutic strategies for the use of these prostaglandin analogs in select renal diseases.
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Rubinstein, Israel. "Subtilisin Increases Macromolecular Efflux from the Oral Mucosa." Clinical Diagnostic Laboratory Immunology 7, no. 5 (September 1, 2000): 794–802. http://dx.doi.org/10.1128/cdli.7.5.794-802.2000.
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ABSTRACT The purpose of this study was to determine whether subtilisin, a potent serine proteinase derived from Bacillus species contaminating smokeless tobacco, increases macromolecular efflux from the oral mucosa and, if so, whether local elaboration of bradykinin mediates this response. Using intravital microscopy, I found that suffusion of subtilisin elicits significant, concentration-dependent leaky site formation and an increase in the clearance of fluorescein isothiocyanate-labeled dextran (molecular mass, 70 kDa) from the in situ hamster cheek pouch (P < 0.05). Heat-inactivated subtilisin had no significant effects on macromolecular efflux. Subtilisin-induced responses were significantly attenuated by Hoe 140 and NPC 17647, two structurally distinct selective bradykinin B2 receptor antagonists, but not by des-Arg9-[Leu8]bradykinin, a selective bradykinin B1 receptor antagonist, or CP-96,345, a selective neurokinin-1 receptor antagonist. Aprotinin, but not leupeptin, significantly attenuated subtilisin-induced increase in macromolecular efflux. Indomethacin had no significant effects on subtilisin-induced responses. Collectively, these data indicate that subtilisin increases the macromolecular efflux from the in situ hamster cheek pouch in a catalytic-site-dependent fashion through local elaboration of bradykinin. This response does not involve the stimulation of local afferent nerves or the production of prostaglandins.
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Freeman, E. J., and E. A. Tallant. "Vascular smooth-muscle cells contain AT1 angiotensin receptors coupled to phospholipase D activation." Biochemical Journal 304, no. 2 (December 1, 1994): 543–48. http://dx.doi.org/10.1042/bj3040543.
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We previously showed that angiotensin II (Ang II) and angiotensin-(2-8)-peptide [Ang-(2-8)] activate a phosphoinositide-specific phospholipase C (PLC) and cause calcium mobilization in rat aortic vascular smooth-muscle cells (VSMC), while Ang II and Ang-(1-7) produce prostaglandins. To define further the signal-transduction mechanisms activated by angiotensin peptides in smooth-muscle cells, we measured diacylglycerol (DAG) accumulation in response to different angiotensin peptides and its inhibition by subtype-selective receptor antagonists. Both an initial (10 s) and secondary (10 min) phase of DAG production in response to 100 nM Ang II were inhibited by 1 microM losartan (DuP 753), an AT1 antagonist, while 1 microM PD 123177, an AT2 antagonist, was ineffective. In contrast, the heptapeptide Ang-(1-7) did not produce DAG in VSMC. Ang II also caused the hydrolysis of phosphatidylinositol and phosphatidylcholine, the formation of phosphatidic acid and the formation of phosphatidylethanol (PEt) in the presence of ethanol, through activation of a PLD and a PLD-induced transphosphatidylation reaction. A similar concentration of Ang-(2-8) also activated PLD; in contrast, Ang-(1-7) was ineffective. PEt production by 100 nM Ang II was significantly attenuated by the AT1 antagonists losartan, its metabolite EXP 3174 or L-158,809 (all at 1 microM), whereas a similar concentration of the AT2 antagonists CGP 42112A or PD 123177 was ineffective. The production of PEt by Ang II was also partially attenuated by the removal of extracellular calcium and potentiated by increasing calcium concentrations, indicating that PLD activity is partially dependent on extracellular calcium. Thus VSMC PLD is coupled to an AT1 receptor and occurs in response to Ang II or Ang-(2-8), but not Ang-(1-7). Since AT1 receptors in VSMC are also coupled to activation of PLC, both PLC and PLD may be coupled to the same or a different AT1 receptor. Alternatively, PLD may be sequentially activated in response to Ang II activation of PLC and a subsequent increase in calcium concentration.
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Church, D. J., S. J. Arkinstall, M. B. Vallotton, A. Chollet, E. Kawashima, and U. Lang. "Stimulation of atrial natriuretic peptide release by neurokinins in neonatal rat ventricular cardiomyocytes." American Journal of Physiology-Heart and Circulatory Physiology 270, no. 3 (March 1, 1996): H935—H944. http://dx.doi.org/10.1152/ajpheart.1996.270.3.h935.
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The effect of substance P (SP) on atrial natriuretic peptide (ANP) release was studied in neonatal rat ventricular cardiomyocytes. Incubation of cells with SP led to a marked increase in ANP secretion, a response accompanied by increases in alpha-type protein kinase C (PKC) in the membranous cell fraction and 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) formation and a small increase in adenosine 3',5'-cyclic monophosphate (cAMP) production. A role for PKC in SP-induced 6-keto-PGF1 alpha formation and ANP release was apparent insofar as the responses were suppressed by PKC inhibitors and in PKC-downregulated cells. Furthermore, SP-induced 6-keto-PGF1 alpha production was strongly correlated with SP-induced ANP secretion (r = 0.91, P < 0.0001, n = 27), suggesting a role for prostaglandins in SP-mediated ANP release. Supporting this, indomethacin abolished SP-induced ANP release, whereas PGE2, PGF2 alpha, and prostacyclin (PGI2) promoted ANP secretion in this system. Both the profile of SP-induced cAMP production and results obtained with prostaglandin antagonists suggest that a prostanoid FP receptor is at the basis of this response. Finally, both neurokinins A and B induced similar ANP responses, whereas cultured cells were found to contain mRNA transcripts coding for both neurokinin NK1 and NK3 receptor subtypes. Overall, these results suggest that SP induces ANP secretion in neonatal ventricular cardiomyocytes through a PKC- and prostaglandin-dependent signaling pathway.
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Fei, Guijun, Yu-Zhong Wang, Sumei Liu, Hong-Zhen Hu, Guo-Du Wang, Mei-Hua Qu, Xi-Yu Wang, et al. "Stimulation of mucosal secretion by lubiprostone (SPI-0211) in guinea pig small intestine and colon." American Journal of Physiology-Gastrointestinal and Liver Physiology 296, no. 4 (April 2009): G823—G832. http://dx.doi.org/10.1152/ajpgi.90447.2008.
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Actions of lubiprostone, a selective type-2 chloride channel activator, on mucosal secretion were investigated in guinea pig small intestine and colon. Flat-sheet preparations were mounted in Ussing flux chambers for recording short-circuit current ( Isc) as a marker for electrogenic chloride secretion. Lubiprostone, applied to the small intestinal mucosa in eight concentrations ranging from 1–3000 nM, evoked increases in Isc in a concentration-dependent manner with an EC50 of 42.5 nM. Lubiprostone applied to the mucosa of the colon in eight concentrations ranging from 1–3000 nM evoked increases in Isc in a concentration-dependent manner with an EC50 of 31.7 nM. Blockade of enteric nerves by tetrodotoxin did not influence stimulation of Isc by lubiprostone. Antagonists acting at prostaglandin (PG)E2, EP1–3, or EP4 receptors did not suppress stimulation of Isc by lubiprostone but suppressed or abolished PGE2-evoked responses. Substitution of gluconate for chloride abolished all responses to lubiprostone. The selective CFTR channel blocker, CFTR(inh)-172, did not suppress lubiprostone-evoked Isc. The broadly acting blocker, glibenclamide, suppressed ( P < 0.001) lubiprostone-evoked Isc. Lubiprostone, in the presence of tetrodotoxin, enhanced carbachol-evoked Isc. The cholinergic component, but not the putative vasoactive intestinal peptide component, of neural responses to electrical field stimulation was enhanced by lubiprostone. Application of any of the prostaglandins, E2, F2, or I2, evoked depolarization of the resting membrane potential in enteric neurons. Unlike the prostaglandins, lubiprostone did not alter the electrical behavior of enteric neurons. Exposure to the histamine H2 receptor agonists increased basal Isc followed by persistent cyclical increases in Isc. Lubiprostone increased the peak amplitude of the dimaprit-evoked cycles.
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Wood, J. G., M. P. Darnell, and L. Y. Cheung. "Adenosine is a mediator of ethanol-induced gastric vasodilation in dogs." American Journal of Physiology-Gastrointestinal and Liver Physiology 264, no. 4 (April 1, 1993): G664—G670. http://dx.doi.org/10.1152/ajpgi.1993.264.4.g664.
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The purpose of this study was to assess the role of histamine, adenosine, and prostaglandins as mediators of ethanol-induced gastric vasodilation. In an ex vivo segment of canine stomach, vasodilation occurred within the first minute of replacing luminal saline with ethanol (40% vol/vol). Ethanol caused vascular resistance to progressively decrease by approximately 53% compared with control values. In other experiments, intra-arterial infusion of histamine (300 ng/ml) or adenosine (30 micrograms/ml) to the gastric segment produced similar degrees of vasodilation as observed with ethanol. The response to these vasodilators could be markedly attenuated with specific antagonists of these substances (histamine: pyrilamine plus cimetidine; adenosine: 8-phenyltheophylline). In our final experiments, indomethacin or histamine- or adenosine-receptor antagonists were given before application of topical ethanol. Indomethacin or histamine antagonists had no significant effect on the time course or magnitude of ethanol-induced vasodilation. In contrast, pretreatment with 8-phenyltheophylline significantly reduced changes in vascular resistance during exposure to luminal ethanol. These results suggest that locally released adenosine is an important mediator of ethanol-induced vasodilation in the canine stomach under these conditions.
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Zhang, David X., Kathryn M. Gauthier, and William B. Campbell. "Mechanisms of histamine-induced relaxation in bovine small adrenal cortical arteries." American Journal of Physiology-Endocrinology and Metabolism 289, no. 6 (December 2005): E1058—E1063. http://dx.doi.org/10.1152/ajpendo.00162.2005.
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Adrenal steroidogenesis is closely correlated with increases in adrenal blood flow. Many reports have studied the regulation of adrenal blood flow in vivo and in perfused glands, but until recently few studies have been conducted on isolated adrenal arteries. The present study examined vasomotor responses of isolated bovine small adrenal cortical arteries to histamine, an endogenous vasoactive compound, and its mechanism of action. In U-46619-precontracted arteries, histamine (10−9-5 × 10−6 M) elicited concentration-dependent relaxations. The relaxations were blocked by the H1 receptor antagonists diphenhydramine (10 μM) or mepyramine (1 μM) (maximal relaxations of 18 ± 6 and 22 ± 6%, respectively, vs. 55 ± 5% of control) but only partially inhibited by the H2 receptor antagonist cimetidine (10 μM) and the H3 receptor antagonist thioperamide (1 μM). Histamine-induced relaxations were also blocked by the nitric oxide synthase inhibitor N-nitro-l-arginine (l-NA, 30 μM; maximal relaxation of 13 ± 7%) and eliminated by endothelial removal or l-NA combined with the cyclooxgenase inhibitor indomethacin (10 μM). In the presence of adrenal zona glomerulosa (ZG) cells, histamine did not induce further relaxations compared with histamine alone. Histamine (10−7-10−5 M) concentration-dependently increased aldosterone production by adrenal ZG cells. Compound 48/80 (10 μg/ml), a mast cell degranulator, induced significant relaxations (93 ± 0.6%), which were blocked by l-NA plus indomethacin or endothelium removal, partially inhibited by the combination of the H1, H2, and H3 receptor antagonists, but not affected by the mast cell stabilizer sodium cromoglycate (1 mM). These results demonstrate that histamine causes direct relaxation of small adrenal cortical arteries, which is largely mediated by endothelial NO and prostaglandins via H1 receptors. The potential role of histamine in linking adrenal vascular events and steroid secretion requires further investigation.
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Gupta, Janesh K., and Nicholas Johnson. "Should we use prostaglandins, tents or progesterone antagonists for cervical ripening before first trimester abortion?" Contraception 46, no. 5 (November 1992): 489–97. http://dx.doi.org/10.1016/0010-7824(92)90152-j.
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Ono, S., and N. F. Voelkel. "PAF antagonists inhibit monocrotaline-induced lung injury and pulmonary hypertension." Journal of Applied Physiology 71, no. 6 (December 1, 1991): 2483–92. http://dx.doi.org/10.1152/jappl.1991.71.6.2483.
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Lung platelet-activating factor (PAF) levels increased in some rats at 1–3 wk after subcutaneous injection of monocrotaline (MCT). We tested the effect of specific PAF antagonists, WEB 2086 and WEB 2170, on MCT-induced lung injury and subsequent pulmonary hypertension and right ventricular hypertrophy. Treatment with either agent decreased MCT-induced pulmonary hypertension and right ventricular hypertrophy at 3 wk after injection. Treatment with WEB 2170 reduced MCT-induced pulmonary vascular leak at 1 wk after injection, and WEB 2086-treatment exclusively during the early leak phase also decreased MCT-induced right ventricular hypertrophy at 3 wk. Treatment with WEB 2170 between the 3rd and 4th wk after MCT injection inhibited the progression of right ventricular hypertrophy at 4 wk. These results suggest that PAF contributes to the early pulmonary vascular leak, and this leak phase is important for the development of pulmonary hypertension and right ventricular hypertrophy in MCT-treated rats. Furthermore, it appears that PAF action contributes to the maintenance of a chronic inflammatory process that involves the synthesis of other lipid mediators (prostaglandins and leukotrienes) and leads to pulmonary hypertension. We conclude that PAF has a role in the MCT-induced inflammatory lung injury and pulmonary hypertension.
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Neely, C. F., I. Matot, D. Haile, J. Nguyen, and V. Batra. "Tone-dependent responses of histamine in feline pulmonary vascular bed." American Journal of Physiology-Heart and Circulatory Physiology 268, no. 2 (February 1, 1995): H653—H661. http://dx.doi.org/10.1152/ajpheart.1995.268.2.h653.
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Under conditions of controlled pulmonary blood flow and constant left atrial pressure, histamine produced tone-dependent responses in the pulmonary vascular (PV) bed of intact-chest, spontaneously breathing cats. At low, baseline PV tone, histamine produced dose-dependent increases in mean lobar arterial pressure that were antagonized by the selective histamine H1-receptor antagonist, diphenhydramine. The cyclooxygenase inhibitor, meclofenamate, and the thromboxane A2 (TxA2) receptor antagonist, SQ-29548, had no effect on these vasoconstrictor responses of histamine. After an increase in PV tone with an intralobar arterial infusion of a TxA2 mimic, U-46619, histamine produced vasodilator responses at low doses, biphasic vasodilator/vasoconstrictor responses at midrange doses, and vasoconstrictor responses at high doses. Diphenhydramine antagonized vasoconstrictor responses and the vasodilator responses of low to midrange doses and enhanced vasodilator responses of high doses of histamine at elevated PV tone. Selective H2-receptor antagonists, ranitidine and meclofenamate, and selective H3-receptor antagonist, thioperamide, did not antagonize vasodilator responses of histamine. H1- and H2-receptor antagonism was more effective in reducing the vasodilator responses of histamine at elevated PV tone than H1-receptor antagonism alone. These data support that histamine produces vasoconstrictor responses at low baseline and elevated PV tone by acting on H1 receptors that do not induce the release of vasoconstrictor prostanoids. At elevated PV tone, histamine produces vasodilation by acting on H1 receptors that are not coupled to the release of vasodilator prostaglandins and also, in part, by acting on H2 receptors.
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Moss, I. R., and J. G. Inman. "Neurochemicals and respiratory control during development." Journal of Applied Physiology 67, no. 1 (July 1, 1989): 1–13. http://dx.doi.org/10.1152/jappl.1989.67.1.1.
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During ontogeny, the central nervous system undergoes neuronal growth, regression, and remodeling. The development of neurotransmitter and modulator systems is a plastic process with individual temporal characteristics for each system. These characteristics include the synthesis, degradation, or uptake of neurochemicals and, largely independently, the appearance of their receptors. Message transmission during ontogeny is compounded by the variable development of these systems and by the coexistence and cofunction among these chemicals. Nine neurochemical systems are discussed: adenosine, gamma-aminobutyric acid, opioids, prostaglandins, serotonin, progesterone, substance P, thyrotropin-releasing hormone, and the catecholamines. The possible role of each of these in natural perinatal respiratory control is evaluated according to predetermined criteria. These include the presence of a substance system in respiratory-related regions, physiologically appropriate changes in its concentration in these regions, elicitation of respiratory effects by agonists and antagonists, and abolition with an antagonist of the effect of a substance during its presumed activation by a physiological process. It is suggested that excessive levels of suppressant neuromodulators or an imbalance among neurochemicals can partly explain the special features of respiratory control in the perinatal period.
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Chen, Daohong, Elena V. Balyakina, Mayme Lawrence, Brian W. Christman, and Barbara Meyrick. "Cyclooxygenase is regulated by ET-1 and MAPKs in peripheral lung microvascular smooth muscle cells." American Journal of Physiology-Lung Cellular and Molecular Physiology 284, no. 4 (April 1, 2003): L614—L621. http://dx.doi.org/10.1152/ajplung.00215.2002.
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We examined the hypothesis that the potent vasoconstrictor endothelin (ET)-1 regulates both its own production and production of the vasodilator prostaglandins PGE2 and prostacyclin in sheep peripheral lung vascular smooth muscle cells (PLVSMC). Confluent layers of PLVSMC were exposed to 10 nM ET-1; expression of the prepro (pp)-ET-1, cyclooxygenase (COX)-1, and COX-2 genes was examined by RT-PCR and Western analysis. Intracellular levels of ET-1 were measured by ELISA with and without addition of the protein synthesis inhibitor brefeldin A (50 μg/ml). Prostaglandin levels were measured by gas chromatography-mass spectrometry. Through use of ETA and ETB antagonists (BQ-610 and BQ-788, respectively), the contribution of the ET receptors to COX-1 and -2 expression and ppET-1 gene expression was examined. The contribution of phosphorylated p38 and p44/42 MAPK on COX-1 and COX-2 expression was also examined with MAPK inhibitors (p38, SB-203580 and p44/42, PD-98056). ET-1 resulted in transient increases in ppET-1, COX-1, and COX-2 gene and protein expression and release of 6-keto-PGF1α and PGE2 ( P < 0.05). Both internalization of ET-1 and synthesis of new peptide contributed to an increase in intracellular ET-1 ( P < 0.05). Although increased ppET-1 was regulated by both ETA and ETB, COX-2 expression was upregulated only by ETA; COX-1 expression was unaffected by either antagonist. ET-1 treatment resulted in transient phosphorylation of p38 and p44/42 MAPK; inhibitors of these MAPKs suppressed expression of COX-2 but not COX-1. Our data indicate that local production of ET-1 regulates COX-2 by activation of the ETA receptor and phosphorylation of p38 and p44/42 MAPK in PLVSMC.
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Jelson, Gregory S., Gina M. DeMasi, Kristen L. Sager, and Jean C. Hardwick. "Modulation of guinea pig intrinsic cardiac neurons by prostaglandins." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 285, no. 3 (September 2003): R682—R689. http://dx.doi.org/10.1152/ajpregu.00123.2003.
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Activation of cardiac mast cells has been shown to alter parasympathetic neuronal function via the activation of histamine receptors. The present study examined the ability of prostaglandins to alter the activity of guinea pig intracardiac neurons. Intracellular voltage recordings from whole mounts of the cardiac plexus showed that antigen-mediated mast cell degranulation produces an attenuation of the afterhyperpolarization (AHP), which was prevented by the phospholipase A2 inhibitor 5,8,11,14-eicosatetraynoic acid. Exogenous application of either PGD2 or PGE2 produced a biphasic change in the membrane potential and an inhibition of both AHP amplitude and duration. Examination of prostanoid receptors using bath perfusions (1 μM PGE2 and PGD2), specific agonists (BW245C, sulprostone, and butaprost), and antagonists (AH6809 and SC19220) found evidence for both the PGE2-specific EP2 and EP3 receptors, but not for EP1 or the PGD2-specific prostanoid (DP) receptors. Sulprostone was able to mimic the PGE2 responses in some cells, but not in all PGE2-sensitive cells. Butaprost was able to mimic the PG-induced hyperpolarization in some cells, but did not alter the AHP. Inhibition of specific potassium channels with either TEA, charybdotoxin, or apamin showed that neither TEA nor charybdotoxin could prevent the PGE2-induced AHP attenuation. Apamin alone inhibited AHP duration, with PGs having no further effect in these cells. These results demonstrate that guinea pig intracardiac neurons can be modulated by PG, most likely through either EP2, EP3, or potentially EP4 receptors, and this response is due, at least in part, to a reduction in small-conductance KCa currents.
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Regoli, D., D. Jukic, F. Gobeil, and N. E. Rhaleb. "Receptors for bradykinin and related kinins: a critical analysis." Canadian Journal of Physiology and Pharmacology 71, no. 8 (August 1, 1993): 556–67. http://dx.doi.org/10.1139/y93-079.
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Kinins exert a variety of biological actions and have been implicated in the pathogenesis of inflammation, pain, asthma, and other diseases. Kinins act through specific receptors that are widespread and belong to two major categories, B1 and B2. B2 has been cloned and shown to be of the rhodopsin type, consisting of seven hydrophobic membrane domains connected by extracellular and intracellular loops. Recent pharmacological findings from various laboratories suggest the existence of new receptor types, which have been named B3, B4, and B5. These findings are analysed critically, especially with respect to the criteria that have been used for affirming the existence of new receptor entities. The analysis is restricted to data obtained in isolated organs, almost exclusively smooth muscle preparations. Criteria for receptor characterization and classification are the order of potency of agonists and the apparent affinities of antagonists. The analysis reveals that receptors for bradykinin and related kinins are of two types, B1 and B2. B1 mediates the rapid acute response (smooth muscle contraction or relaxation) as well as some effects occurring more slowly (e.g., collagen synthesis). B1 receptor functions have been shown to be modulated by interleukins. B2 receptors are responsible for most of the kinins' biological effects, including arterial vasodilatation, plasma extravasation, venoconstriction, activation of sensory fibers (e.g., fibers for pain), and stimulation of the release of prostaglandins, endothelium-dependent relaxing factor (from endothelia), noradrenaline (from nerve terminals and adrenals), and other endogenous agents. The pharmacological characteristics of the receptor sites (B2) mediating this array of biological effects show differences between species, and two B2 receptor subtypes are proposed, namely B2A (rabbit, dog, and possibly man) and B2B (guinea pig, hamster, rat). B2A and B2B receptor subtypes have been characterized by using fairly selective agonists and competitive antagonists (e.g., D-Arg[Hyp3,D-Phe7,Leu8]BK). Noncompetitive antagonists (non-equilibrium), such as HOE 140, do not discriminate between B2A and B2B subtypes. Species differences cannot account for the multiplicity of receptors that have been proposed for rat vas deferens, pre- and post-junctional sites, and rat uterus, guinea pig ileum, and rat blood pressure. The existence of hypothetical new receptor sites was based on data obtained with partial agonists and have not been substantiated by data obtained with potent pure antagonists. The B3 receptor, proposed to explain the unusual behaviour of the guinea pig tracheal response to kinins, has to be carefully reconsidered after the finding that HOE 140 acts as a pure antagonist on this tissue and shows a fairly high affinity for the tracheal site. B3, B4, and B5 receptors described in the esophagus of the opossum have not been sufficiently characterized either with agonists or with antagonists to be considered as new functional sites.Key words: kinins, smooth muscle, receptors, antagonists, action mechanisms.
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Champion, Hunter C., and Philip J. Kadowitz. "Vasodilator responses to ATP and UTP are not dependent on nitric oxide release, K+ATP channel activation, or the release of vasodilator prostaglandins in the hindlimb vascular bed of the cat." Canadian Journal of Physiology and Pharmacology 78, no. 8 (August 1, 2000): 612–21. http://dx.doi.org/10.1139/y00-021.
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The effects of the purinergic agonists, ATP, ATPγS, UTP, and 2-Met-Thio AP, were investigated in the hindlimb vascular bed of the cat. Under constant-flow conditions, injections of the purinergic agonists into the perfusion circuit elicited dose-related decreases in perfusion pressure. The order of potency was 2-Met-Thio ATP > ATPγS > ATP > UTP. In contrast, injections of GTPγS, cAMP, UDP, and UMP had no effect. Vasodilator responses to ATP, ATPγS, UTP, and 2-Met-Thio ATP were increased in duration by the cAMP phosphodiesterase inhibitor rolipram, whereas the cGMP phosphodiesterase inhibitor zaprinast had no effect. Responses to the purinergic agonists were not altered by nitric oxide synthase inhibitors, K+ATP channel antagonists, cyclooxygenase inhibitors, or agents that interfere with the actions of the adrenergic nervous system. These data suggest that ATP, ATPγS, UTP, and 2-Met-Thio ATP dilate the hindlimb vascular bed by a direct cAMP-dependent mechanism, and that the release of nitric oxide, vasodilator prostaglandins, K+ATP channel opening, or an inhibitory effect on the adrenergic nervous system play little, if any, role in mediating or modulating responses to the purinergic agonists in the hindlimb circulation of the cat.Key words: purinergic agonists, P2 purinergic receptors, cAMP-dependent vasodilator activity, adrenergic system, nitric oxide prostaglandins.
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Mikulska, Joanna, Gabriela Juszczyk, Monika Gawrońska-Grzywacz, and Mariola Herbet. "HPA Axis in the Pathomechanism of Depression and Schizophrenia: New Therapeutic Strategies Based on Its Participation." Brain Sciences 11, no. 10 (September 30, 2021): 1298. http://dx.doi.org/10.3390/brainsci11101298.
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The hypothalamic-pituitary-adrenal (HPA) axis is involved in the pathophysiology of many neuropsychiatric disorders. Increased HPA axis activity can be observed during chronic stress, which plays a key role in the pathophysiology of depression. Overactivity of the HPA axis occurs in major depressive disorder (MDD), leading to cognitive dysfunction and reduced mood. There is also a correlation between the HPA axis activation and gut microbiota, which has a significant impact on the development of MDD. It is believed that the gut microbiota can influence the HPA axis function through the activity of cytokines, prostaglandins, or bacterial antigens of various microbial species. The activity of the HPA axis in schizophrenia varies and depends mainly on the severity of the disease. This review summarizes the involvement of the HPA axis in the pathogenesis of neuropsychiatric disorders, focusing on major depression and schizophrenia, and highlights a possible correlation between these conditions. Although many effective antidepressants are available, a large proportion of patients do not respond to initial treatment. This review also discusses new therapeutic strategies that affect the HPA axis, such as glucocorticoid receptor (GR) antagonists, vasopressin V1B receptor antagonists and non-psychoactive CB1 receptor agonists in depression and/or schizophrenia.
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Santiago, J. A., H. C. Champion, and P. J. Kadowitz. "T-kinin has endothelium-dependent vasodilator activity in the cat." American Journal of Physiology-Heart and Circulatory Physiology 272, no. 3 (March 1, 1997): H1491—H1498. http://dx.doi.org/10.1152/ajpheart.1997.272.3.h1491.
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Responses to T-kinin, a peptide formed from the acute-phase substrate T-kininogen, were investigated in the hindlimb vascular bed of the cat. Under constant-flow conditions, injections of T-kinin into the perfusion circuit in doses of 0.03-1 nmol induced rapid dose-related decreases in perfusion pressure. Responses to T-kinin were similar in time course and magnitude to responses to bradykinin and kallidin and were inhibited by the kinin B2-receptor antagonist, Hoe-140. Responses to T-kinin were attenuated by an inhibitor of nitric oxide synthase and by tetraethylammonium chloride and were enhanced in duration by the guanosine 3',5'-cyclic monophosphate (cGMP) phosphodiesterase inhibitor zaprinast. Responses to T-kinin were not altered by inhibitors of K+(ATP) channels, by the cyclooxygenase pathway, or by muscarinic or beta-adrenergic-receptor antagonists. These data suggest that vasodilator responses to T-kinin are mediated by kinin B2-receptor-stimulated release of nitric oxide from the endothelium and increased smooth muscle cGMP levels. These results indicate that activation of K+(ATP) channels and muscarinic or beta-adrenergic receptors and the release of vasodilator prostaglandins are not involved in mediating the response to T-kinin in the hindlimb circulation of the cat.
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Alsaif, Malak, Nayel Helmy, Fatimah Almuallem, Shahad Almagboul, Hilyil Almtrafi, Bashaer Matouq, Nawfal Alsufayan, Ruba Saleh, Sultan Aldalbahi, and Afnan Alshahrani. "Pharmaceutical versus mechanical induction of labor." International Journal of Reproduction, Contraception, Obstetrics and Gynecology 7, no. 10 (September 26, 2018): 4325. http://dx.doi.org/10.18203/2320-1770.ijrcog20183871.
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Labor induction is one of the most common obstetric interventions carried out in obstetric institutions. More than one fifth of labors needs induction. To date, many methods are available for labor induction with the pharmaceutical and mechanical methods being the commonest. The most common pharmaceutical agents used are prostaglandins, oxytocin, synthetic progesterone antagonists, and nitric oxide. Mechanical induction is carried out through using balloon catheters, hygroscopic dilators, artificial membrane rupture, or membrane stripping. Though pharmaceutical methods had largely replaced mechanical induction of labor, no consensus guidelines recommend their use. Studies from literature are still conflicting. However, it is generally agreed that the use of a combined approach with both pharmaceutical and mechanical methods of induction yields the best outcome. This article will review the different methods for labor induction, their effectiveness, and adverse events.
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Baroja-Mazo, Alberto, and Pablo Pelegrín. "Modulating P2X7 Receptor Signaling during Rheumatoid Arthritis: New Therapeutic Approaches for Bisphosphonates." Journal of Osteoporosis 2012 (2012): 1–7. http://dx.doi.org/10.1155/2012/408242.
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P2X7 receptor-mediated purinergic signaling is a well-known mechanism involved in bone remodeling. The P2X7 receptor has been implicated in the pathophysiology of various bone and cartilage diseases, including rheumatoid arthritis (RA), a widespread and complex chronic inflammatory disorder. The P2X7 receptor induces the release into the synovial fluid of the proinflammatory factors (e.g., interleukin-1β, prostaglandins, and proteases) responsible for the clinical symptoms of RA. Thus, the P2X7 receptor is emerging as a novel anti-inflammatory therapeutic target, and various selective P2X7 receptor antagonists are under clinical trials. Extracellular ATP signaling acting through the P2X7 receptor is a complex and dynamic scenario, which varies over the course of inflammation. This signaling is partially modulated by the activity of ectonucleotidases, which degrade extracellular ATP to generate other active molecules such as adenosine or pyrophosphates. Recent evidence suggests differential extracellular metabolism of ATP during the resolution of inflammation to generate pyrophosphates. Extracellular pyrophosphate dampens proinflammatory signaling by promoting alternative macrophage activation. Our paper shows that bisphosphonates are metabolically stable pyrophosphate analogues that are able to mimic the anti-inflammatory function of pyrophosphates. Bisphosphonates are arisingper seas promising anti-inflammatory drugs to treat RA, and this therapy could be improved when administrated in combination with P2X7 receptor antagonists.
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Riley, S. C., and N. L. Poyser. "Prostaglandin production by the guinea-pig endometrium: is calcium necessary?" Journal of Endocrinology 113, no. 3 (June 1987): 463–71. http://dx.doi.org/10.1677/joe.0.1130463.
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ABSTRACT The output of prostaglandin (PG) F2α from guinea-pig endometrium obtained on day 15 of the oestrous cycle and maintained in tissue culture was significantly (P<0·05) reduced by the use of Ca2+-depleted medium, EGTA (a Ca2+ chelator), 8-(N,N-diethyl-amino)octyl-3,4,5-trimethoxybenzoate hydrochloride (TMB-8; an intracellular Ca2+ antagonist), trifluoperazine (TFP) and N-(6-aminohexyl)-5-chloro-1-naphthalenesulphonamide (W-7; both calmodulin antagonists). Nifedipine inhibited PGF2α output at a concentration (100 μmol/l) much greater than that usually required to block Ca2+ channels. Verapamil had a small but significant (P < 0·05) inhibitory effect on PGF2α output at 10–100 μmol/l. The outputs of PGE2 and, to a lesser extent, 6-keto-PGF1α (the hydrated product of PGI2) were also reduced by using Ca2+-depleted medium. EGTA reduced the outputs of PGE2 and 6-keto-PGF1α on day 1 of culture, but stimulated 6-keto-PGF1α output on day 3 of culture. The outputs of PGE2 and 6-keto-PGF1α were increased by TMB-8 (100 μmol/l) on day 3 of culture and by TFP and, to a smaller extent, by W-7 on all 3 days of culture. Nifedipine (100 μmol/l by not 1 or 10 μmol/l) reduced the outputs of PGE2 and 6-keto-PGF1α on all 3 days of culture, whereas verapamil (100 μmol/l but not 1 or 10 μmol/l) increased the outputs of these two prostaglandins on days 2 and 3 of culture. Phorbol 12-myristate 13-acetate (an activator of protein kinase C) had no effect on the outputs of PGF2α, PGE2 and 6-keto-PGF1α from cultured guineapig endometrium obtained on days 7 and 15 of the oestrous cycle. It is concluded that extracellular Ca2+ is necessary for the high output of PGF2α from the guinea-pig uterus after day 11 of the oestrous cycle, and that the action of Ca2+ is not potentiated by the activation of protein kinase C. J. Endocr. (1987) 113, 463–471
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Martey, C. A., C. J. Baglole, T. A. Gasiewicz, P. J. Sime, and R. P. Phipps. "The aryl hydrocarbon receptor is a regulator of cigarette smoke induction of the cyclooxygenase and prostaglandin pathways in human lung fibroblasts." American Journal of Physiology-Lung Cellular and Molecular Physiology 289, no. 3 (September 2005): L391—L399. http://dx.doi.org/10.1152/ajplung.00062.2005.
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Cigarette smoking can lead to chronic lung inflammation and lung cancer. Chronic inflammation, associated with expression of cyclooxygenase-2 (COX-2) and prostaglandins, predisposes to malignancy. We recently demonstrated that human lung fibroblasts are activated by cigarette smoke to express COX-2 and prostaglandin E2 (PGE2). Little is known about the mechanism whereby smoke activates human lung fibroblasts to produce proinflammatory mediators. Herein, we report the central role of the aryl hydrocarbon receptor (AHR) in cigarette smoke extract (CSE)-induced COX-2, microsomal PGE2 synthase (mPGES), and PGE2 production in human lung fibroblasts. Western blot analysis revealed that primary strains of human lung fibroblasts express AHR and aryl hydrocarbon nuclear translocator protein, supporting the possibility that smoke activates lung fibroblasts through this pathway. Experiments were subsequently performed to determine whether the AHR was activated by CSE. Immunocytochemistry and EMSA analysis revealed that CSE induced nuclear translocation of the AHR in human lung fibroblasts. CSE decreased protein levels of the AHR, consistent with AHR ligand-induced proteosome-mediated degradation. CSE also induced mPGES-1 and COX-2 protein and increased PGE2 production. Treatment of human fibroblasts with AHR antagonists in the presence of CSE inhibited AHR nuclear translocation as well as COX-2, mPGES-1, and PGE2 production. These data indicate that the AHR pathway plays an important role in cigarette smoke-mediated COX-2 and PG production in human lung fibroblasts and may contribute to tobacco-associated inflammation and lung disease.
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Nayeem, Sarmah B., Arun Dharmarajan, and Jeffrey A. Keelan. "Paracrine communication modulates production of Wnt antagonists and COX1-mediated prostaglandins in a decidual-trophoblast co-culture model." Molecular and Cellular Endocrinology 405 (April 2015): 52–62. http://dx.doi.org/10.1016/j.mce.2015.02.003.
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Park, Gye Young, and John W. Christman. "Involvement of cyclooxygenase-2 and prostaglandins in the molecular pathogenesis of inflammatory lung diseases." American Journal of Physiology-Lung Cellular and Molecular Physiology 290, no. 5 (May 2006): L797—L805. http://dx.doi.org/10.1152/ajplung.00513.2005.
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Inducible cyclooxygenase (COX-2) and its metabolites have diverse and potent biological actions that are important for both physiological and disease states of lung. The wide variety of prostaglandin (PG) products are influenced by the level of cellular activation, the exact nature of the stimulus, and the specific cell type involved in their production. In turn, the anti- and proinflammatory response of PG is mediated by a blend of specific surface and intracellular receptors that mediate diverse cellular events. The complexity of this system is being at least partially resolved by the generation of specific molecular biological research tools that include cloning and characterization of the enzymes distal to COX-2 and the corresponding receptors to the final cellular products of arachidonic metabolism. The most informative of these approaches have employed genetically modified animals and specific receptor antagonists to determine the exact role of specific COX-2-derived metabolites on specific cell types of the lung in the context of inflammatory models. These data have suggested a number of cell-specific, pathway-specific, and receptor-specific approaches that could lead to effective therapeutic interventions for most inflammatory lung diseases.
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Pak, Sok Cheon, Chang Su Na, Jeong Sang Kim, Woo Suk Chae, Seiji Kamiya, Daisuke Wakatsuki, Yasuhiro Morinaka, and Laird Wilson. "The Effect of Acupuncture on Uterine Contraction Induced by Oxytocin." American Journal of Chinese Medicine 28, no. 01 (January 2000): 35–40. http://dx.doi.org/10.1142/s0192415x00000064.
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Pretern labor (PTL) is one of the main causes of fetal mortality and morbidity in obstetrical medicine. Current methods of treatment are not very effective and often have significant side effects. For this reason new methods of preventing PTL are currently being sought. In Western medicine the newest development is oxytocin antagonists. In Oriental medicine acupuncture and moxibustion are being utilized for the purpose of stopping PTL. The goals of this study were to determine if acupuncture in pregnant rats can suppress oxytocin induced uterine contractions and to compare these results with those inhibited by an oxytocin antagonist. Uterine contractions were induced by continuous infusion of exogenous oxytocin. The first fetus in one uterine horn near the ovarian end was removed and distilled water-filled catheter was inserted into that vacated amniotic sac to measure uterine contractions as intrauterine pressure changes. Two acupoints of Ho-Ku (LI-4) and San-Yin-Chiao (Sp-6) were selected for acupuncture and Kuan-Yüan (Co-4) was used for moxibustion. The oxytocin-induced uterine contractions were significantly suppressed by acupuncture on the LI-4 (p < 0.05), but not by Sp-6. Stimulation of Co-4 by moxibustion had no significant (p > 0.05) tocolytic effect. The administration of oxytocin antagonist eliminated all the uterine contractions induced by oxytocin. The application of acupuncture to re-stimulate the activity that was suppressed by the oxytocin antagonist did not produce any positive results. However, prostaglandins did cause the uterus to contract. In conclusion, acupuncture on LI-4 was found to suppress uterine contractions induced by oxytocin in the pregnant rat. If acupuncture is similarly effective in counteracting the effects of oxytocin in women, then this may an alternative medical treatment for women in preterm labor.
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Lundberg, Jan M. "Tachykinins, sensory nerves, and asthma—an overview." Canadian Journal of Physiology and Pharmacology 73, no. 7 (July 1, 1995): 908–14. http://dx.doi.org/10.1139/y95-125.
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Tachykinin peptides, substance P (SP) and neurokinin A (NKA), are released from airway sensory nerves upon exposure to irritant chemicals and endogenous agents including bradykinin, prostaglandins, histamine, and protons. The released neuropeptides are potent inducers of a cascade of responses, including vasodilatation, mucus secretion, plasma protein extravasation, leukocyte adhesion–activation, and bronchoconstriction. Neurokinin 1 receptors (preferably activated by SP) seem to be most important for inflammatory actions, while neurokinin 2 receptors (preferably activated by NKA) mediate bronchoconstriction. Species differences exist whereby rat and guinea-pig have a more developed neurogenic inflammation response than normal human airways. However, disease states such as inflammation or viral infections lead to enhanced peptide synthesis and (or) increased sensory nerve excitability. Together with increased neurokinin 1 receptor synthesis and loss of major tachykinin-degrading enzymes such as neutral endopeptidase in airway inflammation, this suggests that recently developed, orally active nonpeptide neurokinin receptor antagonists could have a therapeutic potential in asthmatic patients.Key words: neurokinins, sensory nerves, inflammation, bronchoconstriction, receptors.
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Marsh, Brenda J., Allison D. Fryer, David B. Jacoby, and Matthew G. Drake. "Transient receptor potential ankyrin-1 causes rapid bronchodilation via nonepithelial PGE2." American Journal of Physiology-Lung Cellular and Molecular Physiology 318, no. 5 (May 1, 2020): L943—L952. http://dx.doi.org/10.1152/ajplung.00277.2019.
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Transient receptor potential ankyrin-1 (TRPA1) is a ligand-gated cation channel that responds to endogenous and exogenous irritants. TRPA1 is expressed on multiple cell types throughout the lungs, but previous studies have primarily focused on TRPA1 stimulation of airway sensory nerves. We sought to understand the integrated physiological airway response to TRPA1 stimulation. The TRPA1 agonists allyl isothiocyanate (AITC) and cinnamaldehyde (CINN) were tested in sedated, mechanically ventilated guinea pigs in vivo. Reproducible bronchoconstrictions were induced by electrical stimulation of the vagus nerves. Animals were then treated with intravenous AITC or CINN. AITC and CINN were also tested on isolated guinea pig and mouse tracheas and postmortem human trachealis muscle strips in an organ bath. Tissues were contracted with methacholine, histamine, or potassium chloride and then treated with AITC or CINN. Some airways were pretreated with TRPA1 antagonists, the cyclooxygenase inhibitor indomethacin, the EP2 receptor antagonist PF 04418948, or tetrodotoxin. AITC and CINN blocked vagally mediated bronchoconstriction in guinea pigs. Pretreatment with indomethacin completely abolished the airway response to TRPA1 agonists. Similarly, AITC and CINN dose-dependently relaxed precontracted guinea pig, mouse, and human airways in the organ bath. AITC- and CINN-induced airway relaxation required TRPA1, prostaglandins, and PGE2 receptor activation. TRPA1-induced airway relaxation did not require epithelium or tetrodotoxin-sensitive nerves. Finally, AITC blocked airway hyperreactivity in two animal models of allergic asthma. These data demonstrate that stimulation of TRPA1 causes bronchodilation of intact airways and suggest that the TRPA1 pathway is a potential pharmacological target for bronchodilation.
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Spatz, M., N. Kawai, N. Merkel, J. Bembry, and R. M. McCarron. "Functional properties of cultured endothelial cells derived from large microvessels of human brain." American Journal of Physiology-Cell Physiology 272, no. 1 (January 1, 1997): C231—C239. http://dx.doi.org/10.1152/ajpcell.1997.272.1.c231.
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This report describes the fractional separation of microvessels from human brain for establishment of segmentally derived endothelial cell (EC) cultures. The investigation comprised evaluation of media constituents and purity of the cell culture and focused on functional biochemical characterization of endothelium derived from large microvessels (EC) Cells contained endothelial marker factor VIII (von Willebrand antigen), secreted endothelin-1 (ET-1) and prostaglandins, and took up 86Rb+ as a measure of K+. Exogenous ET-1 stimulated phosphatidylinositol hydrolysis and K+ uptake; BQ-123 (selective ETA receptor antagonist) but not IRL-1038 or BQ-788 (selective ETB receptor antagonists) inhibited both. Ouabain (inhibitor of Na(+)-K(+)-ATPase) and bumetanide (inhibitor of Na(+)-K(+)-Cl- cotransport) reduced (74-80 and 20-40%, respectively) the ET-1-stimulated K+ uptake. Staurosporine [protein kinase C (PKC) inhibitor] selectively reduced Na(+)-K(+)-Cl- cotransport, whereas verapamil but not nifedipine (L-type voltage-dependent Ca2+ channel blockers) decreased Na(+)-K(+)-ATPase activity induced by ET-1. Phorbol 12-myristate 13-acetate (PMA; activator of PKC) stimulated K+ uptake, which was only decreased with bumetanide. N-ethylisopropylamiloride (inhibitor of Na+/H+ exchange) reduced the ET-1-stimulated but not the PMA-induced K+ uptake. Results indicate that phosphatidylinositol hydrolysis and ion transport systems in large microvascular EC are stimulated by ET-1 through activation of ETA receptors. The findings also suggest that the ET-1-stimulated Na(+)-K(+)-ATPase activity, in contrast to Na(+)-K(+)-Cl- cotransport, is not mediated by PKC. In addition, the data suggest a linkage between Na(+)-K(+)-ATPase activity and Na+/H+ exchange.
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Haynes, William G. "Endothelins as Regulators of Vascular Tone in Man." Clinical Science 88, no. 5 (May 1, 1995): 509–17. http://dx.doi.org/10.1042/cs0880509.
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1. The vascular pharmacology, physiological relevance and pathophysiological roles of the endothelium-derived vasoconstrictor peptide endothelin-1 have been unclear. These issues were investigated, in vivo in man, using infusion of drugs into the brachial artery or dorsal hand vein, with responses measured by forearm plethysmography and the hand vein displacement technique respectively. 2. Endothelin-1 is a potent and sustained constrictor of resistance and capacitance vessels in vivo in man, acting through both subtypes (ETA and ETB) of endothelin receptors. Endothelin-1 stimulates generation of vasodilator prostaglandins, but not of nitric oxide, that act to oppose its direct constrictor actions. Venoconstriction to endothelin-1 is blocked more effectively by K+-channel openers than by Ca2+-channel antagonists, suggesting a novel cellular mechanism of action for this peptide. 3. The forearm vasculature is able to convert the precursor big endothelin-1 to the mature peptide, endothelin-1, thus demonstrating the local presence of ‘endothelin-converting enzyme’ in man. Local inhibition of this enzyme, or blockade of ETA receptors, causes slow-onset forearm vasodilatation, suggesting that endogenously generated endothelin-1 contributes to basal resistance vessel tone in man. 4. Venoconstriction to endothelin-1 is selectively enhanced in patients with untreated essential hypertension. Endothelin-1 also potentiates sympathetically mediated vasoconstriction, but only in hypertensive subjects. 5. Endogenous generation of endothelin-1 plays a fundamental physiological role in the maintenance of basal vascular tone. Endothlin-converting enzyme inhibitors and endothelin receptor antagonists possess novel vasodilator properties and should represent a major therapeutic advance in cardiovascular disease.
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Karaky, Mohamad, Gabrielle Boucher, Saraï Mola, Sylvain Foisy, Claudine Beauchamp, Marie-Eve Rivard, Melanie Burnette, et al. "Prostaglandins and calprotectin are genetically and functionally linked to the Inflammatory Bowel Diseases." PLOS Genetics 18, no. 9 (September 26, 2022): e1010189. http://dx.doi.org/10.1371/journal.pgen.1010189.
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Background Genome wide association studies (GWAS) have identified and validated more than 200 genomic loci associated with the inflammatory bowel disease (IBD), although for most the causal gene remains unknown. Given the importance of myeloid cells in IBD pathogenesis, the current study aimed to uncover the role of genes within IBD genetic loci that are endogenously expressed in this cell lineage. Methods The open reading frames (ORF) of 42 genes from IBD-associated loci were expressed via lentiviral transfer in the THP-1 model of human monocytes and the impact of each of these on the cell’s transcriptome was analyzed using a RNA sequencing-based approach. We used a combination of genetic and pharmacologic approaches to validate our findings in the THP-1 line with further validation in human induced pluripotent stem cell (hiPSC)-derived-monocytes. Results This functional genomics screen provided evidence that genes in four IBD GWAS loci (PTGIR, ZBTB40, SLC39A11 and NFKB1) are involved in controlling S100A8 and S100A9 genes expression, which encode the two subunits of calprotectin (CP). We demonstrated that increasing PTGIR expression and/or stimulating PTGIR signaling resulted in increased CP expression in THP-1. This was further validated in hiPSC-derived monocytes. Conversely, knocking-down PTGIR endogenous expression and/or inhibiting PTGIR signaling led to decreased CP expression. These analyses were extended to the known IBD gene PTGER4, whereby its specific agonist also led to increased CP expression. Furthermore, we demonstrated that the PTGIR and PTGER4 mediated control of CP expression was dependent on signaling via adenylate cyclase and STAT3. Finally, we demonstrated that LPS-mediated increases in CP expression could be potentiated by agonists of PTGIR and PTGER4, and diminished by their antagonists. Conclusion Our results support a causal role for the PTGIR, PTGER4, ZBTB40, SLC39A11 and NFKB1 genes in IBD, with all five genes regulating the expression of CP in myeloid cells, as well as potential roles for the prostacyclin/prostaglandin biogenesis and signaling pathways in IBD susceptibility and pathogenesis.