Journal articles: 'Vasodilatory peptides'

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Gosney, M. A., J. R. Gosney, and M. Lye. "Orthostatic hypotension and vasodilatory peptides in bronchial carcinoma." Journal of Clinical Pathology 48, no. 12 (December 1, 1995): 1102–5. http://dx.doi.org/10.1136/jcp.48.12.1102.

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Russ, R. D., T. C. Resta, and B. R. Walker. "Pulmonary vasodilatory response to neurohypophyseal peptides in the rat." Journal of Applied Physiology 73, no. 2 (August 1, 1992): 473–78. http://dx.doi.org/10.1152/jappl.1992.73.2.473.

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Experiments were performed on isolated salt-perfused rat lungs to determine the receptor type(s) responsible for the pulmonary vascular effects of the neurohypophyseal peptides arginine vasopressin (AVP) and oxytocin. Bolus administration of AVP to lungs preconstricted with the thromboxane mimetic U-46619 resulted in a dose-dependent vasodilatory response (approximately 65% reversal of U-46619-induced vasoconstriction at the highest dose tested) that was blocked by pretreatment with a selective V1- but not by a selective V2-vasopressinergic receptor antagonist. Administration of a selective V1-agonist to the preconstricted pulmonary vasculature resulted in a vasodilatory response similar to that observed with AVP (approximately 55% reversal of U-46619 vasoconstriction), which was blocked by prior administration of the selective V1-receptor antagonist. Administration of the selective V2-receptor agonist desmopressin to the preconstricted pulmonary vasculature resulted in a small (approximately 8% reversal of U-46619 vasoconstriction) vasodilatory response that was, nevertheless, greater than that produced by addition of vehicle alone and was attenuated by pretreatment with a selective V2-receptor antagonist. Finally, oxytocin also caused vasodilation in the preconstricted pulmonary vasculature; however, the potency of oxytocin was approximately 1% of AVP, and the vasodilation produced by oxytocin was blocked by prior administration of a selective V1-receptor antagonist, suggesting that oxytocin acts via V1-vasopressinergic receptor stimulation. We conclude from these experiments that AVP and oxytocin dilate the preconstricted pulmonary vasculature primarily via stimulation of V1-vasopressinergic receptors. V2-receptor stimulation results in a minor vasodilatory response, although its physiological significance is unclear.

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Kamiya, H., R. Saito, S. Nonaka, H. Konishi, Y. Takano, Y. Shimohigashi, H. Matsumoto, and M. Ohno. "Vasodilatory actions of tachykinin peptides in isolated vascular smooth muscle." European Journal of Pharmacology 183, no. 6 (July 1990): 2222–23. http://dx.doi.org/10.1016/0014-2999(90)93757-h.

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Faury, G., A. Chabaud, M. T. Ristori, L. Robert, and J. Verdetti. "Effect of age on the vasodilatory action of elastin peptides." Mechanisms of Ageing and Development 95, no. 1-2 (April 1997): 31–42. http://dx.doi.org/10.1016/s0047-6374(96)01842-8.

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Eto, Tanenao, and Willis K. Samson. "Adrenomedullin and proadrenomedullin N-terminal 20 peptide: vasodilatory peptides with multiple cardiovascular and endocrine actions." Trends in Endocrinology & Metabolism 12, no. 3 (April 2001): 91–93. http://dx.doi.org/10.1016/s1043-2760(01)00374-5.

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Forte, Madonna, Schiavon, Valenti, Versaci, Zoccai, Frati, and Sciarretta. "Cardiovascular Pleiotropic Effects of Natriuretic Peptides." International Journal of Molecular Sciences 20, no. 16 (August 8, 2019): 3874. http://dx.doi.org/10.3390/ijms20163874.

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Atrial natriuretic peptide (ANP) is a cardiac hormone belonging to the family of natriuretic peptides (NPs). ANP exerts diuretic, natriuretic, and vasodilatory effects that contribute to maintain water–salt balance and regulate blood pressure. Besides these systemic properties, ANP displays important pleiotropic effects in the heart and in the vascular system that are independent of blood pressure regulation. These functions occur through autocrine and paracrine mechanisms. Previous works examining the cardiac phenotype of loss-of-function mouse models of ANP signaling showed that both mice with gene deletion of ANP or its receptor natriuretic peptide receptor A (NPR-A) developed cardiac hypertrophy and dysfunction in response to pressure overload and chronic ischemic remodeling. Conversely, ANP administration has been shown to improve cardiac function in response to remodeling and reduces ischemia-reperfusion (I/R) injury. ANP also acts as a pro-angiogenetic, anti-inflammatory, and anti-atherosclerotic factor in the vascular system. Pleiotropic effects regarding brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP) were also reported. In this review, we discuss the current evidence underlying the pleiotropic effects of NPs, underlying their importance in cardiovascular homeostasis.

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Rodríguez-pérez, Federico, Carlos M. Isales, and Roberto J. Groszmann. "Platelet cytosolic calcium, peripheral hemodynamics, and vasodilatory peptides in liver cirrhosis." Gastroenterology 105, no. 3 (September 1993): 863–67. http://dx.doi.org/10.1016/0016-5085(93)90906-s.

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Kakumanu, Rahini, Wayne C. Hodgson, Ravina Ravi, Alejandro Alagon, Richard J. Harris, Andreas Brust, Paul F. Alewood, Barbara K. Kemp-Harper, and Bryan G. Fry. "Vampire Venom: Vasodilatory Mechanisms of Vampire Bat (Desmodus rotundus) Blood Feeding." Toxins 11, no. 1 (January 8, 2019): 26. http://dx.doi.org/10.3390/toxins11010026.

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Animals that specialise in blood feeding have particular challenges in obtaining their meal, whereby they impair blood hemostasis by promoting anticoagulation and vasodilation in order to facilitate feeding. These convergent selection pressures have been studied in a number of lineages, ranging from fleas to leeches. However, the vampire bat (Desmondus rotundus) is unstudied in regards to potential vasodilatory mechanisms of their feeding secretions (which are a type of venom). This is despite the intense investigations of their anticoagulant properties which have demonstrated that D. rotundus venom contains strong anticoagulant and proteolytic activities which delay the formation of blood clots and interfere with the blood coagulation cascade. In this study, we identified and tested a compound from D. rotundus venom that is similar in size and amino acid sequence to human calcitonin gene-related peptide (CGRP) which has potent vasodilatory properties. We found that the vampire bat-derived form of CGRP (i.e., vCGRP) selectively caused endothelium-independent relaxation of pre-contracted rat small mesenteric arteries. The vasorelaxant efficacy and potency of vCGRP were similar to that of CGRP, in activating CGRP receptors and Kv channels to relax arteriole smooth muscle, which would facilitate blood meal feeding by promoting continual blood flow. Our results provide, for the first time, a detailed investigation into the identification and function of a vasodilatory peptide found in D. rotundus venom, which provides a basis in understanding the convergent pathways and selectivity of hematophagous venoms. These unique peptides also show excellent drug design and development potential, thus highlighting the social and economic value of venomous animals.

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De Plater, G. M., R. L. Martin, and P. J. Milburn. "A C-Type Natriuretic Peptide from The Venom of The Platypus (Ornithorhynchus anatinus) - Structure and Pharmacology." Australian Mammalogy 20, no. 2 (1998): 301. http://dx.doi.org/10.1071/am98302.

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A peptide which relaxes rat uterine smooth muscle and exhibits homology with the mammalian C-type natriuretic peptide (CNP) has previously been identified in platypus venom. In this study we describe detailed structural and pharmacological characteristics of this peptide, which has been labelled ONP-39 (Ornithorhynchus Natriuretic Peptide). Elucidation of its 39-residue primary sequence confirms the substantial homology it shares with mammalian CNPs. These peptides exhibit natriuretic, diuretic and hypotensive activities in vivo and relax smooth muscle in vitro but are poorly characterised in terms of physiological function. ONP-39 is equipotent with CNP in causing cGMP elevation in cultured vascular smooth muscle cells, suggesting that, like CNP, it acts through ANPB receptors. The direct elevation of cGMP in vascular smooth muscle by ONP-39 may underlie vasodilatory effects of platypus venom.

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Sridharan, Sindhuja, and R. Manjunatha Kini. "Decoding the molecular switches of natriuretic peptides which differentiate its vascular and renal functions." Biochemical Journal 475, no. 2 (January 23, 2018): 399–413. http://dx.doi.org/10.1042/bcj20170690.

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Heart failure (HF) is associated with high morbidity and mortality. Dysfunction of blood pressure and/or volume homeostatic processes result in lower perfusion and/or congestion. Treatment strategies exerting differential effects on pressure and volume mechanisms are critical in handling patients with HF. Atrial natriuretic peptides (ANPs) are a key hormone in maintaining circulation. It binds to NP receptor-A (NPR-A) on vasculature, kidneys and nervous system to lowers blood pressure and volume. It exerts a concentration-dependent pharmacological activity, and only increased renal excretion of water and sodium at low doses and vasodilation along with renal effects at slightly higher doses. Recently, we showed that K-Ring (conserved ring of krait venom NP) elicited only vasodilatory properties despite its ability to evoke NPR-A. Through systematic analysis of the structure–function relationships of K-Ring, we have delineated the molecular switches that control vasodilatory and diuretic properties of NPs in anesthetized rats. In the process, we have identified residues that — (a) differentiate vascular and renal functions, (b) affect heart rate and pulse pressure, (c) exhibit sustained effect on vasodilatory function and (d) forceful diuresis switches. Furthermore, we have shown these residues to have equivalent effects on ANP scaffold, thereby introducing modularity in designing function-based ANP analogs. By comparing the ability of designed NPs to evoke cGMP levels, we propose a hypothetical mechanism for the observed tissue-specific effects. The present study opens new avenues in the development of suitable therapeutic agents for personalized care for HF patients.

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Liu, Quan, Ichiro Nakae, Takayoshi Tsutamoto, Atsushi Takaoka, and Masahiko Kinoshita. "In Vivo Vasodilatory Action of Atrial Natriuretic Peptides in Canine Coronary Circulation." Japanese Circulation Journal 60, no. 5 (1996): 300–310. http://dx.doi.org/10.1253/jcj.60.300.

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12

WANG, Yu, Aimin XU, and Garth J. S. COOPER. "Phosphorylation of P20 is associated with the actions of insulin in rat skeletal and smooth muscle." Biochemical Journal 344, no. 3 (December 8, 1999): 971–76. http://dx.doi.org/10.1042/bj3440971.

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Although a large number of protein kinases/phosphatases involved in insulin's actions have been characterized recently, relatively few of the downstream phosphoproteins have been identified. We have employed two-dimensional gel electrophoresis-based proteome analysis to investigate the insulin-evoked phosphorylation cascade in rat soleus muscle. Insulin reproducibly increased phosphorylation of a 20-kDa protein with a pI value of 6.0, which was identified subsequently as a phospho-isoform of P20, a small heat-shock-related protein. The adenylyl cyclase activator, forskolin, decreased phosphorylation of this P20 isoform and increased phosphorylation of another two P20 isoforms, with pI values of 5.9 and 5.6. Two-dimensional peptide mapping revealed that the phospho-peptides of these three P20 isoforms are different. In contrast to its action in soleus muscle, insulin decreased phosphorylation of the P20 isoform with pI 6.0 and increased phosphorylation of the two isoforms with pI values of 5.9 and 5.6 in vascular smooth muscle. This effect is similar to that induced by vasodilatory stimuli, suggesting that insulin could exert its vasodilatory action by affecting phosphorylation of P20. In summary, these results demonstrate that insulin differently modulates phosphorylation of P20 in skeletal and smooth muscle, and suggest that P20 could be a potential modulator of insulin's functions in these tissues.

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Kimer, Nina, Jens Peter Goetze, Flemming Bendtsen, and Søren Møller. "New vasoactive peptides in cirrhosis: organ extraction and relation to the vasodilatory state." European Journal of Clinical Investigation 44, no. 5 (February 26, 2014): 441–52. http://dx.doi.org/10.1111/eci.12249.

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14

Naruse, S., T. Ozaki, and K. Nokihara. "Vasodilatory effect of pituitary adenylate cyclase activating polypeptide (PACAP) and its related peptides." Regulatory Peptides 40, no. 2 (July 1992): 214. http://dx.doi.org/10.1016/0167-0115(92)90346-v.

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15

SUETSUNA, Kunio, and Kazuhiro OSAJIMA. "Blood pressure reduction and vasodilatory effects in vivo of peptides originating from sardine muscle." Nippon Eiyo Shokuryo Gakkaishi 42, no. 1 (1989): 47–54. http://dx.doi.org/10.4327/jsnfs.42.47.

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Oyama, Hirofumi, Yoshio Suzuki, Shin-Ichi Satoh, Yasukazu Kajita, Masakazu Takayasu, Masato Shibuya, and Kenichiro Sugita. "Role of Nitric Oxide in the Cerebral Vasodilatory Responses to Vasopressin and Oxytocin in Dogs." Journal of Cerebral Blood Flow & Metabolism 13, no. 2 (March 1993): 285–90. http://dx.doi.org/10.1038/jcbfm.1993.35.

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We angiographically assessed the vasodilatory effects of vasopressin and oxytocin on the basilar arteries in dogs. Intracisternal bolus injections of vasopressin (100 pmol and 1 nmol) and oxytocin (1 and 10 nmol) produced dose-dependent increases in the internal diameter of the basilar arteries without affecting mean arterial blood pressure. The maximal dilatations of the basilar arteries induced by 1 nmol vasopressin and 10 nmol oxytocin were 142.3 ± 19.9 and 136.8 ± 25.5% of the baseline, respectively. When the same peptides were injected into the vertebral artery, the maximal dilatations were similar, but the duration of response was shorter. Pretreatment with intracisternal injection of 10 μmol NG-monomethyl-l-arginine (l-NMMA), which inhibits the synthesis of nitric oxide from l-arginine, suppressed the vasodilatory responses induced by intracisternal injection of vasopressin and oxytocin and by intraarterial injection of vasopressin. Calcitonin gene-related peptide also caused dilatation of the basilar artery when injected into the cisterna magna, but its effect was not blocked by l-NMMA. l-NMMA reduced the basal diameter of the basilar artery in a dose-dependent manner; l-arginine produced dose-dependent increases in diameter. The vasoconstriction induced by l-NMMA was reversed by high concentrations of l-arginine. These results suggest that vasopressin and oxytocin dilate the basilar arteries via the release of nitric oxide from both the intraluminal and the extraluminal sides and that synthesis and release of nitric oxide in the vascular wall contribute to maintenance of basal vascular tonus.

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Kobayashi, Yuta, Keiko Shimoura, and Keisuke Hattori. "Comparison of vasodilatory mechanism of two biological active peptides, urotensin I and atrial natriuretic polypeptide." Japanese Journal of Pharmacology 40 (1986): 123. http://dx.doi.org/10.1016/s0021-5198(19)59123-5.

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Egom, Emmanuel E., Tiam Feridooni, Adam Hotchkiss, Peter Kruzliak, and Kishore B. S. Pasumarthi. "Mechanisms of renal hyporesponsiveness to BNP in heart failure." Canadian Journal of Physiology and Pharmacology 93, no. 6 (June 2015): 399–403. http://dx.doi.org/10.1139/cjpp-2014-0356.

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The B-type natriuretic peptide (BNP), a member of the family of vasoactive peptides, is a potent natriuretic, diuretic, and vasodilatory peptide that contributes to blood pressure and volume homeostasis. These attributes make BNP an ideal drug that could aid in diuresing a fluid-overloaded patient who had poor or worsening renal function. Despite the potential benefits of BNP, accumulating evidence suggests that simply increasing the amount of circulating BNP does not necessarily increase natriuresis in patients with heart failure (HF). Moreover, despite high BNP levels, natriuresis falls when HF progresses from a compensated to a decompensated state, suggesting the emergence of renal resistance to BNP. Although likely multifactorial, several mechanisms have been proposed to explain renal hyporesponsiveness in HF, including, but not limited to, decreased renal BNP availability, down-regulation of natriuretic peptide receptors, and altered BNP intracellular signal transduction pathways. Thus, a better understanding of renal hyporesponsiveness in HF is required to devise strategies to develop novel agents and technologies that directly restore renal BNP efficiency. It is hoped that development of these new therapeutic approaches will serve to limit sodium retention in patients with HF, which may ultimately delay the progression to overt HF.

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Chan, Kayi Y., Michael Baun, René de Vries, Antoon J. van den Bogaerdt, Clemens MF Dirven, Alexander HJ Danser, Inger Jansen-Olesen, et al. "Pharmacological characterization of VIP and PACAP receptors in the human meningeal and coronary artery." Cephalalgia 31, no. 2 (July 5, 2010): 181–89. http://dx.doi.org/10.1177/0333102410375624.

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Objective: We pharmacologically characterized pituitary adenylate cyclase–activating polypeptides (PACAPs), vasoactive intestinal peptide (VIP) and the VPAC1, VPAC2 and PAC1 receptors in human meningeal (for their role in migraine) and coronary (for potential side effects) arteries. Methods: Concentration response curves to PACAP38, PACAP27, VIP and the VPAC1 receptor agonist ([Lys15,Arg16,Leu27]-VIP[1-7]-GRF[8-27]) were constructed in the absence or presence of the PAC1 receptor antagonist PACAP6-38 or the VPAC1 receptor antagonist, PG97269. mRNA expression was measured using qPCR. Results: PACAP38 was less potent than VIP in both arteries. Both peptides had lower potency and efficacy in meningeal than in coronary arteries, while mRNA expression of VPAC1 receptor was more pronounced in meningeal arteries. PACAP6-38 reduced the Emax of PACAP27, while PG97269 right-shifted the VIP-induced relaxation curve only in the coronary arteries. Conclusion: The direct vasodilatory effect of VIP and PACAP might be less relevant than the central effect of this compound in migraine pathogenesis.

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Parajuli, Nirmal, Tharmarajan Ramprasath, Vaibhav B. Patel, Wang Wang, Brendan Putko, Jun Mori, and Gavin Y. Oudit. "Targeting angiotensin-converting enzyme 2 as a new therapeutic target for cardiovascular diseases." Canadian Journal of Physiology and Pharmacology 92, no. 7 (July 2014): 558–65. http://dx.doi.org/10.1139/cjpp-2013-0488.

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Angiotensin-converting enzyme 2 (ACE2) is a monocarboxypeptidase that metabolizes several vasoactive peptides, including angiotensin II (Ang-II; a vasoconstrictive/proliferative peptide), which it converts to Ang-(1–7). Ang-(1–7) acts through the Mas receptor to mediate vasodilatory/antiproliferative actions. The renin–angiotensin system involving the ACE–Ang-II–Ang-II type-1 receptor (AT1R) axis is antagonized by the ACE2–Ang-(1–7)–Mas receptor axis. Loss of ACE2 enhances adverse remodeling and susceptibility to pressure and volume overload. Human recombinant ACE2 may act to suppress myocardial hypertrophy, fibrosis, inflammation, and diastolic dysfunction in heart failure patients. The ACE2–Ang-(1–7)–Mas axis may present a new therapeutic target for the treatment of heart failure patients. This review is mainly focused on the analysis of ACE2, including its influence and potentially positive effects, as well as the potential use of human recombinant ACE2 as a novel therapy for the treatment cardiovascular diseases, such as hypertension and heart failure.

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Mason, Bianca N., Anne-Sophie Wattiez, Louis K. Balcziak, Adisa Kuburas, William J. Kutschke, and Andrew F. Russo. "Vascular actions of peripheral CGRP in migraine-like photophobia in mice." Cephalalgia 40, no. 14 (August 18, 2020): 1585–604. http://dx.doi.org/10.1177/0333102420949173.

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Background Calcitonin gene-related peptide is recognized as a key player in migraine, yet the mechanisms and sites of calcitonin gene-related peptide action remain unknown. The efficacy of calcitonin gene-related peptide-blocking antibodies as preventative migraine drugs supports a peripheral site of action, such as the trigeminovasculature. Given the apparent disconnect between the importance of vasodilatory peptides in migraine and the prevailing opinion that vasodilation is an epiphenomenon, the goal of this study was to test whether vasodilation plays a role in calcitonin gene-related peptide-induced light aversive behavior in mice. Methods Systemic mean arterial pressure and light aversive behavior were measured after intraperitoneal administration of calcitonin gene-related peptide and vasoactive intestinal peptide in wild-type CD1 mice. The functional significance of vasodilation was tested by co-administration of a vasoconstrictor (phenylephrine, endothelin-1, or caffeine) with calcitonin gene-related peptide to normalize blood pressure during the light aversion assay. Results Both calcitonin gene-related peptide and vasoactive intestinal peptide induced light aversion that was associated with their effect on mean arterial pressure. Notably, vasoactive intestinal peptide caused relatively transient vasodilation and light aversion. Calcitonin gene-related peptide-induced light aversion was still observed even with normalized blood pressure. However, two of the agents, endothelin-1 and caffeine, did reduce the magnitude of light aversion. Conclusion We propose that perivascular calcitonin gene-related peptide causes light-aversive behavior in mice by both vasomotor and non-vasomotor mechanisms.

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Adnot, S., I. Cigarini, R. Herigault, and A. Harf. "Effects of substance P and calcitonin gene-related peptide on the pulmonary circulation." Journal of Applied Physiology 70, no. 4 (April 1, 1991): 1707–12. http://dx.doi.org/10.1152/jappl.1991.70.4.1707.

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To assess the in vivo effects of the neuropeptides calcitonin gene-related peptide (CGRP) and substance P (SP) on the pulmonary vascular bed, the hemodynamic responses to both CGRP and SP were examined in the in situ-perfused lung lobe of open-chest anesthetized pigs. Peptides were infused into the lobar artery under conditions of elevated pulmonary vascular tone by prostaglandin F2 alpha (PGF2 alpha, 20 micrograms/min). Pulmonary airway lobar dynamic compliance (Cdyn) and airway resistance (Re) were computed from simultaneously measured airway pressure and airflow entering the lobe through a Carlens endobronchial divider. PGF2 alpha infusion slightly reduced Cdyn (-20%) and increased Re (+11%) while lobar arterial pressure rose from 14 +/- 1 to 31 +/- 2 mmHg (n = 12). In these conditions, lobar artery infusion of SP (0.5-50 pmol/min) or CGRP (15-5,000 pmol/min) produced a dose-dependent decrease in the pressor response to PGF2 alpha, reaching -54 +/- 3 and -64 +/- 7%, respectively, without alterations in lung mechanics. On a molar basis, SP was more effective than CGRP; its vasodilatory effect was more rapid and of shorter duration. Higher CGRP infusion rates were not studied because of marked systemic hypotension. SP infused at 150, 500, and 1,000 pmol/min significantly reduced Cdyn by 12 +/- 2, 24 +/- 4, and 62 +/- 7%, respectively, but also induced a rise in lobar arterial pressure and a fall in systemic arterial pressure. The results show that both SP and CGRP are potent pulmonary vasodilators. In contrast to CGRP, which did not affect lung mechanics, high infusion rates of SP decreased Cdyn and increased Re.(ABSTRACT TRUNCATED AT 250 WORDS)

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Fraser, Kathleen A., and Samuel S. Lee. "Autonomic Regulation of Splanchnic Circulation." Canadian Journal of Gastroenterology 5, no. 4 (1991): 147–53. http://dx.doi.org/10.1155/1991/949037.

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The role of the autonomic nervous system in circulatory regulation of the splanchnic organs (stomach, small intestine, colon, liver, pancreas and spleen) is reviewed. In general, the sympathetic nervous system is primarily involved in vasoconstriction, while the parasympathetic contributes to vasodilation. Vasoconstriction in the splanchnic circulation appears to be mediated by alpha-2 receptors and vasodilation by activation of primary afferent nerves with subsequent release of vasodilatory peptides, or by stimulation of beta-adrenergic receptors. As well, an important function of the autonomic nervous system is to provide a mechanism by which splanchnic vascular reserve can be mobilized during stress to maintain overall cardiovascular homeostasis.

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Chatterjee, Paulami, Mahmoud Gheblawi, Kaiming Wang, Jeannie Vu, Palsa Kondaiah, and Gavin Y. Oudit. "Interaction between the apelinergic system and ACE2 in the cardiovascular system: therapeutic implications." Clinical Science 134, no. 17 (September 2020): 2319–36. http://dx.doi.org/10.1042/cs20200479.

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Abstract The apelinergic system is widely expressed and acts through autocrine and paracrine signaling to exert protective effects, including vasodilatory, metabolic, and inotropic effects on the cardiovascular (CV) system. The apelin pathway’s dominant physiological role has delineated therapeutic implications for coronary artery disease, heart failure (HF), aortic aneurysm, pulmonary arterial hypertension (PAH), and transplant vasculopathy. Apelin peptides interact with the renin–angiotensin system (RAS) by promoting angiotensin converting enzyme 2 (ACE2) transcription leading to increased ACE2 protein and activity while also antagonizing the effects of angiotensin II (Ang II). Apelin modulation of the RAS by increasing ACE2 action is limited due to its rapid degradation by proteases, including ACE2, neprilysin (NEP), and kallikrein. Apelin peptides are hence tightly regulated in a negative feedback manner by ACE2. Plasma apelin levels are suppressed in pathological conditions, but its diagnostic and prognostic utility requires further clinical exploration. Enhancing the beneficial actions of apelin peptides and ACE2 axes while complementing existing pharmacological blockade of detrimental pathways is an exciting pathway for developing new therapies. In this review, we highlight the interaction between the apelin and ACE2 systems, discuss their pathophysiological roles and potential for treating a wide array of CV diseases (CVDs).

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Chauhan, Madhu, Ancizar Betancourt, Meena Balakrishnan, Uma Yallampalli, Yuanlin Dong, Karin Fox, Michael Belfort, and Chandra Yallampalli. "Impaired Vasodilatory Responses of Omental Arteries to CGRP Family Peptides in Pregnancies Complicated by Fetal Growth Restriction." Journal of Clinical Endocrinology & Metabolism 101, no. 8 (August 2016): 2984–93. http://dx.doi.org/10.1210/jc.2016-1798.

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Kulemina, Lidia V., and David A. Ostrov. "Prediction of Off-Target Effects on Angiotensin-Converting Enzyme 2." Journal of Biomolecular Screening 16, no. 8 (August 22, 2011): 878–85. http://dx.doi.org/10.1177/1087057111413919.

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The authors describe a structure-based strategy to identify therapeutically beneficial off-target effects by screening a chemical library of Food and Drug Administration (FDA)–approved small-molecule drugs matching pharmacophores defined for specific target proteins. They applied this strategy to angiotensin-converting enzyme 2 (ACE2), an enzyme that generates vasodilatory peptides and promotes protection from hypertension-associated cardiovascular disease. The conformation-based structural selection method by molecular docking using DOCK allowed them to identify a series of FDA-approved drugs that enhance catalytic efficiency of ACE2 in vitro. These data demonstrate that libraries of approved drugs can be rapidly screened to identify potential side effects due to interactions with specific proteins other than the intended targets.

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Nokihara, Kiyoshi, Tadashi Yasuhara, Yoshihiro Nakata, Ethan A. Lerner, and Victor Wray. "Chemical Synthesis of Maxadilan, a Non-mammalian Potent Vasodilatory Peptide Consisting of 61 Amino Acids with Two Disulfide Bridges, and Its Related Peptides." International Journal of Peptide Research and Therapeutics 13, no. 1-2 (May 24, 2007): 377–86. http://dx.doi.org/10.1007/s10989-007-9097-9.

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Trojanowicz, Bogusz, Christof Ulrich, and Matthias Girndt. "Uremic Apelin and Leucocytic Angiotensin-Converting Enzyme 2 in CKD Patients." Toxins 12, no. 12 (November 26, 2020): 742. http://dx.doi.org/10.3390/toxins12120742.

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Apelin peptides (APLN) serve as second substrates for angiotensin-converting enzyme 2 (ACE2) and, in contrast to angiotensin II (AngII), exert blood-pressure lowering and vasodilatation effects through binding to G-coupled APLN receptor (APLNR). ACE2-mediated cleavage of the APLN may reduce its vasodilatory effects, but decreased ACE2 may potentiate the hypotensive properties of APLN. The role of APLN in uremia is unclear. We investigated the correlations between serum-APLN, leucocytic APLNR, and ACE2 in 32 healthy controls (NP), 66 HD, and 24 CKD3–5 patients, and the impact of APLN peptides on monocytic behavior and ACE2 expression under uremic conditions in vitro. We observed that serum APLN and leucocytic APLNR or SLCO2B1 were significantly elevated in uremic patients and correlated with decreased ACE2 on uremic leucocytes. APLN-treated THP-1 monocytes revealed significantly increased APLNR and ACE2, and reduced TNFa, IL-6, and MCSF. Uremic toxins induced a dramatic increase of miR-421 followed by significant reduction of ACE2 transcripts, partially counteracted with APLN-13 and -36. APLN-36 triggered the most potent transmigration and reduction of endothelial adhesion. These results suggest that although APLN peptides may partly protect against the decay of monocytic ACE2 transcripts, uremic milieu is the most dominant modulator of local ACE2, and likely to contribute to the progression of atherosclerosis.

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Hooper, Nigel M., Daniel W. Lambert, and Anthony J. Turner. "Discovery and characterization of ACE2 – a 20-year journey of surprises from vasopeptidase to COVID-19." Clinical Science 134, no. 18 (September 2020): 2489–501. http://dx.doi.org/10.1042/cs20200476.

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Abstract Angiotensin-converting enzyme (ACE) is a zinc membrane metallopeptidase that plays a key role in regulating vasoactive peptide levels and hence cardiovascular activity through its conversion of angiotensin I (Ang I) to Ang II and its metabolism of bradykinin. The discovery of its homologue, ACE2, 20 years ago has led to intensive comparisons of these two enzymes revealing surprising structural, catalytic and functional distinctions between them. ACE2 plays multiple roles not only as a vasopeptidase but also as a regulator of amino acid transport and serendipitously as a viral receptor, mediating the cellular entry of the coronaviruses causing severe acute respiratory syndrome (SARS) and, very recently, COVID-19. Catalytically, ACE2 functions as a monocarboxypeptidase principally converting the vasoconstrictor angiotensin II to the vasodilatory peptide Ang-(1-7) thereby counterbalancing the action of ACE on the renin–angiotensin system (RAS) and providing a cardioprotective role. Unlike ACE, ACE2 does not metabolise bradykinin nor is it inhibited by classical ACE inhibitors. However, it does convert a number of other regulatory peptides in vitro and in vivo. Interest in ACE2 biology and its potential as a possible therapeutic target has surged in recent months as the COVID-19 pandemic rages worldwide. This review highlights the surprising discoveries of ACE2 biology during the last 20 years, its distinctions from classical ACE and the therapeutic opportunities arising from its multiple biological roles.

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Tjen-A-Looi, S., R. Ekman, H. Lippton, J. Cary, and I. Keith. "CGRP and somatostatin modulate chronic hypoxic pulmonary hypertension." American Journal of Physiology-Heart and Circulatory Physiology 263, no. 3 (September 1, 1992): H681—H690. http://dx.doi.org/10.1152/ajpheart.1992.263.3.h681.

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Chronic hypoxic pulmonary hypertension (PH), associated with increased pulmonary arterial pressure (PPA) and right ventricular hypertrophy (RVH), correlates significantly with calcitonin gene-related peptide (CGRP) and somatostatin (SOM) levels in lung and blood. CGRP's role in regulation of PPA in chronic hypoxia and its potential interactions with SOM were investigated. CGRP, its antibody (ab) and blocker, CGRP-(8–37), SOM-14, SOM-28, and SOM-ab, respectively, were infused into the pulmonary circulation of hypobaric hypoxia rats for 4, 8, and 16 days. Thereafter, under pentobarbital sodium anesthesia, PPA was measured in the right ventricle and main pulmonary artery. Chronic CGRP infusion prevented PH at all times, whereas immunoneutralization and receptor blocking exacerbated PH. SOM-28 also exacerbated while SOM-14 and SOM-ab decreased PH. RVH generally reflected the PPA. Radioimmunoassay confirmed successful infusion of the peptides with negligible peptide degradation in the pumps throughout 16 days and showed complete immunoneutralization of CGRP with its ab. Peptide levels in lung tissue suggest inhibition of CGRP release by SOM-28 and increased plasma SOM with CGRP infusion. In vitro pharmacological studies suggest that CGRP exerts a receptor-mediated nonadrenergic, nonmuscarinic vasodilatory effect in the lung which is independent of endothelium-derived relaxing factor and does not involve ATP-dependent potassium channels. We conclude that endogenous CGRP plays an important role in pulmonary pressure homeostasis during hypoxia, by directly dilating pulmonary vasculature, thus ameliorating the development of chronic hypoxic pulmonary hypertension in rats.

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MARTÍNEZ, Alfredo, Hae-Ryong OH, Edward J. UNSWORTH, Claudia BREGONZIO, Juan M. SAAVEDRA, William G. STETLER-STEVENSON, and Frank CUTTITTA. "Matrix metalloproteinase-2 cleavage of adrenomedullin produces a vasoconstrictor out of a vasodilator." Biochemical Journal 383, no. 3 (October 26, 2004): 413–18. http://dx.doi.org/10.1042/bj20040920.

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MMPs (matrix metalloproteinases) play a major role in the pathogenesis of hypertension by altering the extracellular matrix during cardiovascular remodelling. In the present study we show that MMP-2, but not MMP-9, cleaves the vasodilator peptide AM (adrenomedullin). Addition of the AM-binding protein, complement factor H, prevents this cleavage, providing a hitherto unknown mechanism of action for this binding protein. We identified the signature cleavage fragments and found some of them in human urine, suggesting that MMP-2 processing of AM may occur in vivo. Synthetic AM fragments regulated blood pressure in rats. The larger peptides are vasodilators, as is intact AM, whereas intermediate fragments did not affect blood pressure. In contrast, AM(11–22) elicited vasoconstriction. Studies of AM receptor activation in Rat2 cells confirm that the larger AM cleavage peptides activated this receptor, whereas AM(11–22) did not. The present study defines a new mechanism through which MMP-2 may regulate blood pressure by simultaneously eliminating a vasodilator and generating a vasoconstrictor.

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Ogawa, Yoshihiro, Naohisa Tamura, Hideki Chusho, and Kazuwa Nakao. "Brain natriuretic peptide appears to act locally as an antifibrotic factor in the heart." Canadian Journal of Physiology and Pharmacology 79, no. 8 (August 1, 2001): 723–29. http://dx.doi.org/10.1139/y01-052.

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In addition to cardiac myocyte hypertrophy, proliferation and increased extracellular matrix production of cardiac fibroblasts occur in response to cardiac overload. This remodeling of the cardiac interstitium is a major determinant of pathologic hypertrophy leading to ventricular dysfunction and heart failure. Atrial and brain natriuretic peptides (ANP and BNP) are cardiac hormones produced primarily by the atrium and ventricle, respectively. Plasma ANP and BNP concentrations are elevated in patients with hypertension, cardiac hypertrophy, and acute myocardial infarction, suggesting their pathophysiologic roles in these disorders. ANP and BNP exhibit diuretic, natriuretic, and vasodilatory activities via a guanylyl cyclase-coupled natriuretic peptide receptor subtype (guanylyl cyclase-A or GC-A). Here we report the generation of mice with targeted disruption of BNP (BNP/ mice). We observed focal fibrotic lesions in ventricles from BNP/ mice with a remarkable increase in ventricular mRNA expression of ANP, angiotensin converting enzyme (ACE), transforming growth factor (TGF)-β3, and pro-α1(I) collagen [Col α1(I)], which are implicated in the generation and progression of ventricular fibrosis. Electron microscopic examination revealed supercontraction of sarcomeres and disorganized myofibrils in some ventricular myocytes from BNP/ mice. No signs of cardiac hypertrophy and systemic hypertension were noted in BNP/ mice. In response to acute cardiac pressure overload induced by aortic constriction, massive fibrotic lesions were found in all the BNP/ mice examined, accompanied by further increase of mRNA expression of TGF-β3 and Col α1(I). We postulate that BNP acts as a cardiocyte-derived antifibrotic factor in the ventricle.Key words: atrial natriuretic peptide, brain natiuretic peptide, cardiac fibrosis, guanylyl cyclase.

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Koga, Motokazu, Yusuke Mizuno, Itaru Watanabe, Hiromasa Kawakami, and Takahisa Goto. "Role of VPAC2 receptor in monocrotaline-induced pulmonary hypertension in rats." Journal of Applied Physiology 117, no. 4 (August 15, 2014): 383–91. http://dx.doi.org/10.1152/japplphysiol.00861.2013.

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Pulmonary hypertension (PH) is associated with significant morbidity and mortality. Vasoactive intestinal peptide (VIP) and pituitary adenylyl cyclase activating peptide (PACAP) have pulmonary vasodilatory and positive inotropic effects via receptors VPAC1 and VPAC2, which possess a similar affinity for both peptides, and PAC1, a PACAP-preferring receptor. VIP is a promising option for PH treatment; however, various physiological effects of VIP have limited its clinical use. We investigated the effects of VPAC1 and VPAC2 selective agonists VIP and PACAP to explore more appropriate means of treatment for PH. We examined hemodynamic changes in right ventricular systolic pressure (RVSP), systemic blood pressure (SBP), total pulmonary resistance index (TPRI), total systemic resistance index, and cardiac index (CI) in response to their agonists with monocrotaline (MCT)-induced PH and explored involvement of VIP/PACAP expression and receptors in PH. Sprague-Dawley rats were divided into the MCT group (administered MCT 60 mg/kg) and control group. In MCT-induced PH, decreased VIP and PACAP were associated with upregulation of VPAC1, VPAC2, and PAC1 in lung tissues. Intravenous injection of VPAC2-selective agonist BAY 55–9837 and VIP, but not [Ala11,22,28]VIP, improved the CI. The decrease in SBP with VPAC2 agonist was significantly less than that in the control. Although they decreased SBP, these agonists hardly affected RVSP in the control. Activation of VPAC2 receptor with BAY 55–9837 effectively improved RVSP, TPRI, and CI in MCT-induced PH, suggesting a VPAC2 agonist as a possible promising treatment for PH.

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Gallagher, Patricia E., Carlos M. Ferrario, and E. Ann Tallant. "MAP kinase/phosphatase pathway mediates the regulation of ACE2 by angiotensin peptides." American Journal of Physiology-Cell Physiology 295, no. 5 (November 2008): C1169—C1174. http://dx.doi.org/10.1152/ajpcell.00145.2008.

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Angiotensin-converting enzyme 2 (ACE2) catalyzes the conversion of the vasoconstrictor angiotensin II (ANG II) to the vasodilatory peptide angiotensin-(1-7) [ANG-(1-7)]. We showed that treatment of hypertensive rats with the AT1 receptor antagonist olmesartan increased ACE2 mRNA and protein in the thoracic aorta, suggesting that endogenous ANG II tonically reduces the enzyme. We now report that ANG II downregulates ACE2 activity and mRNA in rat aortic vascular smooth muscle cells (VSMCs) to reduce the conversion of ANG II to ANG-(1-7). Although ANG-(1-7) alone had no effect on the regulation of ACE2 mRNA, the heptapeptide prevented the ANG II-mediated reduction in ACE2 mRNA, an effect blocked by the selective ANG-(1-7) receptor antagonist [d-Ala7]-ANG-(1-7). The reduction in ACE2 mRNA by ANG II was also prevented by the mitogen-activated protein (MAP) kinase kinase inhibitor PD98059. Treatment of VSMCs with ANG II increased ERK1/ERK2 activity, which was significantly reduced by pretreatment with ANG-(1-7). Blockade of the ANG II-mediated reduction in ACE2 mRNA and increase in MAP kinase activity by ANG-(1-7) was prevented by pretreatment with sodium vanadate, a tyrosine phosphatase inhibitor, or okadaic acid, a serine-threonine phosphatase inhibitor, suggesting that the heptapeptide activates a MAP kinase phosphatase. This study is the first to show that the MAP kinase-phosphatase pathway is a primary molecular mechanism for regulating ACE2 to maintain the balance between ANG II and ANG-(1-7). The modulatory role of ANG-(1-7) in the regulation of ACE2 by ANG II suggests a complex interplay between the two peptides that is mediated by specific receptors to activate distinct signaling pathways.

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Bouzina, Habib, and Göran Rådegran. "Plasma adrenomedullin peptides and precursor levels in pulmonary arterial hypertension disease severity and risk stratification." Pulmonary Circulation 10, no. 3 (June 15, 2020): 204589402093131. http://dx.doi.org/10.1177/2045894020931317.

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Adrenomedullin is a potent vasodilatory peptide, linked to pulmonary arterial hypertension pathology. Proximity extension assays were utilized to study plasma biomarkers related to vasoregulation, with focus on adrenomedullin peptides and precursor levels, collectively referred to as ADM. ADM was measured in 48 treatment-naïve pulmonary arterial hypertension patients at diagnosis, and in 31 of them at an early treatment follow-up. Plasma ADM was additionally assessed in patients with chronic thromboembolic pulmonary hypertension ( n = 20) and pulmonary hypertension due to heart failure with preserved (HFpEF(PH)) ( n = 33) or reduced (HFrEF(PH)) ( n = 36) ejection fraction, as well as healthy controls ( n = 16). ADM was studied in relation to pulmonary arterial hypertension hemodynamics, risk assessment, prognosis, treatment response, and differentiation. Plasma ADM levels in pulmonary arterial hypertension patients at diagnosis were higher than in healthy controls ( p < 0.001), similar as in chronic thromboembolic pulmonary hypertension patients ( p = ns), but lower compared to HFpEF(PH) ( p < 0.03) and HFrEF(PH) ( p < 0.001). In pulmonary arterial hypertension, specifically, plasma ADM at diagnosis correlated mainly to mean right atrial pressure ( r = 0.73, p < 0.001), N-terminal prohormone of brain natriuretic peptide ( r = 0.75, p < 0.001), six-minute walking distance ( r = –0.57, p < 0.001), and venous oxygen saturation ( r = –0.57, p < 0.001). ADM also correlated to the ECS/ERS- ( r = 0.74, p < 0.001) and REVEAL risk scores ( r = 0.54, p < 0.001) at pulmonary arterial hypertension diagnosis. Plasma ADM in pulmonary arterial hypertension patients was unaltered at early treatment follow-up compared to baseline ( p = ns). Pulmonary arterial hypertension patients with supra-median ADM at diagnosis showed worse overall survival than those with infra-median levels (median survival 34 versus 66 months, p = 0.0077). In conclusion, the present results suggest that baseline plasma ADM levels mirror disease severity, correlating to both ECS/ERS- and the REVEAL risk scores.

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Simeoni, Umberto, Thierry Massfelder, Christian Saussine, Clément Judes, Jean Geisert, and Jean-Jacques Helwig. "Involvement of Nitric Oxide in the Vasodilatory Response to Parathyroid Hormone-Related Peptide in the Isolated Rabbit Kidney." Clinical Science 86, no. 3 (March 1, 1994): 245–49. http://dx.doi.org/10.1042/cs0860245.

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1. The present study was designed to explore the role of NO derived from l-arginine in the vasodilatory response to synthetic human parathyroid hormone-related peptide-(1–34) in the isolated rabbit kidney perfused in the presence of indomethacin (10 μmol/l) and preconstricted with noradrenaline (7.2 nmol/min). 2. Under control conditions, bolus administrations of acetylcholine (10 μmol/l), an NO-dependent renal vasodilator, verapamil (0.1 mmol/l), an NO-independent renal vasodilator, and parathyroid hormone-related peptide (87 nmol/l) decreased the preconstriction pressure, by 31%, 71% and 43%, respectively. 3. Bolus administration of 100 μmol/l NG-nitro-l-arginine-methyl ester caused a 20% increment in the perfusion pressure of the noradrenaline-preconstricted kidney. NG-nitro-l-arginine methyl ester inhibited the vasodilatory effect of acetylcholine and parathyroid hormone-related peptide, by 68% and 44%, respectively, but did not alter the verapamil-induced vasodilatation. 4. Unlike l-arginine, the bolus administration of 1 μmol/l of a mono-substituted l-arginine derivative, N-α-benzoyl-l-arginine ethyl ester, durably decreased the noradrenaline/NG-nitro-l-arginine methyl ester-induced preconstriction by 57%. 5. Both l-arginine and N-α-benzoyl-l-arginine ethyl ester effectively reversed the inhibition induced by NG-nitro-l-arginine methyl ester on the vasodilatation elicited by acetylcholine and parathyroid hormone-related peptide. 6. In conclusion, the formation of NO from l-arginine contributes a substantial part to the vasodilatory action of parathyroid hormone-related peptide. Therefore, parathyroid hormone-related peptide appears to have a place among the renal haemodynamically active substances, whose vasodilatory actions are tuned by NO.

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Kageyama, Kazunori, Ken Teui, Naoki Tamasawa, and Toshihiro Suda. "Regulation and Roles of Urocortins in the Vascular System." International Journal of Endocrinology 2012 (2012): 1–6. http://dx.doi.org/10.1155/2012/873723.

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Urocortins (Ucns) are members of the corticotropin-releasing factor (CRF) family of peptides. Ucns would have potent effects on the cardiovascular system via the CRF receptor type 2 (CRF2receptor). Regulation and roles of each Ucn have been determined in the vascular system. Ucns have more potent vasodilatory effects than CRF. Human umbilical vein endothelial cells (HUVECs) express Ucns1-3 mRNAs, and the receptor,CRF2areceptor mRNA. Ucns1-3 mRNA levels are differentially regulated in HUVECs. Differential regulation of Ucns may suggest differential roles of those in HUVECs. Ucn1 and Ucn2 have strong effects on interleukin (IL)-6 gene expression and secretion in rat aortic smooth muscle A7r5 cells. The increase that we observed in IL-6 levels following Ucn treatment of A7r5 cells suggests that smooth muscle cells may be a source of IL-6 secretion under physiological stress conditions. Ucns are important and unique modulators of vascular smooth muscle cells and act directly or indirectly as autocrine and paracrine factors in the vascular system.

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Shiraishi, Yasuyuki, Shun Kohsaka, Toshiomi Katsuki, Kazumasa Harada, Tetsuro Miyazaki, Takamichi Miyamoto, Kenichi Matsushita, et al. "Benefit and harm of intravenous vasodilators across the clinical profile spectrum in acute cardiogenic pulmonary oedema patients." European Heart Journal: Acute Cardiovascular Care 9, no. 5 (January 29, 2020): 448–58. http://dx.doi.org/10.1177/2048872619891075.

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Background: The absence of high quality, large-scale data that indicates definitive mortality benefits does not allow for firm conclusions on the role of intravenous vasodilators in acute heart failure. We aimed to investigate the associations between intravenous vasodilators and clinical outcomes in acute heart failure patients, with a specific focus on patient profiles and type of vasodilators. Methods: Data of 26,212 consecutive patients urgently hospitalised for a primary diagnosis of acute heart failure between 2009 and 2015 were extracted from a government-funded multicentre data registration system. Propensity scores were calculated with multiple imputations and 1:1 matching performed between patients with and without vasodilator use. The primary endpoint was inhospital mortality. Results: On direct comparison of the vasodilator and non-vasodilator groups after propensity score matching, there were no significant differences in the inhospital mortality rates (7.5% vs. 8.8%, respectively; P=0.098) or length of intensive/cardiovascular care unit stay and hospital stay between the two groups. However, there was a substantial difference in baseline systolic blood pressure by vasodilator type; favourable impacts of vasodilator use on inhospital mortality were observed among patients who had higher systolic blood pressures and those who had no atrial fibrillation on admission. Furthermore, when compared to nitrates, the use of carperitide (natriuretic peptide agent) was significantly associated with worse outcomes, especially in patients with intermediate systolic blood pressures. Conclusions: In acute heart failure patients, vasodilator use was not universally associated with improved inhospital outcomes; rather, its effect depended on individual clinical presentation: patients with higher systolic blood pressure and no atrial fibrillation seemed to benefit maximally from vasodilators. Trial registration: UMIN-CTR identifier, UMIN000013128

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Doobay, Marc F., Lauren S. Talman, Teresa D. Obr, Xin Tian, Robin L. Davisson, and Eric Lazartigues. "Differential expression of neuronal ACE2 in transgenic mice with overexpression of the brain renin-angiotensin system." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 292, no. 1 (January 2007): R373—R381. http://dx.doi.org/10.1152/ajpregu.00292.2006.

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Angiotensin-converting enzyme 2 (ACE2) is a newly discovered carboxy-peptidase responsible for the formation of vasodilatory peptides such as angiotensin-(1–7). We hypothesized that ACE2 is part of the brain renin-angiotensin system, and its expression is regulated by the other elements of this system. ACE2 immunostaining was performed in transgenic mouse brain sections from neuron-specific enolase-AT1A (overexpressing AT1A receptors), R+A+ (overexpressing angiotensinogen and renin), and control (nontransgenic littermates) mice. Results show that ACE2 staining is widely distributed throughout the brain. Using cell-type-specific antibodies, we observed that ACE2 staining is present in the cytoplasm of neuronal cell bodies but not in glial cells. In the subfornical organ, an area lacking the blood-brain barrier and sensitive to blood-borne angiotensin II, ACE2 was significantly increased in transgenic mice. Interestingly, ACE2 mRNA and protein expression were inversely correlated in the nucleus of tractus solitarius/dorsal motor nucleus of the vagus and the ventrolateral medulla, when comparing transgenic to nontransgenic mice. These results suggest that ACE2 is localized to the cytoplasm of neuronal cells in the brain and that ACE2 levels appear highly regulated by other components of the renin-angiotensin system, confirming its involvement in this system. Moreover, ACE2 expression in brain structures involved in the control of cardiovascular function suggests that the carboxypeptidase may have a role in the central regulation of blood pressure and diseases involving the autonomic nervous system, such as hypertension.

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Shibata, M., H. Parfenova, S. L. Zuckerman, J. M. Seyer, J. M. Krueger, and C. W. Leffler. "Interleukin-1 beta peptides induce cerebral pial arteriolar dilation in anesthetized newborn pigs." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 270, no. 5 (May 1, 1996): R1044—R1050. http://dx.doi.org/10.1152/ajpregu.1996.270.5.r1044.

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Inflammatory cytokines may affect cerebral circulation under pathological conditions. Responses of cerebral pial arterioles to one such cytokine, interleukin (IL)-1 beta and its inhibitor [soluble IL-1 receptor (sIL-1R)] were examined in anesthetized newborn pigs using closed cranial windows. Levels of prostanoids and cyclic nucleotides in periarachnoid cerebral spinal fluid (CSF) were measured. To examine the structure-activity relationship of the parent IL-1 beta molecule, two IL-1 beta fragments with amino acid sequences of 187-204 [IL-1 beta-(187-204)] and 208-240 [IL-1 beta-(208-240)] were tested for their effects on pial arterioles. Diameter changes of pial arterioles were sequentially recorded every 5 min for 30 min after topical application of IL-1 peptides. CSF was sampled at the end of the 30 min. IL-1 beta dose dependently induced arteriolar dilation and increased prostaglandin E2 (PGE2), 6-keto-PGF1 alpha adenosine 3',5'-cyclic monophosphate (cAMP), and guanosine 3',5'-cyclic monophosphate (cGMP). Intravenous indomethacin blocked the IL-1 beta-induced vasodilation, the increased prostanoids, and the increased cAMP, but not the increased cGMP. Neither heat-inactivated IL-1 beta nor IL-1 beta vehicle affected arteriolar diameter or CSF levels of prostanoids. The sIL-1R blocked the IL-1 beta-induced vasodilation and the increased CSF prostanoids. IL-1 beta-(208-240) also induced pial arteriolar dilation; however, its vasodilatory potency was 1,000 times less than that of the whole IL-1 beta molecule. IL-1 beta-(187-204) did not induce pial arteriolar dilation even when its dose was increased to the level of IL-1 beta-(208-240). These results suggest that IL-1 beta, through the activation of membrane-bound IL-1 beta receptors, induces pial arteriolar dilation via mechanisms that involve prostanoids and cyclic nucleotides. The results also indicate that the 208-240 amino acid sequence of IL-1 beta has a sequence-specific physiological function.

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Rubio-Beltrán, Eloísa, Alejandro Labastida-Ramírez, Kristian A. Haanes, Antoon van den Bogaerdt, Ad JJC Bogers, Clemens Dirven, AH Jan Danser, Cen Xu, Josefin Snellman, and Antoinette MaassenVanDenBrink. "Characterisation of vasodilatory responses in the presence of the CGRP receptor antibody erenumab in human isolated arteries." Cephalalgia 39, no. 14 (July 8, 2019): 1735–44. http://dx.doi.org/10.1177/0333102419863027.

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Background Migraine is associated with activation of the trigeminovascular system, release of calcitonin gene-related peptide (CGRP) and dilation of dural arteries. Novel treatments target calcitonin gene-related peptide or its receptor, which are present in all vascular beds, raising cardiovascular concerns. Erenumab is a human CGRP-receptor antibody approved for the prophylactic treatment of migraine. Methods We characterised the relaxant responses to CGRP in the absence and presence of erenumab (1 μM) in isolated human middle meningeal, internal mammary and (proximal and distal) coronary arteries. Furthermore, in human internal mammary arteries from cardiovascularly-compromised patients, we assessed the pharmacological specificity of erenumab by investigating whether the vasodilatory responses to acetylcholine, sodium nitroprusside, pituitary adenylate cyclase activating polypeptide-38 (PACAP), vasoactive intestinal peptide and nicardipine, along with the vasoconstrictor responses to dihydroergotamine, were modified by erenumab. Results Calcitonin gene-related peptide induced concentration-dependent vasodilatory responses in all vessels studied that were significantly antagonised by erenumab. In human internal mammary arteries from cardiovascularly-compromised patients, the responses to acetylcholine, sodium nitroprusside, PACAP, vasoactive intestinal peptide, nicardipine and dihydroergotamine were unaffected by erenumab. Conclusion Erenumab inhibits calcitonin gene-related peptide-induced vasodilatory responses in human middle meningeal arteries, human internal mammary arteries and human coronary arteries. Moreover, erenumab shows functional specificity as no interaction was observed with the relaxant responses to several vasodilators, nor the dihydroergotamine-dependent vasoconstrictor responses.

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Krause, Lucinda M. Hilliard, Brandon A. Kemp, Amanda Suan Jui Tan, Emma S. Jones, Mark P. Del Borgo, Marie-Isabel Aguilar, Kate M. Denton, Robert M. Carey, and Robert E. Widdop. "Renal functional effects of the highly selective AT2R agonist, β-Pro7 Ang III, in normotensive rats." Clinical Science 134, no. 7 (April 2020): 871–84. http://dx.doi.org/10.1042/cs20200153.

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Abstract Recently, we designed a group of peptides by sequential substitution of the naturally occurring α-amino acid throughout the Ang III peptide sequence with the corresponding β-amino acid. β-Amino acid substitution at the proline residue of Ang III (β-Pro7-Ang III) resulted in a highly selective AT2R ligand, demonstrating remarkable selectivity for the AT2R in both binding and functional studies. To provide additional functional evidence for the suitability of β-Pro7 Ang III as a novel AT2R agonist, we tested effects of acute systemic administration of β-Pro7-Ang III on renal hemodynamic and excretory function in anesthetized normotensive male and female rats. We also compared the natriuretic effects of acute intrarenal administration of native Ang III and β-Pro7-Ang III in the presence of systemic AT1R blockade in anesthetized female rats to allow for the differentiation of systemic versus direct intrarenal natriuretic actions of β-Pro7-Ang III. In both male and female rats, acute systemic administration of β-Pro7-Ang III elicited renal vasodilatation and natriuresis. Notably, greater renal vasodilatory effects were observed in female versus male rats at the highest dose of β-Pro7-Ang III administered. Moreover, intra-renal administration of β-Pro7-Ang III produced significant natriuretic effects in female rats and, like Ang III, evoked AT2R translocation to the apical plasma membrane in renal proximal tubular cells. Taken together, our findings support the use of β-Pro7-Ang III as a novel AT2R agonist and experimental tool for exploring AT2R function and its potential as a therapeutic target. Furthermore, our findings provide further evidence of a sex-specific influence of AT2R stimulation on renal function.

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Stirrat, Alison, Marie Gallagher, Stephen A. Douglas, Eliot H. Ohlstein, Colin Berry, A. Kirk, M. Richardson, and Margaret R. MacLean. "Potent vasodilator responses to human urotensin-II in human pulmonary and abdominal resistance arteries." American Journal of Physiology-Heart and Circulatory Physiology 280, no. 2 (February 1, 2001): H925—H928. http://dx.doi.org/10.1152/ajpheart.2001.280.2.h925.

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The peptide human urotensin-II (hUT-II) and its receptor have recently been cloned. The vascular function of this peptide in humans, however, has yet to be determined. Vasoconstrictor and vasodilator responses to hUT-II were investigated in human small muscular pulmonary arteries [∼170 μm internal diameter (ID)] and human abdominal resistance arteries (∼200 μm ID). Vasodilator responses were investigated in endothelin-1 (3 nM) precontracted vessels and, in the small pulmonary vessels, compared with the known vasodilators adrenomedullin, sodium nitroprusside, and acetylcholine. In human small pulmonary arteries, hUT-II did not induce vasoconstriction but was a potent vasodilator [−log M concentration causing 50% of the maximum vasodilator effect (pIC50) 10.4 ± 0.5; percentage of reduction in tone ( E max) 81 ± 8% (vs. 23 ± 11% in time controls), n = 5]. The order of potency for vasodilation was human urotensin-II = adrenomedullin (pIC50 10.1 ± 0.4, n = 6) > sodium nitroprusside (pIC50 7.4 ± 0.2, n = 6) = acetylcholine (pIC50 6.8 ± 0.3, n = 6). In human abdominal arteries, hUT-II did not induce vasoconstriction but was a potent vasodilator [pIC50 10.3 ± 0.7; E max96 ± 8% (vs. 43 ± 16% in time controls), n = 4]. This is the first report that hUT-II is a potent vasodilator but not a vasoconstrictor of human small pulmonary arteries and systemic resistance arteries.

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Onoue, Hisashi, Nobuyoshi Kaito, Shogo Tokudome, Toshiaki Abe, Koichi Tashibu, Hiroyasu Nagashima, and Norio Nakamura. "Investigation of Postmortem Functional Changes in Human Cerebral Arteries." Journal of Cerebral Blood Flow & Metabolism 13, no. 2 (March 1993): 346–49. http://dx.doi.org/10.1038/jcbfm.1993.44.

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This study demonstrated the time-dependent changes in postmortem responses of isolated human middle cerebral artery strips to vasodilators. The relaxation induced by prostaglandin (PG) I2 or nitroglycerin remained stable for 24 h postmortem. In arterial strips precontracted with PGF2α, substance P and bradykinin both elicited relaxation that was almost completely abolished by removal of the endothelium. The endothelium-dependent response to both peptides was significantly degraded in strips obtained >12 h postmortem. These results indicate a selective functional or anatomical vulnerability of the vascular endothelium compared with that of the vasodilator mechanisms of the smooth muscle in the postmortem period. However, cerebral arteries isolated from human cadavers within 12 h postmortem should be adequate for studies of both smooth muscle and endothelial reactivity to vasodilators.

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Zellner, Christian, Andrew A. Protter, Eitetsu Ko, Madhusudhan R. Pothireddy, Teresa DeMarco, Stuart J. Hutchison, Tony M. Chou, Kanu Chatterjee, and Krishnankutty Sudhir. "Coronary vasodilator effects of BNP: mechanisms of action in coronary conductance and resistance arteries." American Journal of Physiology-Heart and Circulatory Physiology 276, no. 3 (March 1, 1999): H1049—H1057. http://dx.doi.org/10.1152/ajpheart.1999.276.3.h1049.

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Brain natriuretic peptide (BNP), a hormone secreted predominantly in ventricular myocytes, may influence coronary vascular tone. We studied the coronary vasodilatory response to BNP under physiological conditions and after preconstriction with endothelin-1 (ET-1) in anesthetized pigs. Average peak-flow velocity (APV) was measured using intracoronary Doppler, and cross-sectional area (CSA) was measured using intravascular ultrasound. Coronary blood flow (CBF) was calculated. Intracoronary BNP induced dose-dependent increases in CSA, APV, and CBF similar in magnitude to those induced by nitroglycerin (NTG). The magnitude of BNP-induced vasodilation was accentuated after preconstriction with ET-1. Pretreatment with either the nitric oxide synthase inhibitor N ω-nitro-l-arginine methyl ester or the cyclooxygenase inhibitor indomethacin attenuated the coronary vasodilator effect of BNP in resistance arteries without influencing epicardial vasodilation. Pretreatment with the ATP-sensitive potassium-channel blocker glibenclamide enhanced epicardial vasodilation in response to BNP. We conclude that BNP exerts coronary vasodilator effects, predominantly in epicardial conductance vessels. An accentuated vasodilatory response to BNP occurs in ET-1-preconstricted arteries. BNP-induced vasodilation in coronary resistance arteries may be partially mediated via nitric oxide and/or prostaglandin release.

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Hill, N. S., J. R. Klinger, R. R. Warburton, L. Pietras, and D. S. Wrenn. "Brain natriuretic peptide: possible role in the modulation of hypoxic pulmonary hypertension." American Journal of Physiology-Lung Cellular and Molecular Physiology 266, no. 3 (March 1, 1994): L308—L315. http://dx.doi.org/10.1152/ajplung.1994.266.3.l308.

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To test the hypothesis that brain natriuretic peptide (BNP) plays a role similar to that of atrial natriuretic peptide (ANP) in modulating pulmonary vascular responses to hypoxia, we measured the vasodilator potency of ANP and BNP in rat pulmonary artery (PA) and thoracic aorta (TA) rings and in isolated rat lungs. We also measured the effect of chronic hypoxia on plasma levels and cardiac gene expression of both peptides. BNP had a vasorelaxant effect equipotent to that of ANP on preconstricted TA and PA rings, but was less potent than ANP in relaxing the vasoconstrictor response to hypoxia in isolated lungs [mean 50% inhibitory concentration (IC50) 10(-7) vs. 10(-6) M for ANP and BNP, respectively]. Plasma BNP levels were 30-fold lower than ANP, but both peptides increased approximately 70% during chronic hypoxia. In the right atrium, hypoxia lowered BNP mRNA slightly, but had no effect on ANP mRNA or tissue levels of either peptide. However, hypoxia increased right ventricular content and mRNA levels of both peptides by three- to fourfold. We conclude that BNP and ANP have similar pulmonary vasodilator effects and are upregulated proportionally during chronic hypoxia. These results support a role for BNP in modulating the pulmonary hypertensive response to chronic hypoxia.

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Williams, Gareth, Helena Cardoso, Joanna A. Ball, Peter K. Mulderry, Ernest Cooke, and Stephen R. Bloom. "Potent and comparable vasodilator actions of A- and B-calcitonin-gene-related peptides on the superficial subcutaneous vasculature of man." Clinical Science 75, no. 3 (September 1, 1988): 309–13. http://dx.doi.org/10.1042/cs0750309.

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1. Vasoactivity of human A- and B-calcitonin-gene-related peptides was studied in normal subjects, using reflectance plethysmography to measure relative changes in blood flow produced by superficial subcutaneous injections of the peptides. 2. Injection of 10−11 mol of either peptide caused an immediate 200% increase in local blood flow and prolonged hyperaemia lasting up to 3 h. The hyperaemic response to 10−13 mol of each peptide was significantly (P < 0.01) smaller and shorter in duration than that elicited by 10−1 mol of the same peptide, and 10−15 mol of both peptides produced no hyperaemia other than that attributable to needle insertion alone. 3. At all three dosages examined, there were no significant differences between A- and B-calcitonin-gene-related peptides in magnitude or time course of the hyperaemic response. 4. Human A- and B-calcitonin-gene-related peptides are therefore potent vasodilators in man, causing comparable dose-related vasodilatation in the superficial tissues.

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Fernandez-Patron, Carlos, Marek W. Radomski, and Sandra T. Davidge. "Role of matrix metalloproteinase-2 in thrombin-induced vasorelaxation of rat mesenteric arteries." American Journal of Physiology-Heart and Circulatory Physiology 278, no. 5 (May 1, 2000): H1473—H1479. http://dx.doi.org/10.1152/ajpheart.2000.278.5.h1473.

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The vasodilator effects of thrombin depend on activation of proteinase-activated receptor (PAR)-1 and the subsequent release of endothelin (ET)-1, which stimulates the generation of nitric oxide and PGs. We recently showed that thrombin released matrix metalloproteinase-2 (MMP-2) from rat arteries. We have now studied the significance of this release for the vasodilator effects of thrombin. Thrombin (≥100 pmol), but not a PAR-1-activating peptide (TFLLR-NH2), produced a long-lasting (>10 min) vasorelaxation of rat mesenteric arteries, as detected by a microperfusion bioassay. Thrombin induced a simultaneous release of vascular MMP-2 into arterial perfusates, as revealed by zymography. Interestingly, the vasodilator effects of thrombin were inhibited by a tissue inhibitor of MMP-2 (TIMP-2, 10 pmol). Moreover, infusion of exogenous MMP-2 (5 pmol) resulted in vasorelaxation. These vasodilatory effects of thrombin and MMP-2 were significantly ( P < 0.05) inhibited by endothelium denudation and by PD-142893 (2 nmol), an antagonist of ET receptors. Furthermore, both thrombin and MMP-2 constricted endothelium-denuded arteries. These results show that the vasodilator effects of thrombin may depend, in part, on a release of vascular MMP-2 and downstream activation of ETs. Thus MMP-2-dependent signaling may complement the PAR-1-dependent pathway of vasodilator action of thrombin.

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Champion, H. C., J. A. Santiago, W. A. Murphy, D. H. Coy, and P. J. Kadowitz. "Adrenomedullin-(22-52) antagonizes vasodilator responses to CGRP but not adrenomedullin in the cat." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 272, no. 1 (January 1, 1997): R234—R242. http://dx.doi.org/10.1152/ajpregu.1997.272.1.r234.

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The effects of adrenomedullin (ADM)-(22-52), a putative ADM receptor antagonist, on vasodilator responses to ADM and the structurally related peptide, calcitonin gene-related peptide (CGRP), were investigated in the hindlimb vascular bed of the cat under constant-flow conditions. ADM-(22-52) had no significant effect on hindlimb perfusion pressure when injected in doses up to 120 nmol; after administration of ADM-(22-52), vasodilator responses to ADM were unchanged, whereas vasodilator responses to CGRP were inhibited. The inhibitory effects of ADM-(22-52) on responses to CGRP were selective and reversible and were similar to the inhibitory effects of the CGRP antagonist CGRP-(8-37). Hindlimb vasodilator responses to CGRP and to ADM were increased in duration by the adenosine 3',5'-cyclic monophosphate (cAMP) phosphodiesterase inhibitor rolipram but were not altered by inhibitors of guanosine 3',5'-cyclic monophosphate phosphodiesterase, nitric oxide synthetase, K(+)-ATP channels, the cyclooxygenase pathway, or the adrenergic nervous system. These results demonstrate that ADM-(22-52) is a selective CGRP receptor antagonist in the hindlimb vascular bed of the cat. The present data suggest that vasodilator responses to CGRP and ADM are mediated by different receptors but that these peptides dilate the hindlimb vascular bed of the cat by a similar cAMP-dependent mechanism.

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Suzuki, Yoshio, Shin-ichi Satoh, Masaaki Kimura, Hirofumi Oyama, Toshio Asano, Masato Shibuya, and Kenichiro Sugita. "Effects of vasopressin and oxytocin on canine cerebral circulation in vivo." Journal of Neurosurgery 77, no. 3 (September 1992): 424–31. http://dx.doi.org/10.3171/jns.1992.77.3.0424.

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✓ In vivo experiments on the vasoactive effects of vasopressin and oxytocin on cerebral circulation were carried out in anesthetized dogs, using an electromagnetic flowmeter to measure vertebral blood flow and angiography to measure the internal diameter of the basilar artery. Direct bolus infusion of 1 pmol to 1 nmol of vasopressin or 10 pmol to 10 nmol of oxytocin into a femoral-vertebral artery shunt produced a dose-dependent decrease in vertebral artery blood flow without significantly affecting mean arterial blood pressure. Vasopressin was more potent than endothelin and neuropeptide Y, which have also been demonstrated to induce long-lasting decreases in vertebral artery blood flow. However, direct bolus infusion of vasopressin (100 pmol and 1 nmol) or oxytocin (1 nmol and 10 nmol) into the vertebral artery dilated major vessels including the vertebral, anterior spinal, and basilar arteries, as well as the circle of Willis and its main branches, while endothelin (1 nmol) and neuropeptide Y (5 nmol) caused no change in the diameters of major cerebral arteries. The V1 antagonist d(CH2)5tyrosine(methyl) arginine vasopressin suppressed the effects of both vasopressin and oxytocin. Vasopressin was over 10 times as potent as oxytocin in both assays. The vasodilatory effect of vasopressin, which may be mediated by an endothelium-dependent mechanism, was functionally damaged in dogs after experimental subarachnoid hemorrhage. These data suggest regional differences in the sensitivity and responsiveness of vasculature to vasopressin and oxytocin, and specifically that both peptides act through V1 receptors to decrease the resistance of large vessels and increase the resistance of small vessels.

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Journal articles on the topic 'Vasodilatory peptides'

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