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1
Riba, Serrano Jordi. "Human pharmacology of ayahuasca." Doctoral thesis, Universitat Autònoma de Barcelona, 2003. http://hdl.handle.net/10803/5378.
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La ayahuasca es una bebida psicotrópica obtenida de las plantas Banisteriopsis caapi y Psychotria viridis, que ha sido utilizada desde hace siglos en las cuencas de los ríos Amazonas y Orinoco con finalidades mágico-religiosas y en la medicina tradicional de estas áreas geográficas. La bebida contiene alcaloides que muestran actividad inhibidora del enzima monoamino oxidasa o MAO (harmina, harmalina y tetrahidroharmina) y un compuesto alucinógeno (la N,N-dimetiltriptamina o DMT) que es inactivo por vía oral en ausencia de los anteriores. El consumo de ayahuasca se ha ido popularizando lentamente en Europa desde principios de la década de los 90. Dada la escasa información existente sobre los efectos de la ayahuasca en humanos, se llevaron a cabo dos estudio clínicos con voluntarios sanos a los que se administraron distintas dosis de ayahuasca liofilizada y encapsulada. En un primer estudio piloto se administraron en orden creciente un placebo y tres dosis de ayahuasca correspondientes a 0.50, 0.75 y 1.0 mg DMT/kg peso a 6 voluntarios sanos en condiciones de simple ciego. En el estudio final se administraron de forma aleatorizada y balanceada un placebo y dos dosis de ayahuasca correspondientes a 0.6 y 0.85 mg DMT/kg peso a 18 voluntarios sanos en condiciones de doble ciego. Las variables estudiadas incluyeron medidas de efectos subjetivos, medidas cardiovasculares, farmacocinética, niveles de metabolitos de neurotransmisores en orina, registros de electroencefalografía (EEG), potenciales evocados (supresión del potencial auditivo P50) y electromiografía (supresión del reflejo de sobresalto). La ayahuasca produjo efectos subjetivos de activación, bienestar y euforia, cambios en la percepción somática y visual y cambios en el contenido y velocidad del pensamiento. Los efectos subjetivos máximos se observaron a los 60-120 minutos y desaparecieron a las 4-6 horas postadministración. Los efectos cardiovasculares fueron moderados con incrementos estadísticamente significativos únicamente en la presión arterial diastólica (9 mm Hg a los 75 minutos tras la dosis de 0.85 mg DMT/kg). El estudio farmacocinético determinó la presencia en plasma de DMT, harmalina y THH, pero no de harmina. Se midieron así mismo niveles de dos compuestos O-demetilados, harmol y harmalol, metabolitos de la harmina y la harmalina, respectivamente. Las concentraciones máximas de DMT fueron de 12.14 ng/ml y 17.44 ng/ml tras las dosis de 0.6 y 0.85 mg DMT/kg, respectivamente. Estas concentraciones se obtuvieron a los 90 minutos postadministración tras ambas dosis. La semivida de eliminación de la DMT fue de 1 hora tras ambas dosis. Se estimó la biodisponibilidad de la DMT tras la administración de ayahuasca en un 10-15%. La administración de ayahuasca produjo un aumento en la excreción de normetanefrina, metabolito de la noradrenalina COMT-dependiente, sin que se evidenciaran disminuciones en la excreción de metabolitos MAO-dependientes. A nivel del EEG, se observaron disminuciones en el valor de potencia absoluta para las bandas delta, teta, alfa-2 y beta-1. Estas disminuciones fueron máximas a la 1-2 horas postadministración. La aplicación de una técnica de localización de los cambios observados en el EEG mostró disminuciones de densidad de potencia a nivel intracerebral en el córtex temporo-parieto-occipital, frontomedial y temporomedial. Finalmente, la administración de ayahuasca produjo disminuciones en la tasa de supresión del potencial auditivo P50 (paradigma utilizado para determinar el grado de supresión sensorial), pero no en la tasa de supresión del reflejo de sobresalto por un preestímulo (paradigma utilizado para determinar el grado de supresión sensoromotora). Los resultados obtenidos ponen de manifiesto que la ayahuasca muestra un patrón de efectos alucinógenos y psicoestímulantes análogos a los reportados por otros autores para la DMT administrada por vía parenteral, pero de menor intensidad y duración más prolongada.Ayahuasca is a psychotropic plant tea, obtained from Banisteriopsis caapi and Psychotria viridis, which has been used for centuries in the Amazon and Orinoco River Basins for magico-religious purposes and folk medicine. This tea contains alkaloids with monoamine-oxidase (MAO)-inhibiting properties (harmine, harmaline and tetrahydroharmine), together with a psychedelic compound (N,N-dimethyltryptamine or DMT), which is inactive per os in the absence of the first three. The use of ayahuasca has gradually spread to Europe since the early 1990s, and given the scarce information available on the effects of ayahuasca in humans, two clinical trials were conducted in healthy volunteers, who were administered various doses of encapsulated freeze-dried ayahuasca. In an initial pilot study, a placebo and three doses of ayahuasca equivalent to 0.50, 0.75 and 1.0 mg DMT/kg body weight were administered in increasing order to 6 healthy volunteers in single-blind conditions. In a subsequent study, a placebo and two doses of ayahuasca equivalent to 0.6 and 0.85 mg DMT/kg were administered to 18 healthy volunteers according to a double-blind randomized balanced design. The studied variables included measures of subjective and cardiovascular effects, pharmacokinetic parameters, urine neurotransmitter metabolites, electroencephalography recordings (EEG), evoked potentials (suppression of the auditive P50 potential) and electromyography (suppression of the startle reflex). Ayahuasca induced subjective feelings of increased activation, euphoria and well-being, modifications in somatic and visual perception, and also in thought content and speed. Peak subjective effects were observed between 60-120 minutes and were resolved by 4-6 hours. Cardiovascular effects were moderate, with statistically significant increases obtained only for diastolic blood pressure (9 mm Hg at 75 minutes after the 0.85 mg DMT/kg dose). The pharmacokinetic assessment revealed measurable plasma levels for DMT, harmaline and THH, but not for harmine. Levels of two O-demethylated compounds, i.e., harmol and harmalol, putative metabolites of harmine and harmaline, respectively, were detected in all volunteers. Cmax values for DMT after the low and the high ayahuasca doses were 12.14 ng/ml and 17.44 ng/ml, respectively. Tmax was observed at 90 minutes after both doses. Elimination half-life for DMT was 1 hour after both doses. DMT bioavailability in ayahuasca was estimated in 10-15%. Ayahuasca administration increased normetanephrine excretion, a COMT-dependent norepinephrine metabolite, and produced no change in the excretion of MAO-dependent metabolites. Regarding the EEG, decreases in absolute power were obtained for the delta, theta, alpha-2 and beta-1 bands. These decreases were maximal at 1-2 hours. The application of a source location technique to the topographical changes obtained, yielded intracerebral power density decreases in the temporo-parieto-occipital, frontomedial and temporomedial cortices. Finally, ayahuasca decreased suppression of the P50 potential (measuring sensory gating), but did not change prepulse inhibition of the startle reflex (measuring sensorimotor gating). The results obtained indicate for ayahuasca a pattern of psychedelic and stimulatory effects analogous to those reported by other authors for parentheral DMT, but with a lower intensity and a longer duration.
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Cumming, Paul Kenneth. "Pharmacology of cerebral histamine." Thesis, University of British Columbia, 1990. http://hdl.handle.net/2429/30687.
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Four aspects of the function of histaminergic systems were studied in the rat brain: toxicology, catabolism, release in vivo, and high affinity binding of histamine. Preparations of histamine-N-methyltransferase (HNMT) derived from kidney and brain were employed in the radioenzymatic quantification of histamine in biological samples. Tritiated S-adenosyl-L-methionine ([³H]-SAM) served as the co-substrate.
A toxicological study was conducted to determine the sensitivity of the HA innervation to prenatal treatment with methylazoxymethanol (MAM), an inhibitor of mitosis. In adult rats, the MAM treatment was without effect on cerebral histamine content, although forebrain HNMT activity was 50% reduced. In another study, C-57 mice were treated with the selective dopamine neurotoxin l-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Substantial dopamine depletions were not associated with alterations in the cerebral histamine content.
In a study of the structural requirements for HNMT inhibition, 9-amino-1,2,3,4-tetrahydroacridine (THA), was found to be one of the most potent inhibitors yet described. The β-carboline alkaloids, of which harmaline is the prototype, were also found to be moderately potent HNMT inhibitors. Because of the lack of high-affinity re-uptake and the absence of alternate catabolic pathways, blockade of HNMT can potentially alter central histaminergic tone. Peripheral administration of THA was able to produce dose-dependent increases in cerebral histamine content, as was the more potent HNMT inhibitor, metoprine. The issue of structural requirements for HNMT inhibition are discussed in the light of these results.
The in vivo release of histamine was studied by the cerebral microdialysis technique. After chronic implantation of horizontal probes, TTX-insensitive and partially calcium-sensitive efflux of histamine was detected in the dorsal striatum and the bed nucleus of the stria terminalis. In striatum, histamine efflux was elevated 50% after peripheral histidine loading (500 mg/kg, i.p.). After synthesis blockade with α-fluoromethylhistidine (100 mg/kg,i.p.), extracellular histamine levels in striatum disappeared in a bi-exponential manner. The half-lives of this disappearance, 32 minutes and 7 hours, indicate the presence of at least two histamine pools. Striatal histamine efflux was elevated by yohimbine treatment (10 mg/kg, i.p.), suggesting the presence of a tonic α₂-adrenergic inhibition of histamine release in vivo.
In addition to the classical H₁ and H₂ receptors, histamine is able to bind to a pharmacologically distinct site, H₃, recently characterized as an autoreceptor regulating the synthesis and release of histamine. The binding properties of the H₃ ligand [³H]-N[symbol omitted]-methylhistamine ([³H]-N-MeHA) were studied in forebrain cryostat sections by
autoradiography. Determination of Bmax (25 fmole/section) and displacement studies indicated that [³H]-N-MeHA bound to the same site as [³H]-histamine: the high affinity
histamine binding site. Binding was greatest in the basal ganglia and had a complex
distribution within the cerebral cortex. Quinolinic acid lesion studies indicated that the
majority of the binding in the basal ganglia was on striato-nigral projection neurons. Cortical
binding was also sensitive to local excitotoxic lesions. Therefore, the majority of H₃ binding
is located on postsynaptic structures intrinsic to these brain regions, rather than on presynaptic
autoreceptors on terminals of histamine neurons.Medicine, Faculty of
Graduate
3
Karbwang, J. "Clinical pharmacology of mefloquine." Thesis, University of Liverpool, 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.234865.
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Ordway, Gregory A. "Molecular Pharmacology of Antidepressants." Digital Commons @ East Tennessee State University, 2006. https://dc.etsu.edu/etsu-works/8657.
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Langford, Nigel James. "Beta-receptor pharmacology and therapeutics." Thesis, University of Birmingham, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.404060.
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Hahn, Robert G. "Clinical pharmacology of infusion fluids." Linköpings universitet, Anestesiologi med intensivvård, 2012. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-91319.
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Fluids are used for intravenous infusion during practically all surgeries, but several different compositions are available on the market. Crystalloid fluids comprise lactated or acetated Ringer solutions, normal saline, Plasma-Lyte, hypertonic saline, and glucose. They lack allergic properties but are prone to cause peripheral tissue oedema. Their turn over is governed by physiological factors such as dehydration and drug effects. Colloid fluids include hydroxyethyl starch, albumin, dextran, and gelatin. These fluids have various degrees of allergic properties and do not promote peripheral oedema. Their half-life is usually about hours. Factors increasing the turnover rate are poorly known but might include inflammatory states. Current debates include the widespread use of normal saline, which should be replaced by Ringer’s or Plasma-Lyte in most situations, and the kidney damage associated with the use of starch in septic patients. New studies show that hypertonic saline does not improve survival or neurological damage in prehospital care.
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Farquhar, Michelle Jane. "Molecular pharmacology of chimeric peptides." Thesis, University of Wolverhampton, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.247780.
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Pasanisi, F. "Clinical pharmacology of calcium antagonists." Thesis, University of Glasgow, 1986. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.381477.
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Al-Malki, Waleed Hassan. "Pharmacology of aqueous humour formation." Thesis, University of Glasgow, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.443403.
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Ward, S. A. "The biochemical pharmacology of primaquine." Thesis, University of Liverpool, 1985. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.354530.
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Moss, Nicholas K. "TRPC channel activation and pharmacology." Thesis, University of Leeds, 2015. http://etheses.whiterose.ac.uk/9713/.
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Ion channel permeability and calcium ion (Ca2+) signalling are essential in regulating cellular responses to external and internal stimuli. Changes in the Ca2+ signalling machinery during pathologies of the cardiovascular system are a common occurrence, with an underlying deregulation of Ca2+ signalling a driving force for many pathological processes. This study particularly focusses on the change in Ca2+ regulatory mechanisms under conditions of adversity that are often attributed to pathological environments. An elevation of inflammatory mediators and an acidic extracellular environment can be present in multiple pathologies, including cancer and atherosclerosis. This study uses Ca2+ measurement techniques and patch-clamp electrophysiology to demonstrate that the transient receptor potential canonical (TRPC) class of ion channels are stimulated in an environment where high levels of the inflammatory mediator arachidonic acid (AA) are present alongside extracellular acidosis. This environment was demonstrated in both human umbilical vein endothelial cells (HUVECs) and HT29 colorectal adenocarcinoma cells. Antibody inhibition of individual TRPC subunits could inhibit AA-evoked signalling by greater than 40 % in HUVECs and greater than 50 % in HT29 cells. It is suggested that these signalling pathways are partly mediated by TRPC1, TRPC4 and TRPC5 heteromeric ion channel formations. This hypothesis was supported by the ability to stimulate TRPC5 homomeric channels overexpressed in HEK293 cells with AA in conditions of extracellular acidosis. Tools for investigating endogenous TRPC ion channel function are limited and lack potency and specificity. A search for small molecule TRPC modulators identified two novel TRPC5 inhibitor series. C42a1 was the most potent of those compounds investigated, with an IC50 of 4.28 ± 0.04 μM against Gd3+-evoked TRPC5 activity. The TRPC4β/TRPC5 activator Englerin-A ((-)EA) was utilised to demonstrate a 4.1-fold selectivity for TRPC5 over TRPC4β for C42a1. This is the first study utilising this direct channel agonist in both Ca2+ measurement and patch-clamp assays against these channel types. Modifying the chemical structure of the C42 inhibitor series identified compounds with altered selectivity and potency. This compound series also demonstrated good selectivity for TRPC5 over closely related ion channels that were investigated (TRPC6, TRPM2, TRPM3, and Orai1). TRPC activation by AA and (-)EA could both evoke cell death in a variety of cell types with (-)EA particularly effective in renal cell carcinoma, as has been previously reported. Our ability to modulate cell death using our novel TRPC inhibitors was limited, assumed to be due to our inability to completely block Ca2+ signalling. Protection of cells against (-)EA-evoked cell death using the C42 inhibitor series was more successful compared to that for AA-evoked cell death. This was likely due to the wide-array of activity of AA and its metabolites on protein function, with only a small cell death component likely attributable to TRPC activation. This study identified novel TRPC-mediated activation mechanisms that have relevance in cellular functions during cardiovascular disease and cancer pathology. The newly identified classes of TRPC inhibitors are in the early stage of development though initially demonstrate the potential to be developed to yield highly potent and therapeutically valuable modulators of endogenous TRPCs.
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Appleby, Hollie Leanne. "Orai channel physiology and pharmacology." Thesis, University of Leeds, 2016. http://etheses.whiterose.ac.uk/15950/.
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Background: Cardiovascular disease is often characterised by functional and structural changes in the blood vessel wall, usually associated with endothelial dysfunction. Therefore, interest in targeting the dysfunctional endothelial cell has heightened. Ca2+ signalling is crucial to endothelial cell physiology as it drives a number of intracellular signalling pathways. Store-operated Ca2+ entry (SOCE) mediated by Orai1 channels is of particular interest as it provides a major Ca2+ influx pathway in endothelial cells, driving cell migration and proliferation, ultimately contributing to endothelial repair and integrity, angiogenesis and wound healing events. The novel hypothesis is that modulation of Orai1 channels will have important physiological effects on endothelial cell function. Methods and Results: A novel series of Orai1 inhibitors has been identified in this thesis with improved pharmacological and physicochemical properties compared to existing SOCE inhibitors. Optimisation of compounds’ structure-activity relationships (SAR) via Ca2+ measurement assays using human umbilical vein endothelial cells (HUVECs) has revealed important insights into functionally important features of SOCE blockers. In conjunction with in silico modelling, a novel binding site in the Orai1 channel located in a small extracellular pocket has been proposed. The generation and subsequent testing of a quaternary ammonium analogue of the parent compound, JPIII supports the hypothesis. The novel SOCE inhibitors suppressed endothelial cell migration and proliferation without affecting cell viability. Reassuringly, the small molecules were well tolerated in vivo, supporting further development and testing of such blockers in animal models of cardiovascular disease. Here, a novel transgenic murine model with the potential for temporal and conditional disruption of Ca2+ permeation in Orai1 channels has been generated and characterised, offering new possibilities for better understanding of the physiological and pathological roles of Orai1 and the therapeutic potential of targeting this channel. Conclusion: Novel SOCE inhibitors have been characterised in vitro, their mechanism of action interrogated and their properties optimised for the next stages of in vivo testing in an animal model of cardiovascular disease.
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Keiser, Michael James. "Relating protein pharmacology by ligand chemistry." Diss., Search in ProQuest Dissertations & Theses. UC Only, 2009. http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:3378494.
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Sherwin, Catherine M. T., and n/a. "Clinical pharmacology of aminoglycosides in neonates." University of Otago. Dunedin School of Medicine, 2009. http://adt.otago.ac.nz./public/adt-NZDU20090821.160736.
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The aims of this Thesis were to investigate early markers of neonatal sepsis and patient-factors affecting the pharmacokinetics and pharmacodynamics (PKPD) of aminoglycosides in the treatment of neonatal sepsis.
A prospective cohort study of neonates commenced on gentamicin for suspected sepsis was performed between 1 July 2002 and 28 February 2007. Receiver operator characteristics (ROC) plots were used to assess potential markers of sepsis against culture positive sepsis. When sepsis was first suspected, the most promising tests were interleukin (IL) IL-12(p70) with an area under the curve (95% CI) for the ROC of 0.74 (0.63-0.86), and which (with a cut-off at 75 pg/mL) had a sensitivity (95% CI) of 28% (20-36%) and a specificity of 98% (96-100%). IL-10 had a sensitivity of 17% (10-23%) and a specificity of 99% (97-100%).
Retrospective studies of neonates treated with gentamicin, amikacin and netilmicin for suspected sepsis were used to identify patient characteristics that affected aminoglycoside PKPD properties. Population PK modelling used NONMEM� v.5 to determine aminoglycoside clearance (CL) and volume of distribution (V). Logistic regression was used to examine the treatment outcome measures (serum peak and trough concentrations and ototoxicity). Simulations of new dosing regimens were undertaken for netilmicin and amikacin using MATLAB�
The final gentamicin PK covariate model gave CL = 0.097 x (current weight/2)[1.3] x (postnatal age/7)[0.29] and V = 1.07 x (current weight/2)[0.8]+ (confirmed sepsis) x 0.13. A 10% increase in gentamicin V in neonates with sepsis was estimated. For amikacin, 17 (35%) of 49 episodes of confirmed sepsis met the treatment failure criteria from 12 (15%) individual patients. The final amikacin PK covariate model was CL = 0.23 x (current weight/2)[0.691] x (postmenstrual age/40)[3.23] and V = 0.957 x (current weight/2)[0.89]. PD analysis determined risk factors linked to hearing impairment in neonates treated with amikacin included: co-medication with vancomycin, high C-reactive protein concentration and low gestational age. Simulation of a new amikacin dosing regimen recommended: 15 mg/kg 36 hourly, 14 mg/kg 24 hourly, and 15 mg/kg 24 hourly, for neonates [less than or equal to] 28 weeks, 29 to 36 weeks, and [greater than or equal to] 37 postmenstrual age, respectively.
For netilmicin, the final PK covariate model was CL = 0.192 x (current weight/2)[1.35] x (postmenstrual age/40)[1.03], V = 1.5 x (current weight/2)[0.3]. Simulation of a new optimal dosing regimen for netilmicin was: 5 mg/kg 36 hourly, 5 mg/kg 24 hourly, 6 mg/kg 24 hourly, and 7 mg/kg 24 hourly, for neonates [less than or equal to] 27, 28 to 30, 31 to 33, and [greater than or equal to] 34 weeks postmenstrual age, respectively.
IV infusions representing gentamicin administration to neonates of 2.5 kg and 0.5 kg in the NICU setting (30 minutes gentamicin infusion then a 30 minute saline flush) showed the larger neonates received 80% of the drug within 60 minutes. This increased to 90-95% by 75 minutes. However, in extremely low birth weight neonates (0.5 kg), only 60% of the intended gentamicin dose was delivered by 60 minutes (70% by 75 minutes).
In conclusion: IL-12(p70) and IL-10 were identified as promising diagnostic tests to confirm sepsis in neonates. Confirmed sepsis caused a 10% increase in V of gentamicin in neonates, suggesting larger initial dosages (mg/kg) are required for effective treatment of neonates with sepsis. Aminoglycoside clearance in neonates is predominantly affected by current weight, postmenstrual age or postnatal age. Adjusting netilmicin and amikacin doses based on current weight, and dosing interval based on both postmenstrual age and current weight improves drug efficacy. Identification of co-medication with vancomycin, low gestational age, and high C-reactive protein during treatment with amikacin increases risk of hearing impairment. The delivery of gentamicin administrated by IV infusion is substantially extended in extremely low birth weight neonates.
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Jonsson, Kent-Olov. "Pharmacology of Palmitoylethanolamide and Related Compounds." Doctoral thesis, Umeå : Dept. of pharmacology and clinical neuroscience, Univ, 2005. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-445.
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Wells, Christine. "Hippopcampal function : theta, pharmacology and novelty." Thesis, University of Leeds, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.540763.
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Beckett, P. A. "Pharmacology of airway remodelling in asthma." Thesis, University of Cambridge, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.596514.
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Ho, M. T. B. "Pharmacology of the orphan opioid receptor." Thesis, University of Cambridge, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.604104.
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The neuropeptide nociceptin/orphanin FQ (OFQ) was recently identified as the endogenous agonist of the orphan opioid receptor ORL1. In this thesis pharmacological studies on the ORL1 receptor were advanced by the comparison of the potencies and efficacies of several ligands at the rat ORL1 receptor stably transfected into chinese hamster ovary (CHO) cells, with those at the native receptor in the central (frontal cortex) and peripheral (anococcygeus muscle) nervous systems. Most notably, the work involved a close examination of the pharmacology of the first selective non-peptide antagonist for the ORL1 receptor, J-113397, and in this case the work extended to the use of in-vivo techniques measuring effects on locomotor activity and food consumption. The work on the pharmacology of the ORL1 receptor in the anococcygeus followed our discovery of the presence of the receptor in this tissue. Under conditions where electrical-field stimulation produced a selective activation of the sympathetic nerves, nociceptin/OFQ fully inhibited the pure adrenergic motor response. The hexapeptides Ac-RYYRWK-NH2 (RWK) and Ac-RYYRIK-NH2 (RIK) were potent partial-agonists whereas [Phe1ψ(CH2-NH)Gly2]nociceptin(1-13)NH2 (FGNC13) and J-113397 had little or no efficacy and were competitive antagonists. This thesis reflects on the various pharmacological actions of nociceptin/OFQ, concentrating on establishing discriminatory effects for selected compounds and possible functional role of the ORL1 receptor in the brain.
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Baker, Jillian G. "Molecular pharmacology of β-adrenoceptor ligands." Thesis, University of Nottingham, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.401579.
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Little, Margaret. "The cellular pharmacology of thiopurine drugs." Thesis, University of Newcastle Upon Tyne, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.405347.
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Bangchang, Kesara Na. "Clinical and biochemical pharmacology of mefloquine." Thesis, University of Liverpool, 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.317200.
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Riviere, Judith Helen. "Biochemical and clinical pharmacology of Mefloquine." Thesis, University of Liverpool, 1986. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.328152.
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Bailey, A. C. "Biochemistry and pharmacology of beta-bungarotoxin." Thesis, University of Essex, 1985. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.372585.
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Al-Zamil, Zeid Muhammed Zeid. "Pharmacology of isolated mammalian spinal cord." Thesis, University of Southampton, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.280402.
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Barkan, Kerry. "An investigation into glucagon receptor pharmacology." Thesis, University of Warwick, 2017. http://wrap.warwick.ac.uk/98781/.
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The glucagon receptor (GCGR), a family B G protein-coupled receptor (GPCR), plays an important role in regulating blood glucose levels through its ability to bind the 29 amino acid peptide hormone, glucagon (GCG). Antagonising GCG action is a potential therapeutic option for reducing hepatic glucose production. However, GCG-based therapy is currently limited to acute emergency treatment of hypoglycemia in patients with type 1 diabetes (T1D) (Habegger et al., 2010). Further insight into GCGR-mediated signalling pathways and mechanism of activation may provide the basis for therapeutic development. We investigated the ligand stimulated GCGR signalling using multiple assays including those measuring cAMP accumulation, ERK1/2 phosphorylation and intracellular Ca2+ (Ca2+ i) mobilisation. Through site directed mutagenesis and FACS analysis for the investigation of cell-surface expression, we identified several important residues. They included K16812.49, L16912.50 , H17012.51 and T1722.45 of the ICL1 region (G1651.63 -T1722.45 ) as potential determinant in signalling bias at the GCGR through Gq/11-coupling, C1712.44 as a critical determinant of GCGR expression and R1732.46 as an essential residue for G protein-coupling. Helix 8 residue E4068.49 was implicated in maintaining GCGR in an inactive state. Finally, TM4 residues G2714.49 , L2774.55 and V2804.58 were found to plays an important role in successful translation and/or trafficking of GCGR and (Ca2+ i) mobilisation. The GCGR-mediated pERK1/2 response way found to be both Gq/11 and β-arrestin1/2 mediated, whereas it was independent of PKA or Gβγ-subunits. The GCG analogue TH-GCG, contrary to previous reports (Wakelam et al., 1986, Lenzen et al., 1990), was characterised as a partial agonist at the GCGR, inducing a robust cAMP response but fails to induce a detectable Ca2+ i or IP1 response. We also identified a RAMP2-dependent potentiation of the GCG stimulated cAMP response at the GCGR. The research described in this thesis has produced novel data that contributes to a clearer understanding of GCGR pharmacology.
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Lewis, Clive Jonathan. "Pharmacology of the 'putative' Beta4-adrenoceptor." Thesis, University of Cambridge, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.615696.
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Martin, Richard John. "Veterinary pharmacology, ion-channels and anthelmintics." Thesis, University of Edinburgh, 1997. http://hdl.handle.net/1842/30450.
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In this collection of papers modes of action of anthelmintic and anaesthetic drugs used in Veterinary Practice are investigated using electrophysiological techniques. New preparations and analytical techniques for investigation are described along with properties of ion-channel target sites. The pharmacology of piperazine, levamisole, pyrantel, morantel, oxtantel, avermectins, cyclic depsipeptides, ketamine, metomidate, alphaxalone and xylazine are studied. This information is reviewed in formats suitable for graduate and undergraduate study. Two-micropipette current-clamp and voltage-clamp techniques for recording effects of GABA agonists and antagonists on nematode muscle are developed using Ascaris suum. Piperazine, an anthelmintic, is shown to act as a GABA agonist of low potency and, like GABA, to mediate an increase in Cl conductance by an action on extrasynaptic receptors. Diethylcarbamazine, a piperazine derivative, did not act as a GABA agonist but blocked a voltage-activated K current. The agonist profile of the Ascaris GABA receptor was similar to vertebrate GABAA receptors but the antagonist profile was very different, indicating the presence of a distinctive type of receptor (GABAN). Novel arylaminopyridazine derivatives were synthesised and tested as competitive antagonists on the GABAN receptor. The KB for NCS 281-93, was 4.7 μM. A preparation suitable for patch-clamp studies was developed and GABA receptors activated by GABA and piperazine. Both agonists activated channels with a mean single-channel conductance of 22 pS but GABA mean open-times were longer (32ms) than those of piperazine (14 ms). The effects of ivermectin on muscle GABA receptors in Ascaris and on 19 pS Cl channels were observed using cell-attached and isolated inside-out patches. Ivermectin locked open the small Cl channels when applied to the outside membrane. A novel fluorescent and active bodily ivermectin analogue was synthesised and the movement of the probe followed in vesicle membranes using the FRAP (fluorescence recovery after photobleaching) technique. Quenching experiments showed that the ivermectin probe did not move through the cell membrane in the time scale of the experiment (30 min). A novel two-microelectrode current-clamp preparation of the Ascaris pharynx was used to show that an ivermectin analogue potentiated a glutamate gated Cl channel at low concentrations and produced an increase in the Cl conductance at a higher concentration. The actions of potent and novel potential anthelmintic cyclic depsipeptides were investigated using conventional parasitological techniques and the mode of action investigated in Ascaris muscle using current-clamp. It was found that these compounds did not act directly as a GABA agonist or acetylcholine antagonist. The actions of the anthelmintic praziquantel are reviewed and a tegumental preparation of Schistosoma mansoni developed for single-channel recording.
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Ahtyamova, D. V. "Anti-aging pharmacology: promises and pitfalls." Thesis, Київський національний університет технологій та дизайну, 2018. https://er.knutd.edu.ua/handle/123456789/10636.
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Novozhilova, Ekaterina B. "Physiology and pharmacology of flatworm muscle." [Ames, Iowa : Iowa State University], 2008.
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Spratt, James Christopher Samuel. "Endothelin : cardiovascular pharmacology, physiology & pathophysiology." Thesis, University of Edinburgh, 2003. http://hdl.handle.net/1842/23202.
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Winstanley, Peter Andrew. "The pharmacology and toxicology of amodiaquine." Thesis, University of Liverpool, 1988. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.237571.
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Nielsen, Carsten K. "Studies on the preclinical pharmacology of oxycodone /." St. Lucia, Qld, 2003. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe17560.pdf.
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Yubero, Lahoz Samanta 1985. "MDMA pharmacology in humans and serotonergic effects." Doctoral thesis, Universitat Pompeu Fabra, 2013. http://hdl.handle.net/10803/145481.
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3,4-methylenedioxymethamphetamine (MDMA, ecstasy) is one of the most abused recreational
drugs in the world. It has been extensively reported that this drug inhibits its own metabolism by
inhibiting a polymorphic liver enzyme, CYP2D6, which is responsible for the clearance of one
quarter of drugs used in therapeutics. This phenomenon has important clinical implications,
since MDMA users display a higher prevalence of psychopathology, particularly of mood
disorders, compared to control population. Importantly, these psychiatric diseases are treated
with drugs most of them substrate of this enzyme. In addition, it is not elucidated how MDMA
is still metabolically cleared even after repeated drug doses. Therefore, the first part of this
thesis was focused on studying the metabolic autoinhibition by MDMA assessing several liver
enzyme activities in men and women.
Although MDMA pharmacology is well established, is it still not clear which is the mechanism
of action of the drug. MDMA interacts with the serotonergic system at several levels, but
nowadays is technically difficult to study the serotonergic function in living human brain.
Imaging methods are limited by a number of factors. Thus, it would be advantageous to have a
reliable peripheral index of the serotonergic activity in the blood. The second part of this thesis
presents the development of several approaches aimed to assess whether the serotonin
transporter in platelets can be used as a peripheral biomarker for central serotonergic activity,
and determine if it plays any role in drug mechanism of action.La 3,4-metilendioximetanfetamina (MDMA, èxtasi) és una de les drogues més consumides al món. Aquesta droga inhibeix el seu propi metabolisme, inhibint un enzim polimòrfic del fetge, el CYP2D6, que és el responsable de l’eliminació d’una quarta part dels medicaments. Aquest fet té implicacions clíniques rellevants, ja que els consumidors de MDMA presenten una prevalença de psicopatologia més alta respecte a la població no consumidora, i moltes de la patologies psiquiàtriques es tracten amb fàrmacs substrats d’aquest enzim. A més, encara no s’ha discernit com aquesta droga pot ser eliminada de l’organisme, inclús després d’haver-ne consumit dosis de manera repetida. Així doncs, la primera part d’aquesta tesi es centra en estudiar l’autoinhibició de la MDMA determinant l’activitat de diferents enzims del fetge, en homes i dones. Encara que la farmacologia de la MDMA està descrita a fons, no està del tot clar quin és el seu mecanisme d’acció. La MDMA interactua amb el sistema serotonèrgic de diverses maneres, però avui en dia és molt difícil estudiar tècnicament el sistema serotonèrgic en el cervell humà. Les tècniques d’imatge estan limitades per molts factors, i per tant, seria molt útil tenir un índex perifèric a la sang de l’activitat serotonèrgica al sistema nerviós central. La segona part d’aquest tesi s’enfoca en el desenvolupament de tècniques per determinar a diferents nivells si el transportador de la serotonina a les plaquetes podria ser un bon biomarcador perifèric de la seva activitat al cervell, i d’aquesta manera veure si el sistema serotonèrgic està implicat en el mecanisme d’acció de la MDMA.
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McGonigle, Ian Vincent. "Molecular pharmacology of an insect GABA receptor." Thesis, University of Cambridge, 2010. https://www.repository.cam.ac.uk/handle/1810/226857.
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Cys-loop receptors are ligand-gated ion channels that are involved in fast synaptic neurotransmission in the central and peripheral nervous system. The Cys-loop receptor RDL ('resistant to dieldrin') is a GABA-gated chloride channel from Drosophila melanogaster and is a major target site for insecticides. The aim of this dissertation was to characterise RDL receptors with particular focus on the agonist binding site. To assess the potency of a range of GABA analogues on RDL receptors, I expressed receptors in Xenopus oocytes and used voltage-clamp electrophysiology to detect receptor responses. I carried out computational modelling of these analogues to determine the dipole separation distances and atomic charges. Computational calculations and functional experiments revealed that agonists require a charged ammonium and an anionic centre, with the most potent agonists having a dipole separation distance of ~5 Å. I made a homology model of the extracellular domain of RDL and docked the active analogues into the putative binding site. I then conducted mutagenesis studies to test the accuracy of this model. Functional data from mutagenesis studies broadly support the location of GABA within this model. This model may be useful for further structure-activity studies and rational drug design. Natural compounds from the traditional Chinese medicine 'Ginkgo biloba' (ginkgolide A, ginkgolide B and bilobalide) have potent insecticidal properties and are similar in structure to picrotoxin. I tested the effect of these compounds on RDL receptor function using voltage-clamp electrophysiology. All compounds were found to inhibit RDL receptor function. I probed the binding site of these compounds using site-directed mutagenesis and electrophysiology. Mutations to the 2'A and 6'T channel-lining (M2) residues greatly reduced the potency of these compounds. I then made a homology model of the transmembrane domain of RDL and docked these compounds into the channel. Compounds docked into the channel pore close to the 2' and 6' channel-lining residues and H-bonding interactions were detected at these locations. Ginkgolides are therefore antagonists of RDL receptors, binding in the channel close to the 2' and 6' residues and this may be the mechanism underlying their potent insecticidal properties. The 5-HT3 receptor is a member of the Cys-loop receptor family and shows homology to RDL receptors. To explore different techniques for studying Cys-loop receptor function I assessed the functionality of two brain derived transcripts of the 5-HT3B subunit (Br1 and Br2) using single-channel electrophysiology and a fluorometric assay. Receptors containing Br1 were found to have a conductance identical to the 5-HT3B subunit whilst Br2 receptors were found not to be expressed. This finding has implications for 5-HT3 brain signalling, in which Br1 may play an important role. In conclusion, work here has described how agonists bind to and activate RDL GABA receptors and I have identified a candidate mechanism for the potent insecticidal properties of Ginkgo biloba extracts. I have also confirmed that 5-HT3 receptor brain transcript Br1 forms functional channels with similar properties to the 5-HT3B subunit.
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Bolton, John Francis. "Urinary tract smooth muscle physiology and pharmacology." Thesis, University of Bristol, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.432685.
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Hand, C. W. "Studies on the human pharmacology of opiates." Thesis, University of Oxford, 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.379946.
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Mallon, Andrew Peter. "An investigation of NMDA receptor subunit pharmacology." Thesis, University of Glasgow, 2004. http://theses.gla.ac.uk/3127/.
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N-Methyl-D-aspartate (NMDA) receptors are critically involved in synaptic transmission, neural development and various forms of neuronal plasticity including long-term potentiation (LTP) and long-term depression (LTD). They are also involved in the production of neuronal damage following excessive activation by glutamate released as a result of hypoxia or ischaemia. Each heteromeric receptor includes one or two NRl subunits, at least two of the four NR2A-D subunits and less usually the NR3AJB subunits. This study demonstrates that the putative NR2B subunit-containing NMDA receptor antagonist Ro 25-6981 potentiates the effects ofNMDA on rat hippocampal slices. The NR2A subunit antagonist PEAQX blocks the effects of NMDA alone and the potentiated response following Ro 25-6981 application. Furthermore, Ro 25-6981 was not neuroprotective as reported previously but unexpectedly precipitated excitotoxicity. The potentiating effect of Ro 25-6981 required around 20 minutes to become apparent, took a further 30 minutes to reach its maximum effect and was irreversible. It was not prevented by staurosporine (a broad-spectrum protein kinase inhibitor), okadaic acid (a potent inhibitor of the serine/threonine protein phosphatases types 1 and 2A) or anisomycin (a protein synthesis inhibitor). However, the potentiation was prevented by cyclosporin A (an inhibitor of Ca2+/calmodulin-dependent phosphatase 2B [calcineurin]). The results indicate that in an intact neuronal network, NR2B subunits tonically gate NR2A subunit-containing receptor function by a negative coupling mechanism involving ca1cineurin activation. NMDA receptor-dependent LTP induced by high frequency stimulation was prevented by PEAQX, an NR2A antagonist. Ro 25-6981 was unable to prevent L TP induction but was associated with a marginal reduction in the magnitude of LTP induced. There is evidence for the binding of homoquinolinic acid to an NMDAinsensitive novel binding site in the brain. This study investigated the pharmacology of homoquinolinate on the evoked field excitatory synaptic potential (fEPSP) recorded from the CAl area of rat hippocampal slices. Two NMDA receptor agonists, quinolinic acid 150/lM and homoquinolinic acid 2.5/lM, caused an approximately 50% inhibition of fEPSP slope. Paired-pulse studies suggested there might be a presynaptic component to this action that is independent of presynaptic adenosine Al receptor activation. The broad-spectrum EAA antagonist kynurenic acid and the NMDA receptor blockers 2-amino-5-phosphonopentanoic acid and dizocilpine could prevent the inhibition of fEPSP slope. None of these antagonists revealed any other NMDA-insensitive activity of homoquinolinic acid. The use of 2-carboxy-3-carboxymethylquinoline (CCMQ) to displace the reported NMDA-insensitive binding had no effect on either baseline fEPSP slope or the depression caused by homoquinolinic acid. It was also apparent that responses to homoquinolinic acid were blocked completely by the NR2A subunit-selective antagonist PEAQX, but not by the NR2B subunit-selective blocker Ro 25-6981. It was concluded that the novel binding site for homoquinolinic acid does not affect synaptic potentials in the hippocampus and that homoquinolinic acid appears to be a selective agonist at NMDA receptors that include the NR2A subunit. Although the NR2B agonist site may be maximally activated under normal conditions and therefore it is not possible to observe any additional effects upon fEPSP slope. This study next investigated the negative coupling between NR2B and NR2A subunit-containing receptors, combining the NR2A1B subunit selective agonist HQA with the NR2B and NR2A selective antagonists Ro 25-6981 and PEAQX. The negative coupling observed previously with applications of NMDA was also seen using HQA and QA. The potentiation of responses to HQA by Ro 25-6981 application was also associated with an enhancement of paired-pulse interactions. The subsequent application of PEAQX was able to block both the depression of fEPSP slope and the associated enhancement of paired-pulse interactions. The presence of a presynaptic element during applications of HQA alone and potentiated responses alike and the blockade of these effects by PEAQX suggests the NR2A subunit-containing NMDA receptor is responsible for the presynaptic effects acting either directly at presynaptic sites or indirectly at postsynaptic sites leading to the raising of a retrograde signal. The NR2B subunit in both its activated and antagonised state was associated with enhancements in paired-pulse interactions which suggest that it is not able to modulate directly the presynaptic element. However, whilst paired-pulse interactions are generally accepted to he presynaptic phenomena, it does not follow that postsynaptic effects cannot influence the appearance of changes in these interactions in field recordings. The absence of any observable difference between HQA, QA and NMDA results suggests that the NR2D subunit is not obviously involved in these processes.
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Whittaker, Steven Robert. "The molecular pharmacology of purine CDK inhibitors." Thesis, Institute of Cancer Research (University Of London), 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.404908.
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Croughton, Karen. "Novel pharmacology of the lipophilic antifolate methylbenzoprim." Thesis, University of Nottingham, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.368236.
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Roberts, Claire. "5-HT terminal autoreceptor : pharmacology and function." Thesis, University of Nottingham, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.263094.
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Brown, Andrew M. G. "Biochemistry, tissue culture and pharmacology of Tanacetum." Thesis, University of Nottingham, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.363563.
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Kasorn, Anongnard. "The molecular pharmacology of lysophosphatidic acid receptors." Thesis, University of Nottingham, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.441003.
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Alyami, A. M. "Pharmacology of benzodiazepines and GABA in intestine." Thesis, University of Bradford, 1988. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.384251.
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Barnes, Matthew Joseph. "The cellular pharmacology of antifolates in leukaemia." Thesis, University of Newcastle Upon Tyne, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.244470.
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Yule, S. M. "The clinical pharmacology of cyclophosphamide in children." Thesis, University of Newcastle Upon Tyne, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.309831.
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Pearson, Hugh Anthony. "Physiology and pharmacology of insect calcium channels." Thesis, University College London (University of London), 1990. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.308295.
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Milton, Kevin Ashley. "The clinical and biochemical pharmacology of halofantrine." Thesis, University of Liverpool, 1990. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.291722.
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Choonara, I. A. "Clinical pharmacology of warfarin and vitamin K." Thesis, University of Liverpool, 1986. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.383440.
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Clark, Kenneth Lyle. "Pharmacology of renal dopamine and angiotensin receptors." Thesis, Open University, 1991. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.293275.
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Dopamine and angiotensin II (Ang II) are naturally occurring molecules with profound but contrasting effects in the kidney. This study aimed to increase knowledge of the pharmacology and physiology of renal dopamine and angiotensin receptors. Little evidence was found to the presence of dopamine DA1 receptors, mediating dilatation, or angiotensin receptors, mediating constriction, in canine isolated main branch, interlobar, or arcuate renal artery rings. However, in anaesthetised dogs, renal vascular angiotensin and dopamine receptors were clearly demonstrated, suggesting that they are located primarily on renal resistance vessels. In anaesthetised dogs, intra-renal artery (i.r.a.) infusion of the selective dopamine DA1 agonist, fenoldopam, caused local dose-related vasodilatation, and a diuresis which appeared to be due to reduced tubular reabsorption. No evidence was found to suggest that subtypes of renal vascular and tubular dopamine DA1 receptors occur, since the renal vasodilator and diuretic responses to fenoldopam were blocked to a similar extent by the DA1 receptor antagonist, SCH 23390. The inhibitory effect of fenoldopam on renal tubular sodium reabsorption, and its vasodepressor activity were enhanced when angiotensin converting enzyme was inhibited. Thus, these effects may normally be limited by fenoldopam-induced renin release. Attempts to characterise renal tubular dopamine receptors in anaesthetised cats were unfruitful. Renal dopamine DA1 receptors could not be demonstrated in this species, and in contrast to literature reports, the diuretic response to intravenous infusions of dopamine seemed to be mediated by -adrenoceptors. In the renal and mesenteric vascular beds of anaesthetised cats, comparisons were made of the vasoconstrictor potency of Ang II relative to Ang III, and of the antagonist potency (versus Ang II) of the peptide antagonists, lle^7-Ang III and saralasin, and the novel, non-peptide angiotensin AT_1 receptor antagonist, DuP 753. The results suggest that angiotensin receptors in the renal vascular bed share similar broad characteristics to those in the mesenteric. Using lle^7-Ang III, DuP 753, and the non-peptide angiotensin AT_2 receptor ligand, PD 123,177, renal angiotensin receptor pharmacology was further studied in anaesthetised dogs. Tonic effects of endogenous Ang II on renal haemodynamic/tubular function, blood pressure, and aldosterone release appeared to be mediated by angiotensin AT_1 receptors. Similarly, AT_1 receptors appeared to mediate the effects of exogenous Ang II infusions (i.r.a.) on renal haemodynamic and tubular function. However, evidence was found suggesting the presence of subtypes of angiotensin AT_1 receptors on the renal arterioles. Moreover, the AT_2 ligand, PD 123,177 caused some inhibition of renal vasoconstrictor responses to high doses of Ang II, possibly indicating further heterogeneity of renal vascular angiotensin receptors. These findings, and their potential implications, are critically discussed.
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Ridley, John Malcolm. "Pharmacology of the HERG K⺠channel." Thesis, University of Bristol, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.411068.
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