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Title: Pharmacology of renal dopamine and angiotensin receptors
Author: Clark, Kenneth Lyle
ISNI:       0000 0001 3555 3324
Awarding Body: CNAA
Current Institution: Open University
Date of Award: 1991
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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.
Supervisor: Not available Sponsor: Glaxo Group Research
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Pharmacology & pharmacy & pharmaceutical chemistry