Effects of the angiotensin AT1 receptor antagonist GRI38950 on haemodynamic function in dogs.
1. The antagonist activity of the angiotensin AT1 receptor antagonist, GR138950, and its haemodynamic effects have been investigated in beagle dogs. 2. In four anaesthetized dogs, GR138950 (0.1, 1 and 10 mg kg-1 i.v.), displaced dose-response curves to angiotensin II (AngII) rightwards, in a parallel manner; GR138950, at 1 mg kg-1 i.v., produced a 15-fold displacement of the AngII dose-response curve. In four conscious dogs, GR138950 (1 mg kg-1 i.v. or p.o.) antagonized AngII, and produced rightward and parallel displacements of the AngII dose-pressor response curves. Maximum displacements of approximately 33- and 16-fold occurred at 1 h after intravenous and 5 h after oral administration, respectively. The inhibitory effect of GR138950 was long lasting; AngII dose-pressor response curves were still displaced by 10-fold from control values, 24 h after intravenous or oral administration of GR138950. 3. In comparison with its vehicle, GR138950 (0.1-10 mg kg-1) caused a significant decrease in resting blood pressure as a consequence of a significant decrease in total peripheral resistance in anaesthetized dogs. Effects on cardiac output, stroke volume and heart rate were not significantly different between GR138950- or vehicle-treated dogs. 4. Compared with vehicle, GR138950 administration did not significantly affect blood flow to the mesenteric and femoral vascular beds but did significantly increase blood flow to the renal vascular bed. Vascular resistance of the femoral bed was unaffected but that of the mesenteric and renal vascular beds was significantly reduced by GR138950, compared with the changes produced by vehicle treatment. 5. Compared with vehicle, left ventricular end diastolic pressure was significantly reduced by GR138950, but GR138950 had no significant effect on indices of cardiac contractility (+dP/dtmax and +dP/dt@40) or cardiac relaxation during early diastole (-dP/dt). 6. In conclusion, GR138950 acts as a competitive, surmountable antagonist at vascular angiotensin II receptors in beagle dogs. GR138950 reduced arterial blood pressure by reducing total peripheral resistance, attributable partly to reduction in resistance in the mesenteric and renal vascular beds. GR138950 reduced left ventricular end diastolic pressure whilst having no direct effect on cardiac contractility or relaxation.
Hunt
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Biology Research Division, Glaxo Wellcome Medicines Research & Development Ltd, Glaxo Wellcome Medicines Research Centre, Stevenage, Herts, UK.
Hilditch
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Drew
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GM
D000284:Administration, Oral; D000804:Angiotensin II / Q000037:antagonists & inhibitors / Q000494:pharmacology; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001572:Benzofurans / Q000008:administration & dosage / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D002302:Cardiac Output / Q000187:drug effects; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005263:Femoral Artery / Q000187:drug effects / Q000502:physiology; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D007275:Injections, Intravenous; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000502:physiology; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009200:Myocardial Contraction / Q000187:drug effects; D012039:Regional Blood Flow / Q000187:drug effects; D012077:Renal Artery / Q000187:drug effects / Q000502:physiology; D013318:Stroke Volume / Q000187:drug effects; D014655:Vascular Resistance / Q000187:drug effects
D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D001572:Benzofurans; D000804:Angiotensin II; C089586:saprisartan potassium