Effect of dopamine beta-hydroxylase inhibition on systemic hemodynamics in conscious, spontaneously hypertensive rats.
The acute and chronic effects of a potent and selective dopamine beta-hydroxylase inhibitor, SK&F 102698 [1-(3,5-difluorobenzyl)imidazole-2-thiol], on systemic hemodynamic variables were assessed in chronically instrumented spontaneously hypertensive and normotensive Wistar rats. The changes observed in the hypertensive rats were compared with those obtained by vehicle in a different group of rats. Following intragastric administration of SK&F 102698 (75 mg/kg), blood pressure and cardiac output decreased gradually in both strains of rats, while total peripheral vascular resistance remained unchanged. The antihypertensive effect of repeated daily administration of SK&F 102698 in the hypertensive rats was sustained for the duration of treatment. During the acute phase, the decrease in cardiac output was due to bradycardia. In addition, as a result of hemodynamic changes, SK&F 102698 significantly reduced the minute work output of the heart. The results indicate that SK&F 102698 lowers blood pressure primarily by decreasing cardiac output.
Gellai
M
M
Department of Pharmacology, Smith Kline Beecham Pharmaceuticals, King of Prussia, Pa.
DeWolf
R E
RE
Ruffolo
R R
RR
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D002302:Cardiac Output / Q000187:drug effects*; D004299:Dopamine beta-Hydroxylase / Q000037:antagonists & inhibitors*; D004334:Drug Administration Schedule; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D014677:Pharmaceutical Vehicles / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D011919:Rats, Inbred Strains; D013997:Time Factors; D014655:Vascular Resistance / Q000187:drug effects*
C052414:1-(3,5-difluorobenzyl)imidazole-2-thiol; D007093:Imidazoles; D014677:Pharmaceutical Vehicles; D004299:Dopamine beta-Hydroxylase