Acute myocardial and vascular responses to specific angiotensin II antagonism in the spontaneously hypertensive rat.
As the AT1 receptor is the primary angiotensin II receptor in the myocardium and vasculature, we assessed the acute myocardial and vascular response to the AT1 angiotensin II antagonist losartan in the spontaneously hypertensive rat (SHR) to determine the contribution of angiotensin II in this genetic form of hypertension. In a preliminary dose response study, which evaluated losartan at 1.0, 3.0, and 10 mg/kg, 10 mg/kg uniformly lowered blood pressure. In a second group of experiments, 10 mg/kg also completely attenuated the pressor effects of angiotensin II administration. In nine adult SHR, intravenous losartan, 10 mg/kg, was given, with hemodynamics measured immediately and at steady-state intervals to delineate the hemodynamic response to angiotensin II antagonism. Losartan significantly lowered systolic, diastolic, and mean blood pressures, yet heart rate was unchanged. Cardiac function, as assessed by cardiac output and blood flow acceleration, demonstrated only transient increases which were not sustained during steady-state blood pressure reduction. Significant increases of peak blood flow and pulse pressure were sustained throughout the blood pressure response. At immediate and steady-state determinations, system vascular resistance and characteristic aortic impedance were significantly reduced with losartan (both P < .01). In addition, concomitant reduction of the wave reflectance index also occurred, achieving significance at steady state (P < .05). These changes demonstrate that the AT1 angiotensin II receptor contributes to both central and peripheral vasoconstriction in the spontaneously hypertensive rat. Absence of sustained increase of cardiac output and blood flow acceleration are consistent with inhibition of the previously reported positive inotropic effect of angiotensin II.
Cody
R J
RJ
Department of Medicine, Ohio State University Medical Center, Columbus 43210, USA.
Binkley
P F
PF
Haas
G J
GJ
Brown
D M
DM
D000804:Angiotensin II / Q000037:antagonists & inhibitors* / Q000502:physiology; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D004562:Electrocardiography; D006321:Heart / Q000187:drug effects*; D006439:Hemodynamics / Q000187:drug effects* / Q000502:physiology; D006973:Hypertension / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology*; D007093:Imidazoles / Q000494:pharmacology*; D019808:Losartan; D008297:Male; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D013777:Tetrazoles / Q000494:pharmacology*; D014661:Vasoconstriction / Q000187:drug effects
D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D001713:Biphenyl Compounds; D007093:Imidazoles; D013777:Tetrazoles; D000804:Angiotensin II; D019808:Losartan