Blockade and stimulation of renal, adrenal, and vascular angiotensin II receptors with 1-Sar, 8-Ala angiotensin II in normal man

Abstract

We have assessed the capacity of an analogue of angiotensin II (A II), 1-Sar, 8-Ala A II (P113) in normal man to stimulate and block responses to A II in four systems: blood pressure was monitored directly from an arterial catheter, and renal blood flow was measured with 133Xe and arterial renin and aldosterone concentrations by radioimmunoassay. The 31 normal subjects were in balance on a daily intake of 200 meg sodium and 100 meq potassium to suppress endogenous renin. P113 administered intravenously induced a dose-related renal blood flow reduction, with a threshold dose of 0.1 mug/kg/min. This dose also induced a small but significant increase in arterial blood pressure and plasma aldosterone as well as a reduction in plasma renin activity. In contrast to its effect on the renal vasculature, no tendency to a progressive response in the latter three parameters was noted as the P113 dose was increased 30-fold, to 3.0 mug/kg/min. P113 also reduced the clearance of para-aminohippurate, creatinine, sodium, and potassium, a pattern similar to that induced by A II. P113 at 0.1 mug/kg/min reduced significantly the blood pressure and renal vascular and aldosterone responses to graded doses of A II. Higher P113 doses totally obliterated all three responses to A II infused at 10 ng/kg/min, a dose that provides arterial A II concentrations in the range found in angiotensin-mediated hypertension. When A II was infused first, to induce a pressor, renal vascular, and aldosterone response, P113 induced a dose-related reversal of the response in each system. In conclusion, P113 is a partial agonist in normal man, inducing an angiotensin-like response in settings in which endogenous A II is not playing a tonic role, and displaying dominant antagonist activity in settings in which A II is active. Moreover, the studies suggest that the receptors mediating the responses to A II are different in the renal vasculature and other systemic vascular beds. The adrenal receptor must also differ. This agent should be useful in dissecting the role of A II in diseases characterized by hypertension or abnormalities of renal and adrenal function.