Angiotensin II causes renal vasoconstriction in mice with AT1A
receptor deleted by gene targeting
The aim of this study was to determine whether angiotensin II (Ang II) would affect renal blood flow in AT1A knockout mice. Acute renal hemodynamic studies were performed on 30-40 g mice with or without AT1A receptor during pentobarbital anesthesia. Blood flow in the renal artery was measured by a small V-shaped non-cannulating ultrasonic flow probe and a Transonic flowmeter. Mean arterial pressure averaged 90 and 68 mmHg, respectively, in mice with and without AT1A receptor. Basal renal blood flow was similar in the two groups, averaging 5 ml/min/g kidney wt. A vasoactive agent was injected as a 10 μl bolus into the left renal artery via a femoral arterial catheter. Injection of Ang II produced a transient, dose-dependent reduction in renal blood flow in wild-type and AT1A knockout mice. The effects were localized to the renal vasculature as vasoconstriction was independent of a change in systemic arterial pressure. The blood flow response in the knockout animals, however, was less pronounced (-5% for 0.1 ng and -15% for 1 ng Ang II) relative control responses. To minimize the modulatory action of endogenous Ang II, the inhibitor of renin activity CP-71362 (5 μg/kg/min) was infused into renal artery. Reanl vascular reactivity to administered Ang II increased during renin inhibition. Ang II (1 ng) decreased renal blood flow by -28% during control and by -45% of basal flow during renin hihibition in wild-type mice; Ang II -induced changes in blood flow increased from -11 to -25% during inhibition of Ang II formation in AT1A-knockout mice. Co-administration of an AT1 receptor antagonist (losartan or candesartan (1-1000 ng) with Ang II (1 ng) elicited dose-dependent inhibition of Ang II effects, with maximum blockage of 70-80% of the Ang II effect in both groups of mice. In conclusion, Ang II can elicit renal vasoconstriction AT1A-knockout mice. Mediation by the AT1B receptor is suggested by inhibition by an AT1 receptor antagonist. The 20% effect of Ang II remaining during near maximum AT1 receptor antagonism appears to be mediated by a non-AT1 receptor.
Ruan, X; Oliverio, MI; Coffman, T; Arendshorst, WJ
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