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Renal Vascular Reactivity in Mice

AngII-Induced Vasoconstriction inAT_1A Receptor Null Mice

XIAOPING RUAN^*, MICHAEL I. OLIVERIO, THOMAS M. COFFMAN and WILLIAM J. ARENDSHORST^*

^* Department of Cell and Molecular Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
Department of Medicine, Duke University, Durham, North Carolina.

Correspondence to Dr. William J. Arendshorst, Department of Cell and Molecular Physiology, CB #7545, School of Medicine, Room 152, Medical Sciences Research Building, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7545. Phone: 919-966-1067; Fax: 919-966-4960; E-mail: arends{at}med.unc.ed

Abstract

Abstract. The present study describes methodology and its application to evaluate renal reactivity in acute studies on anesthetized mice. Renal blood flow (RBF) was measured using an ultrasonic transit-time flowmeter and a non-cannulating V-shaped probe. An intrarenal artery injection technique established feasibility and reproducibility of studies of renal vascular reactivity to angiotensin II (AngII) in adult wild-type mice. The study also examined whether AngII would affect RBF in mice lacking AT_1A receptors due to gene targeting. Mean arterial pressure averaged 83 and 62 mmHg, respectively, in mice with and without AT_1A receptors. The RBF was similar in both groups, averaging 7 ml/min per g kidney wt. AngII injection (10-µl bolus) into the renal artery produced transient, dose-dependent, selective reductions in RBF in AT_1A knockout mice as well as wild-type mice. The response was considerably greater in mice with AT_1A receptors: 10% for 0.1 ng, 30% for 1 ng, and 45% for 5 ng AngII in control animals versus respective decreases of 6, 15, and 17% in knockout mice. In other studies, angiotensin-converting enzyme (captopril) or renin (CP-71362-14) was inhibited. During inhibition of AngII formation, renal vascular reactivity to AngII increased twofold in both groups. Coadministration of the AT₁ receptor antagonist losartan (1 to 1000 ng) elicited dose-dependent inhibition of AngII effects, with near maximum blockage of 80 to 90% in both groups of mice. The putative AT₂ receptor antagonist PD 123319 inhibited 30 to 40% of AngII-induced vasoconstriction, whereas CGP 42112 had no effect in either group. In conclusion, AngII can elicit renal vasoconstriction, albeit attenuated, in AT_1A knockout mice. The weaker RBF effects are most likely due to the absence of the AT_1A receptor. Inhibition of the response by AT₁ receptor antagonist suggests mediation by the AT_1B receptor in these animals. The residual constrictor effect observed during AT₁ receptor blockade and sensitive to PD 123319 appears to be mediated by a non-AT₁ receptor.

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