Phenotypic Characterization of Acute Systemic and Renal Vascular Responses to Angiotensin II, Norepinephrine, and Endothelin‐1 in Mice Lacking the ADP Ribosyl Cyclase CD38

Abstract

Vasoconstriction is mediated by increases in cytosolic calcium concentration ([Ca2+]i). ADP ribosyl cyclases regulate [Ca2+]i via metabolite activation of Ca2+‐induced Ca2+ release. We tested the hypothesis that mice lacking CD38, the predominant mammalian ADP ribosyl cyclase, have attenuated acute hemodynamic responses to angiotensin II (Ang II), norepinephrine (NE), and endothelin‐1 (ET‐1). Despite similar body wt, kidney wt, heart wt, anesthetized mean arterial pressure (MAP), and hematocrit (P>0.1, n≥8), CD38−/− mice (from Dr. Frances Lund) had decreased heart rate and urinary excretion (P<0.01) compared to wild type controls. Using an ultrasonic flow transducer and pressure transducer, we measured renal blood flow (RBF) and MAP in anesthetized mice during iv bolus injections of vasoconstrictor agents. Maximum reductions in RBF produced by Ang II (4–40 ng), NE (2–20 ng), or ET‐1 (20 ng) were attenuated 30–70% in CD38−/− mice (P<0.05) vs. control mice. A trend was seen toward a weaker peak MAP response to Ang II (0.05<P<0.1), but not NE or ET‐1 (P>0.2). We conclude that CD38 contributes to roughly 50% of acute renal vasoconstriction elicited by Ang II, NE, and ET‐1. Our studies indicate participation of CD38 in RBF responses to all agonists tested, while an impaired systemic pressor response was selective to Ang II. CD38 appears to play a more important role in the renal vasculature than other vascular beds.