ADP‐ribosyl Cyclase (CD38) and Superoxide Mediate Renal Vasoconstriction Due to Thromboxane Receptor (tpr) Activation

The calcium mobilizing second messenger, cyclic ADP ribose (cADPR, the product of ADP‐ribosyl cyclase) is an important component in the renal vasoconstrictor response to G‐protein coupled receptor stimulation. The role of cADPR in TpR‐mediated renal vasoconstriction was tested with the stable thromboxane mimetic U‐46619 in wild type (WT) and CD38 −/− mice. Arterial blood pressure (ABP) and renal blood flow (RBF) were not different between WT and CD38−/− mice during basal conditions. Bolus injections of U‐46619 (10–50ng in 10μl) caused a dose‐dependent decrease in RBF and increase in ABP in both strains but to a lesser extent for both in CD38−/− mice. Compared to control, 50 ng of U‐46619 reduced RBF by 37±4% and 22±3% and increased ABP by 36±6% and 22±6% in WT and CD38−/− mice, respectively (p<0.05 n=7). Intravenous infusion of Tempol to scavenge superoxide reduced renal vasoconstrictor response to U‐46619 by 40–45% in both strains of mice. The data show that the renal vasoconstriction produced by TpR stimulation is mediated by ADP‐ribosyl cyclase activity and depends upon superoxide for full expression. The comparable inhibition of the RBF response by Tempol in both strains of mice indicates that the vasoconstrictor action of superoxide is independent of CD38 and cannot explain the attenuated response to TpR activation in CD38−/− mice. Funded by NIH grant RO1 HL‐02334