Thromboxane-induced renal vasoconstriction is mediated by the ADP-ribosyl cyclase CD38 and superoxide anion.
The present renal hemodynamic study tested the hypothesis that CD38 and superoxide anion (O2(·-)) participate in the vasoconstriction produced by activation of thromboxane prostanoid (TP) receptors in the mouse kidney. CD38 is the major mammalian ADP-ribosyl cyclase contributing to vasomotor tone through the generation of cADP-ribose, a second messenger that activates ryanodine receptors to release Ca(2+) from the sarcoplasmic reticulum in vascular smooth muscle cells. We evaluated whether the stable thromboxane mimetic U-46619 causes less pronounced renal vasoconstriction in CD38-deficient mice and the involvement of O2(·-) in U-46619-induced renal vasoconstriction. Our results indicate that U-46619 activation of TP receptors causes renal vasoconstriction in part by activating cADP-ribose signaling in renal resistance arterioles. Based on maximal renal blood flow and renal vascular resistance responses to bolus injections of U-46619, CD38 contributes 30-40% of the TP receptor-induced vasoconstriction. We also found that the antioxidant SOD mimetic tempol attenuated the magnitude of vasoconstriction by U-46619 in both groups of mice, suggesting mediation by O2(·-). The degree of tempol blockage of U-46619-induced renal vasoconstriction was greater in wild-type mice, attenuating renal vasoconstriction by 40% compared with 30% in CD38-null mice. In other experiments, U-46619 rapidly stimulated O2(·-) production (dihydroethidium fluorescence) in isolated mouse afferent arterioles, an effect abolished by tempol. These observations provide the first in vivo demonstration of CD38 and O2(·-) involvement in the vasoconstrictor effects of TP receptor activation in the kidney and in vitro evidence for TP receptor stimulation of O2(·-) production by the afferent arteriole.
['Moss|Nicholas G|NG|', 'Vogel|Paul A|PA|', 'Kopple|Tayler E|TE|', 'Arendshorst|William J|WJ|']
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid D051997:ADP-ribosyl Cyclase 1 D000818:Animals D001160:Arterioles D003497:Cyclic N-Oxides D007668:Kidney D008562:Membrane Glycoproteins D051379:Mice D008810:Mice, Inbred C57BL D017482:Receptors, Thromboxane D013113:Spin Labels D013481:Superoxides D014661:Vasoconstriction
kidney U-46619 renal vascular resistance tempol afferent arteriole O2·- production oxidative stress renal circulation superoxide dismutase thromboxane prostanoid receptor