title: Thromboxane-induced renal vasoconstriction is mediated by the ADP-ribosyl cyclase CD38 and superoxide anion.
abstract: 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.
authors.affiliation: Dept. of Cell Biology and Physiology, Rm. 6341, Medical Biomedical Research Bldg., CB no. 7545, School of Medicine, Univ. of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7545. nmoss@email.unc.edu.
authors.forename: Nicholas G
authors.initials: NG
authors.lastname: Moss
authors.forename: Paul A
authors.initials: PA
authors.lastname: Vogel
authors.forename: Tayler E
authors.initials: TE
authors.lastname: Kopple
authors.forename: William J
authors.initials: WJ
authors.lastname: Arendshorst
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D051997:ADP-ribosyl Cyclase 1 / Q000172:deficiency / Q000502:physiology*; D000818:Animals; D001160:Arterioles / Q000187:drug effects; D003497:Cyclic N-Oxides / Q000494:pharmacology; D007668:Kidney / Q000098:blood supply* / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D017482:Receptors, Thromboxane / Q000187:drug effects / Q000502:physiology; D013113:Spin Labels; D013481:Superoxides / Q000494:pharmacology*; D014661:Vasoconstriction / Q000187:drug effects*
chemical_list: D003497:Cyclic N-Oxides; D008562:Membrane Glycoproteins; D017482:Receptors, Thromboxane; D013113:Spin Labels; D013481:Superoxides; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; C498155:Cd38 protein, mouse; D051997:ADP-ribosyl Cyclase 1; C001803:tempol
keywords: O2·- production; U-46619; afferent arteriole; kidney; oxidative stress; renal circulation; renal vascular resistance; superoxide dismutase; tempol; thromboxane prostanoid receptor