(Hypertension. 2000;35:231.)
© 2000 American Heart Association, Inc.
Scientific Contributions |
Increased Nitrovasodilator Sensitivity in Endothelial Nitric Oxide Synthase Knockout Mice
Role of Soluble Guanylyl Cyclase
From the Institut für Kardiovaskuläre Physiologie (R.P.B., F.-H.S.-W., M.A., A.M., R.B), Klinikum der J.W. Goethe-Universität, and the Institut für Herz- und Kreislaufphysiologie (A.G.), Heinrich-Heine Universität Düsseldorf, Germany.
Correspondence to Ralf P. Brandes, MD, Institut für Kardiovaskuläre Physiologie, Klinikum der J.W. Goethe-Universität, Theodor-Stern-Kai 7, 60596 Frankfurt/Main, Germany. E-mail R.Brandes{at}em.uni-frankfurt.de
Abstract—Endogenously produced nitric oxide (NO) modulates nitrovasodilator-induced relaxation. We investigated the underlying mechanism in wild-type (WT) mice and endothelial NO synthase knockout (eNOS-/-) mice to determine whether a chronic lack of endothelial NO alters the soluble guanylyl cyclase (sGC) pathway. In aortic segments from eNOS-/- mice, the vasodilator sensitivity to sodium nitroprusside (SNP) was significantly greater than that in WT mice. There was no difference in sensitivity to the G-kinase I activator 8-para-chlorophenylthio-cGMP or to cromakalim. N
-Nitro-L-arginine had no effect on the SNP-induced relaxation in eNOS-/- but increased the sensitivity in WT mice so it was no longer different than that of eNOS-/-. Basal cGMP levels in aortic rings were significantly lower in eNOS-/- mice than in WT mice. SNP (300 nmol/L) induced a significantly greater cGMP accumulation in eNOS-/- mice than in WT mice. The maximal SNP-induced (10 µmol/L) increase in cGMP was similar in both strains. SNP-stimulated sGC activity was significantly greater in eNOS-/- mice than in WT mice. Incubation of aortic segments from WT mice with N-nitro-L-arginine increased sGC activity, an effect prevented by coincubation with SNP (10 µmol/L). The aortic expressions of the sGC 
1 and ß1 subunits in WT and eNOS-/- mice were identical as determined with Western blot analysis. These data suggest that chronic exposure to endothelium-derived NO, as well as acute exposure to nitrovasodilator-derived NO, desensitizes sGC to activation by NO but does not alter sGC expression. Both the acute cessation of endothelial NO formation in WT mice and the chronic deficiency of NO in eNOS-/- mice restore the NO sensitivity of sGC and enhance vascular smooth muscle relaxation in response to nitrovasodilator agents.
Key Words: nitric oxide • mice • genes • vasodilator agents
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