Increased nitrovasodilator sensitivity in endothelial nitric oxide synthase knockout mice - Role of soluble guanylyl cyclase

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 sensitivi ty 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-omega-Nitro-L-arginine had n o effect on the SNP-indluced relaxation in eNOS(-/-) but increased the sens itivity in WT mice so it was no longer different than that of eNOS(-/-). Ba sal cGMP levels in aortic rings were significantly lower in eNOS(-/-) mice than in WT mice. SNP (300 nmol/L) induced a significantly greater cGMP accu mulation in eNOS(-/-) mice than in WT mice. The maximal SNP-induced (10 mu mol/L) increase in cGMP was similar in both strains. SNP-stimulated sGC act ivity was significantly greater in eNOS(-/-) mice than in WT mice. Incubati on of aortic segments from WT mice with N-omega-nitro-L-arginine increased sGC activity, an effect prevented by coincubation with SNP (10 mu mol/L). T he aortic expressions of the sGC alpha 1 and beta 1 subunits in WT and eNOS (-/-) mice were identical as determined with Western blot analysis. These d ata suggest that chronic exposure to endothelium-derived NO, as well as acu te exposure to nitrovasodilator-derived NO, desensitizes sGC to activation by NO but does not alter sGC expression. Both the acute cessation of endoth elial 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.