VASODILATOR DYSFUNCTION IN AGED SPONTANEOUSLY HYPERTENSIVE RATS - CHANGES IN NO SYNTHASE III AND SOLUBLE GUANYLYL CYCLASE EXPRESSION, AND IN SUPEROXIDE ANION PRODUCTION

Objective/Methods: Genetic hypertension is associated with an apparent endothelial dysfunction and impaired endothelium-dependent vasodilata tion in response to increased flow and receptor-dependent agonists. Ho wever, the link between impaired vasodilatation and nitric oxide (NO) synthase expression is still unclear. In the present study, dilator re sponses were determined in the aorta and coronary circulation of 16 mo nth old spontaneously hypertensive (SHR) and Wistar Kyoto rats (WKY). Changes in vascular reactivity were compared with alterations in super oxide anion production as well as endothelial NO synthase (NOS III) an d soluble guanylyl Cyclase expression. Results: In the isolated perfus ed heart both the bradykinin-and sodium nitroprusside-induced vasodila tor responses were attenuated in SHR compared to WKY. Western blot ana lysis revealed a parallel reduction in NOS III expression in coronary microvascular endothelial cells from SHR. Superoxide anion production in aortae from SHR was markedly elevated over that of aortae from WKY, and was almost completely abolished by pretreatment with superoxide d ismutase. Superoxide dismutase induced similar relaxations in phenylep hrine-preconstricted aortic rings from both SHR and WKY, but failed to restore the attenuated acetylcholine- and sodium nitroprusside-induce d relaxations in SHR. No difference in NOS III expression was detected in the aortae from either strain whereas soluble guanylyl cyclase exp ression was markedly decreased in SHR. Conclusions: These results demo nstrate that NOS III expression in different tissues is differentially affected by hypertension. Moreover, althoug an elevated superoxide an ion production is apparent in the aorta, a reduced soluble guanylyl cy clase expression appears to account for the observed vasodilator dysfu nction in SHR, (C) 1998 Elsevier Science B.V.