Received for publication December 27, 2004.
Revised February 23, 2005.
Accepted for publication February 24, 2005.

Opposing Roles of Endothelial and Smooth Muscle Phosphatidylinositol 3-Kinase in Vasoconstriction: Effects of Rho-Kinase and Hypertension

Abstract

Phosphatidylinositol 3-kinase (PI3K) can activate endothelial nitric oxide synthase (eNOS), leading to production of the vasodilator nitric oxide (NO). By contrast, vascular smooth muscle (VSM) PI3K may partially mediate vascular contraction, particularly during hypertension. We tested whether endothelial and VSM PI3K may have opposing functional roles in regulating vascular contraction. Secondly, we tested whether the pro-contractile protein rho-kinase can suppress endothelial PI3K/eNOS activity in intact arteries, thus contributing to vasoconstriction by G protein-coupled receptor (GPCR) agonists. We studied contractile responses to the GPCR agonist phenylephrine, and the receptor-independent vasoconstrictor potassium chloride (KCl), in aortic rings from Sprague-Dawley rats. In endothelium-intact rings, the PI3K inhibitor wortmannin (0.1 µmol/L), markedly augmented responses to phenylephrine (P<0.05) by~50%, but not to KCl. However, in endothelium-denuded or L-NAME (100 µmol/L)-treated rings, wortmannin reduced responses to phenylephrine and KCl (P<0.05). Furthermore, the rho-kinase inhibitor Y-27632 (1 µmol/L) abolished responses to phenylephrine, and this effect was partially reversed by wortmannin or L-NAME. The ability of wortmannin to oppose the effect of rho-kinase inhibition on contractions to phenylephrine was L-NAME-sensitive. In aortas from angiotensin II-induced hypertensive rats, relaxation to acetylcholine (10 µmol/L) was impaired in normotensive controls (P<0.05), and vasoconstriction by phenylephrine was markedly enhanced and not further augmented by wortmannin. These data suggest that endothelial PI3K-induced NO production can modulate GPCR agonist-induced vascular contraction, and that this effect is impaired in hypertension in association with endothelial dysfunction. In addition, endothelial rho-kinase may act to suppress PI3K activity, and hence attenuate NO-mediated relaxation and augment GPCR-dependent contraction.

Key words: PI3-kinase, endothelium, hypertension, nitric oxide, rho-kinase, vasoconstriction

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