Role of Phosphatidylinositol 3-Kinase in Acetylcholine-Induced Dilatation of Rat Basilar Artery


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Abstract

Background and PurposeWe tested the hypothesis that activation of phosphatidylinositol (PI) 3-kinase is involved in dilator responses of the basilar artery to acetylcholine in vivo.MethodsResponses of the basilar artery were measured by the cranial window technique in anesthetized rats. To examine the role of PI 3-kinase in acetylcholine-induced calcium signaling, we measured intracellular free calcium concentration ([Ca2+]i) of cultured rat basilar arterial endothelial cells using a fluorescent calcium indicator, indo 1.ResultsTopical application of acetylcholine (10−6, 10−5.5, and 10−5 mol/L) increased the diameter of the basilar artery by 8±1%, 14±2%, and 24±3%, respectively. An inhibitor of PI 3-kinase, wortmannin (10−8 mol/L), did not change the baseline diameter of the artery. In the presence of wortmannin, acetylcholine (10−6, 10−5.5, and 10−5 mol/L) dilated the artery only by 3±2%, 6±2%, and 12±2%, respectively. Thus, wortmannin attenuated acetylcholine-induced dilatation of the basilar artery (P <0.05 versus control). Wortmannin had no effect on dilatation of the artery in response to a nitric oxide donor, sodium nitroprusside. LY294002, another inhibitor of PI 3-kinase, also inhibited dilator response of the basilar artery to acetylcholine. Acetylcholine produced an increase in [Ca2+]i of the endothelial cells. Genistein, an inhibitor of tyrosine kinase, markedly attenuated acetylcholine-induced calcium influx to the cells; however, wortmannin had no effect on acetylcholine-induced calcium changes.ConclusionsThese results suggest that acetylcholine-induced dilatation of the basilar artery is mediated, at least in part, by activation of PI 3-kinase in vivo. Acetylcholine-induced [Ca2+]i changes of the endothelial cells may not be mediated by activation of the kinase. PI 3-kinase as well as [Ca2+]i may play an important role in the acetylcholine-induced nitric oxide production of the basilar arterial endothelial cells.

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