Potential role of inositol 1,4,5 - triphosphate receptors in the pathogenesis of hypertension

Abstract

Abstract Inositol 1,4,5-triphosphate receptors (IP3R) are tetrameric intracellular channels that mediate the release of Calcium (Ca2+) from sarcoplasmic reticulum (SR) into the cytosol in response to IP3 binding. Modulation of vascular smooth muscle cells (VSMC) contractility allows small arteries to regulate blood flow and determine peripheral vascular resistance and blood pressure levels. The level of contraction of VSMC relies on a rise in cytoplasmic Ca2+ mediated by IP3-dependent Ca2+ release and voltage dependent Ca2+ influx through L-type Ca2+ (CaL) channels. Strong evidence supports a role for the vascular CaL channels in hypertension but little is known about the functional role of IP3R including the modulation of IP3R-Ca2+ signaling by the vascular endothelium. The goal of this study is to elucidate the functional contribution of IP3R-Ca2+ signaling to the pathogenesis of hypertension. Our preliminary results showed that IP3R are up regulated in small mesenteric arteries of two different forms of hypertensive rats. In the same arteries, activation of IP3R results in accentuated vasoconstriction whereas the endothelium-derived nitric oxide exerts a tonic dilator influence. The findings of this study will greatly improve our basic understanding of the etiology of hypertension by defining the abnormalities of IP3-dependent Ca2+ signaling and contraction in VSMC and its regulation by the endothelium. This may provide critical insights into the pathogenesis of hypertension, and set the groundwork for developing novel therapeutic strategies for the treatment of hypertensive disease.