Changes in IP3 receptor expression and function in aortic smooth muscle of atherosclerotic mice

Peroxynitrite is an endothelium - independent vasodilator which induces relaxation via membrane hyperpolarisation. A ctivation of IP3 receptors triggers opening of potassium channels and hyperpolarisation. Previously we found that relaxation to peroxynitrite was maintained during development of atherosclerosis due to changes in expression of calcium regulatory proteins. In this study we investigated 1) the mechanism of peroxynitrite - induced relaxation in mouse aorta 2) the effect of atherosclerosis on relaxation to peroxynitrite and other vasodilators 3) the effect of atherosclerosis on expression and function of the IP3 receptor. Aortic function was studied using wire myography and atherosclerosis was induced by fat - feeding ApoE - / - mice . Expression of IP3 receptors was studied using Western blotting and immunohistochemistry . Relaxation to peroxynitrite was attenuated by the IP3 antagonists 2 - APB and xestospongin C and also the Kv channel blocker 4 - AP. Atherosclerosis attenuated vasodilation to cromakalim and the AMPK activator A769662 but not peroxynitrite. Relaxation was attenuated to a greater extent by 2 - APB in atherosclerotic aortae despite reduced expression of IP3 receptors. 4 - AP was less effective in 4 month fat fed ApoE - / - mice. Peroxynitrite relaxation involves IP3 - induced calcium release and K V channel activation. This mechanism becomes less important as atherosclerosis develops and relaxation to peroxynitrite may be maintained by increased calcium extrusion