Abstract P002: Mechanism Of Mesenteric Artery Vasodilation And Blood Pressure Regulation By Statins

Abstract

Purpose: Statins are the world’s most prescribed drugs with a wide variety of cholesterol-dependent and -independent cardiovascular effects. Pre-clinical and clinical data suggest that statins lower blood pressure (BP) in some patients but have no effect in others. However, the underlying mechanism for such differences remain unclear. By studying the direct vascular effects of therapeutically relevant concentrations of statins in resistance mesenteric arteries from normotensive Sprague Dawley (SD) rats and Spontaneously Hypertensive (SHR) rats, we sought to determine the mechanism of differential BP regulation by statins. Methods: Pressurized arterial myography, phosphodiesterase (PDE) activity assay, ELISA-based cGMP measurement, blood pressure measurement with tail-cuff. Results: Our pressure myography data revealed that statins induce rapid vasodilation in resistance mesenteric arteries. Endothelium denudation, inhibition of endothelial nitric oxide (NO) synthase (eNOS) with L-NNA, smooth muscle cell (SMC) guanylyl cyclase (sGC) inhibition with ODQ, or the inhibition of protein kinase G (PKG) with KT5823 each abolished statin-evoked vasodilation, demonstrating a critical role of endothelium and NO signaling in this process. However, contrary to previous reports, mevalonate application had no effect on vasodilation. Statins selectively inhibited PDE1A in SMCs, elevated [cGMP] i , which could potentiate NO-GC-cGMP-PKG signaling, leading to vasodilation. Statin-evoked vasodilation is attenuated in SHR rat mesenteric arteries that have reduced eNOS expression and impaired NO signaling. Consistent with the vasodilatory action, acute statin treatment lowered systolic and diastolic BP in healthy SD rats. In contrast, acute statin treatment failed to lower systemic BP in SHR rats with reduced eNOS expression. Conclusion: Statins are endothelium-dependent vasodilator, and selective inhibitor of PDE1A in resistance mesenteric arteries. Intact endothelial function and NO production are essential for statin-induced vasodilation and the reduction of BP. Our study could provide explanation to the anti-hypertensive and BP neutral effects of statins.