(W0930-04-27) Novel Blood Pressure Lowering Effects of Statins

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 direct statin-induced regulation of resistance mesenteric artery contractility and systemic blood pressure in normotensive Sprague Dawley (SD) rats and Spontaneously Hypertensive (SHR) rats, we sought to determine the mechanism of differential BP regulation by statins to maximize the benefits of statin therapy to lower BP.

Methods: We used pressurized arterial myography for diameter measurement. Small mesenteric artery segments isolated from the SD (6-10 weeks) and SHR rats (20-22 weeks) were cannulated, and maintained at 37˚C in a perfusion chamber. Intraluminal pressure was gradually increased to 80 mmHg. Then statins (0.01-10nM) and pharmacological modulators were applied after the development of myogenic tone at 80 mmHg. Diameter changes were tracked and analyzed. Blood pressure analysis was also conducted on awake rats by passing the tail through a cuff and immobilizing it by an adhesive tape. Blood flow in the tail was read photoelectrically by analyzing the oscillating waveforms via computer programming. Phosphodiesterase (PDE) activity assay and ELISA-based cGMP measurement were performed for validation of the novel mechanism.

Results: Our pressure myography data revealed that statins induced 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 but not PDE5 in SMCs, thereby, elevated [cGMP]_i to potentiate NO-GC-cGMP-PKG signaling, leading to vasodilation. Statin-evoked vasodilation was attenuated in SHR rat mesenteric arteries that had 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. Interestingly, long-term treatment of SHR rats with rosuvastatin preserved NO signaling and statin-induced vasodilation and blood pressure reduction.

Conclusion: Acute statin administration stimulates resistance mesenteric artery vasodilation and lowers BP by selectively inhibiting PDE1A in the presence of intact endothelial function and NO signaling. In contrast, long-term statin therapy maintains eNOS expression and NO bioavailability for statins to relax SHR vessels and lower systemic BP. Our study for the first time sheds lights on the anti-hypertensive and BP neutral effects of statins, and suggests a framework for converting the BP neutral effect into an anti-hypertension effect.

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Acknowledgements: This work was funded by a NIH/NHLBI research grant HL156138- 01A1 and a start-up grant from the Mercer University College of Pharmacy to Raquibul Hasan, PhD.

Fig. 2: Role of endothelium (endo) in statin-induced vasodilation in SD rat mesenteric arteries. (A) Original traces showing diameter changes in endo-intact and -denuded mesenteric arteries, and (B) Mean data showing % reversal of PE-induced vasoconstriction. (C) Original traces comparing simvastatin-evoked vasodilation in endo-intact and -denuded vessels, and (D) Mean data for simvastatin (simva) and rosuvastatin (rosuva)-induced vasodilation. * P < 0.05 versus endo-intact.

Fig. 4. Role of PDE inhibition in statin-induced mesenteric artery dilation. (A) Mean data for [cGMP]i in statin-treated SD rat mesenteric arteries, n=4 * P < 0.05 control. (B) Mean data for in-vitro PDE1A inhibition, n=4 * P < 0.05 vs control. (C) Mean data for potentiation of sildenafil (10 nM) responses, n=4 * P < 0.05 vs sildenafil. (D) Mean data for PDE5A inhibition. n=4 * P < 0.05 vs control.

Fig. 9: Effect of 12-week rosuvastatin treatment on eNOS expression and statin-induced vasodilation in SHR rats. (A) A Western blot image for eNOS protein expression, and (B) Mean data. (C) Original traces comparing 1 nM simvastatin-induced vasodilation in Sal-SHR, Rosu-SHR with WKY, (D) Mean data for diameter changes. n = 4. * P < 0.05 versus WKY, # P < 0.05 versus Rosu-SHR