Abstract 062: Inhibition of Phosphodiesterase 5 Attenuates Angiotensin II Dependent Hypertension and Renal Vascular Dysfunction in C57BL/6 but Not in eNOS-KO Mice
Angiotensin (Ang) II is a key player in the pathogenesis of hypertension by influencing the NO/cGMP signaling cascade. Thus, Ang II induces vascular dysfunction by activating phosphodiesterase (PDE) 1 and PDE5 mediated cGMP-degradation. PDE1 is activated by increased intracellular Ca2+ concentrations observed during Ang II mediated vasoconstriction. PDE5 is activated by a cGMP mediated negative feedback mechanism. The present study examines the role of PDE1 and PDE5 in regulation of renal hemodynamics and blood pressure (BP) during Ang II induced hypertension.
In unconscious C57BL/6 (WT) mice, changes in renal blood flow (RBF) and BP was measured in the presence of specific PDE5- (sildenafil) or PDE1- (vinpocetine) inhibitors. Secondly, in WT and eNOS-KO mice, a mouse model characterized by low NO/cGMP levels, hypertension was induced by chronic Ang II infusion (500 ng/kg/min) for 14 days. Vascular relaxation was tested in the presence of acute or chronic PDE1 or PDE5 inhibition in isolated perfused kidneys.
During acute Ang II infusion, sildenafil increased RBF and decreased BP more potently than under baseline conditions. In contrast, vinpocetin had no effect on RBF and BP during normotensive or hypertensive conditions, Moreover, sildenafil but not vinpocetine improved NO (GSNO) dependent vasodilation in isolated perfused kidneys of Ang II treated WT mice. Next, we tested the impact of chronic PDE5 inhibition on Ang II dependent hypertension. Sildenafil (100mg/kg/d) attenuated Ang II dependent hypertension in WT (156±4 vs. 139±7mmHg; p<0.05) but not in eNOS-KO mice (166±4 vs. 172±4mmHg). Respectively, chronic Sildenafil treatment improved NO dependent vasodilation in isolated perfused kidneys of Ang II treated WT but not in eNOS-KO mice. In addition, urinary nitrite excretion, a marker for NO generation was significantly increased during Ang II-infusion compared to baseline in WT but not in eNOS-KO mice.
In conclusion, PDE5 seems to be the predominant PDE regulating RBF and renal vascular function. Moreover, sildenafil ameliorates Ang II dependent hypertension and improves vascular dysfunction. No effect of PDE5 inhibiton was observed in eNOS-KO mice supporting the hypothesis that Ang II activates PDE5 initially by increased NO/cGMP generation.
Author Disclosures: M. Thieme: None. S. Sivritas: None. S.A. Potthoff: None. G. Yang: None. L.C. Rump: None. J. Stegbauer: None.
- © 2015 by American Heart Association, Inc.