Sildenafil, a phosphodiesterase V inhibitor potentiates the renal actions of subcutaneously administered BNP without adverse hemodynamic effects in experimental overt heart failure

Abstract

Background: BNP is a cardiac peptide with vasodilating and natriuretic properties that are mediated via cyclic GMP. Cyclic GMP is metabolized by type V phosphodiesterase (PDE V) which is abundant in the kidney. Sildenafil is a PDE V inhibitor that is used clinically for erectile dysfunction. The objective of this study is to test the hypothesis that inhibition of PDE V will potentiate the renal actions of subcutaneously (SQ) administered BNP in experimental overt heart failure (HF). Methods: We determined the cardiorenal and humoral response to acute SQ BNP (5μg/Kg) administration in 2 groups of dogs with rapid ventricular pacing induced overt HF (240 bpm for 10 days); Group 1 (n = 5) received Sildenafil 50 mg po tid during the 10 days of pacing and an hour before the administration of SQ BNP on day 11, Group 2 (n = 4) received no PDE V inhibitor but did receive SQ BNP alone on day 11 of HF. (∗ = P<0.05) Results: Cardiorenal functions were similar between the two groups before the administration of SQ BNP despite the fact that Group 1 had significantly higher plasma (44±2 vs19±2 pmol/ml∗) and urinary cGMP (5566±349 vs 2222±161 pmol/min∗) than Group 2. With SQ BNP, Group 1 had a greater natriuretic (Group 1: 18±10 μEq/min vs Group 2: 5±3 μEq/min∗) and diuretic response than Group 2. Glomerular filtration rate increased (30±6 to 53±10 ml/min∗) in Group 1, but was unchanged in Group 2 (27±7 to 29±9 ml/min). Plasma and urinary BNP increased similarly in both groups with SQ BNP. Increase in plasma cGMP (Group 1: 44±2 to 49±3 pmol/ml∗, vs Group 2: 19±2 to 24±3 pmol/ml∗) were similar in both groups with SQ BNP. However, Group 1 (PDE V inhibitor + BNP) had a much greater∗ increase in urinary cGMP (5566±349 to 10602±1500 pmol/min∗ than Group 2 (BNP) (2222±161 to 3329±298 pmol/min∗). Cardiac filling pressures decreased similarly and cardiac output was unchanged in both groups. Mean blood pressure trended to decrease in both groups but was not statistically significant. Conclusion: In experimental overt HF, chronic administration of the PDE V inhibitor Sildenafil enhanced the renal response to acute SQ BNP. Specifically, PDE V inhibition together with SQ BNP resulted in a greater natriuretic response and increase in GFR and urinary cGMP as compared to SQ BNP alone. This study supports the conclusion that Sildenafil, a PDE V inhibitor, potentiates the renal response to SQ BNP without adverse hemodynamic effects in experimental overt HF.