Phosphodiesterase Type 5 Is Highly Expressed in the Hypertrophied Human Right Ventricle, and Acute Inhibition of Phosphodiesterase Type 5 Improves Contractility

Abstract

Background-Sildenafil was recently approved for the treatment of pulmonary arterial hypertension. The beneficial effects of phosphodiesterase type 5 (PDE5) inhibitors in pulmonary arterial hypertension are thought to result from relatively selective vasodilatory and antiproliferative effects on the pulmonary vasculature and, on the basis of early data showing lack of significant PDE5 expression in the normal heart, are thought to spare the myocardium. Methods and Results-We studied surgical specimens from 9 patients and show here for the first time that although PDE5is not expressed in the myocardium of the normal human right ventricle (RV), mRNA and protein are markedly upregulated in hypertrophied RV (RVH) myocardium. PDE5 also is upregulated in rat RVH. PDE5 inhibition (with either MY-5445 or sildenafil) significantly increases contractility, measured in the perfused heart (modified Langendorff preparation) and isolated cardiomyocytes, in RVH but not normal RV. PDE5 inhibition leads to increases in both cGMP and cAMP in RVH but not normal RV. Protein kinase G activity is suppressed in RVH, explaining why the PDE5 inhibitor-induced increase in cGMP does not lead to inhibition of contractility. Rather, it leads to inhibition of the cGMP-sensitive PDE3, explaining the increase in cAMP and contractility. This is further supported by our findings that, in RVH protein kinase A, inhibition completely inhibits PDE5-induced inotropy, whereas protein kinase G inhibition does not. Conclusions-The ability of PDE5 inhibitors to increase RV inotropy and to decrease RV afterload without significantly affecting systemic hemodynamics makes them ideal for the treatment of diseases affecting the RV, including pulmonary arterial hypertension. (Circulation. 2007;116:238-248.)

Sildenafil in a cigarette smoke-induced model of COPD in the guinea-pig

“…The preservation of the intrapulmonary vascular surface, which allows reduced vascular resistance, might explain the reduced PAP in sildenafil-treated animals despite the lack of change in vessel remodelling. The inverse relationship between small-vessel density and RV hypertrophy also points in that direction, although we cannot disregard a direct effect of sildenafil on RV itself as a mechanism of reduced hypertrophy [24,29]. We have observed similar effects employing an sGC stimulator, which prevented both pulmonary vascular remodelling and emphysema development in CS-exposed guinea-pigs [18].…”

Saxagliptin and Tadalafil Differentially Alter Cyclic Guanosine Monophosphate (cGMP) Signaling and Left Ventricular Function in Aortic‐Banded Mini‐Swine

“…The cGMP‐PKG‐PDE5 signaling axis has been hypothesized to contribute to the pathophysiology of human HF 6, 50, 51, 52. However, this finding is not definitive in a setting of human HFpEF5, 9 where clinical data have failed to show benefits previously reported in multiple animal models 47, 50.…”

The Need to Recognize the Pulmonary Circulation and the Right Ventricle as an Integrated Functional Unit: Facts and Hypotheses (2013 Grover Conference series)

“…Common targets are yet to be identified, but until discovered any new pharmacotherapy should also address a potential effect on the RV. For example, sildenafil has been shown to increase RV inotropy, 37 and conversely agents like bosentan exert a negative effect on RV function. 38 We propose that when evaluating the effects of a pulmonary hypertension drug, researchers should look for a concomitant improvement in RV function.…”