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(Circulation. 2007;116:238-248.)
© 2007 American Heart Association, Inc.

Heart Failure

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

Jayan Nagendran, MD; Stephen L. Archer, MD; Daniel Soliman, BS; Vikram Gurtu, BS; Rohit Moudgil, PhD; Alois Haromy, BS; Chantal St. Aubin, BS; Linda Webster, MN; Ivan M. Rebeyka, MD; David B. Ross, MD; Peter E. Light, PhD; Jason R.B. Dyck, PhD; Evangelos D. Michelakis, MD

From the Pulmonary Hypertension Program (J.N., V.G., R.M., A.H., L.W., E.D.M.), Division of Cardiac Surgery, Department of Surgery (J.N., I.M.R., D.B.R.), and Department of Pharmacology (D.S., C.S.A., P.E.L., J.R.B.D.), University of Alberta, Alberta, Edmonton, Canada; and Section of Cardiology, Department of Medicine, University of Chicago, Chicago, Ill (S.L.A.).

Correspondence to Evangelos D. Michelakis, MD, Pulmonary Hypertension Program, Department of Medicine, University of Alberta, Edmonton, Canada T6G 2B7. E-mail emichela{at}cha.ab.ca

Received July 29, 2006; accepted April 20, 2007.

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 PDE5 is 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.

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