Phosphodiesterase type 5 is highly expressed in the hypertrophied human right ventricle, and acute inhibition of phosphodiesterase type 5 improves contractility

• Published in: Circulation (New York, N.Y.) Vol. 116; no. 3; pp. 238 - 248
• Main Authors: NAGENDRAN, Jayan, ARCHER, Stephen L, LIGHT, Peter E, DYCK, Jason R. B, MICHELAKIS, Evangelos D, SOLIMAN, Daniel, GURTU, Vikram, MOUDGIL, Rohit, HAROMY, Alois, AUBIN, Chantal St, WEBSTER, Linda, REBEYKA, Ivan M, ROSS, David B
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 17-07-2007
• Subjects: 3',5'-Cyclic-GMP Phosphodiesterases - antagonists & inhibitors; 3',5'-Cyclic-GMP Phosphodiesterases - biosynthesis; 3',5'-Cyclic-GMP Phosphodiesterases - genetics; Adult; Animals; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Cardiovascular system; Child, Preschool; Cyclic Nucleotide Phosphodiesterases, Type 5; Diabetes. Impaired glucose tolerance; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Female; Gene Expression Regulation, Enzymologic - drug effects; Gene Expression Regulation, Enzymologic - physiology; Humans; Hypertrophy, Right Ventricular - drug therapy; Hypertrophy, Right Ventricular - enzymology; Infant; Infant, Newborn; Male; Management. Various non-drug treatments. Langerhans islet grafts; Medical sciences; Middle Aged; Myocardial Contraction - drug effects; Myocardial Contraction - physiology; Pharmacology. Drug treatments; Phosphodiesterase Inhibitors - pharmacology; Phosphodiesterase Inhibitors - therapeutic use; Rats; Rats, Sprague-Dawley; Vasodilator agents. Cerebral vasodilators; Human; inhibitors; Respiratory disease; Enzyme; 3',5'-Cyclic-GMP phosphodiesterase; hypertrophy; Right ventricle; Contractility; hypertension, pulmonary; Cardiovascular disease; Esterases; Phosphoric diester hydrolases; Pulmonary hypertension; inotropic agents; Hydrolases
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/CIRCULATIONAHA.106.655266

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.
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.
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.