Published Online
on July 2, 2007

A more recent version of this article appeared on July 17, 2007

This Article Full Text (PDF) Data Supplement All Versions of this Article: 116/3/238    most recent CIRCULATIONAHA.106.655266v1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Nagendran, J. Articles by Michelakis, E. D. Search for Related Content PubMed PubMed Citation Articles by Nagendran, J. Articles by Michelakis, E. D. Related Collections Contractile function Animal models of human disease Hypertrophy Physiological and pathological control of gene expression Pulmonary circulation and disease

Submitted on July 29, 2006
Accepted on April 20, 2007

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, and 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.).

^* To whom correspondence should be addressed. E-mail: emichela{at}cha.ab.ca.

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.

Key words: contractility • hypertension, pulmonary • hypertrophy • inhibitors • inotropic agents

This article has been cited by other articles:

				S. L. Archer and E. D. Michelakis Phosphodiesterase Type 5 Inhibitors for Pulmonary Arterial Hypertension N. Engl. J. Med., November 5, 2009; 361(19): 1864 - 1871. [Full Text] [PDF]

				Z-C Jing, X Jiang, B-X Wu, X-Q Xu, Y Wu, C-R Ma, Y Wang, Y-J Yang, J-L Pu, and W Gao Vardenafil treatment for patients with pulmonary arterial hypertension: a multicentre, open-label study Heart, September 15, 2009; 95(18): 1531 - 1536. [Abstract] [Full Text] [PDF]

				F. Vandeput, J. Krall, R. Ockaili, F. N. Salloum, V. Florio, J. D. Corbin, S. H. Francis, R. C. Kukreja, and M. A. Movsesian cGMP-Hydrolytic Activity and Its Inhibition by Sildenafil in Normal and Failing Human and Mouse Myocardium J. Pharmacol. Exp. Ther., September 1, 2009; 330(3): 884 - 891. [Abstract] [Full Text] [PDF]

				K. T. B. Mouchaers, I. Schalij, A. M. G. Versteilen, A. M. Hadi, G. P. van Nieuw Amerongen, V. W. M. van Hinsbergh, P. E. Postmus, W. J. van der Laarse, and A. Vonk-Noordegraaf Endothelin receptor blockade combined with phosphodiesterase-5 inhibition increases right ventricular mitochondrial capacity in pulmonary arterial hypertension Am J Physiol Heart Circ Physiol, July 1, 2009; 297(1): H200 - H207. [Abstract] [Full Text] [PDF]

				D. B. Badesch, H. C. Champion, M. A. Gomez Sanchez, M. M. Hoeper, J. E. Loyd, A. Manes, M. McGoon, R. Naeije, H. Olschewski, R. J. Oudiz, et al. Diagnosis and assessment of pulmonary arterial hypertension. J. Am. Coll. Cardiol., June 30, 2009; 54(1 Suppl): S55 - S66. [Abstract] [Full Text] [PDF]

				T. Zaobornyj, L. B. Valdez, D. E. Iglesias, M. Gasco, G. F. Gonzales, and A. Boveris Mitochondrial nitric oxide metabolism during rat heart adaptation to high altitude: effect of sildenafil, L-NAME, and L-arginine treatments Am J Physiol Heart Circ Physiol, June 1, 2009; 296(6): H1741 - H1747. [Abstract] [Full Text] [PDF]

				J. Nagendran and E. D. Michelakis Mitochondrial NOS is upregulated in the hypoxic heart: implications for the function of the hypertrophied right ventricle Am J Physiol Heart Circ Physiol, June 1, 2009; 296(6): H1723 - H1726. [Full Text] [PDF]

				R. Wolk, W. B. Smith, J. M. Neutel, J. Rubino, D. Xuan, J. Mancuso, J. Gilbert, and M. L. Pressler Blood Pressure Lowering Effects of a New Long-Acting Inhibitor of Phosphodiesterase 5 in Patients With Mild to Moderate Hypertension Hypertension, June 1, 2009; 53(6): 1091 - 1097. [Abstract] [Full Text] [PDF]

				E. D. Michelakis Soluble guanylate cyclase stimulators as a potential therapy for PAH: enthusiasm, pragmatism and concern Eur. Respir. J., April 1, 2009; 33(4): 717 - 721. [Full Text] [PDF]

				M. Kuhn Cardiac anti-remodelling effects of phosphodiesterase type 5 inhibitors: afterload-(in)dependent? Cardiovasc Res, April 1, 2009; 82(1): 4 - 6. [Full Text] [PDF]

				S. Rich The Effects of Vasodilators in Pulmonary Hypertension: Pulmonary Vascular or Peripheral Vascular? Circ Heart Fail, March 1, 2009; 2(2): 145 - 150. [Full Text] [PDF]

				H. J. Bogaard, K. Abe, A. Vonk Noordegraaf, and N. F. Voelkel The Right Ventricle Under Pressure: Cellular and Molecular Mechanisms of Right-Heart Failure in Pulmonary Hypertension Chest, March 1, 2009; 135(3): 794 - 804. [Abstract] [Full Text] [PDF]

				P. Pokreisz, S. Vandenwijngaert, V. Bito, A. Van den Bergh, I. Lenaerts, C. Busch, G. Marsboom, O. Gheysens, P. Vermeersch, L. Biesmans, et al. Ventricular Phosphodiesterase-5 Expression Is Increased in Patients With Advanced Heart Failure and Contributes to Adverse Ventricular Remodeling After Myocardial Infarction in Mice Circulation, January 27, 2009; 119(3): 408 - 416. [Abstract] [Full Text] [PDF]

				T. Nagayama, S. Hsu, M. Zhang, N. Koitabashi, D. Bedja, K. L. Gabrielson, E. Takimoto, and D. A. Kass Sildenafil stops progressive chamber, cellular, and molecular remodeling and improves calcium handling and function in hearts with pre-existing advanced hypertrophy caused by pressure overload. J. Am. Coll. Cardiol., January 13, 2009; 53(2): 207 - 215. [Abstract] [Full Text] [PDF]

				A. Andersen, J. M. Nielsen, C. D. Peters, U. K. Schou, E. Sloth, and J. E. Nielsen-Kudsk Effects of phosphodiesterase-5 inhibition by sildenafil in the pressure overloaded right heart Eur J Heart Fail, December 1, 2008; 10(12): 1158 - 1165. [Abstract] [Full Text] [PDF]

				M. J. Semigran Phosphodiesterase Type 5 Inhibition: A Support of the Left Ventricular Assist Device Bridge to Transplant Circ Heart Fail, November 1, 2008; 1(4): 211 - 212. [Full Text] [PDF]

				R. J. Tedford, A. R. Hemnes, S. D. Russell, I. S. Wittstein, M. Mahmud, A. L. Zaiman, S. C. Mathai, D. R. Thiemann, P. M. Hassoun, R. E. Girgis, et al. PDE5A Inhibitor Treatment of Persistent Pulmonary Hypertension After Mechanical Circulatory Support Circ Heart Fail, November 1, 2008; 1(4): 213 - 219. [Abstract] [Full Text] [PDF]

				M. Guazzi Clinical Use of Phosphodiesterase-5 Inhibitors in Chronic Heart Failure Circ Heart Fail, November 1, 2008; 1(4): 272 - 280. [Full Text] [PDF]

				E. D. Michelakis, M. R. Wilkins, and M. Rabinovitch Emerging Concepts and Translational Priorities in Pulmonary Arterial Hypertension Circulation, September 30, 2008; 118(14): 1486 - 1495. [Full Text] [PDF]

				T. Nagayama, M. Zhang, S. Hsu, E. Takimoto, and D. A. Kass Sustained Soluble Guanylate Cyclase Stimulation Offsets Nitric-Oxide Synthase Inhibition to Restore Acute Cardiac Modulation by Sildenafil J. Pharmacol. Exp. Ther., August 1, 2008; 326(2): 380 - 387. [Abstract] [Full Text] [PDF]

				M. R. Wilkins, J. Wharton, F. Grimminger, and H. A. Ghofrani Phosphodiesterase inhibitors for the treatment of pulmonary hypertension Eur. Respir. J., July 1, 2008; 32(1): 198 - 209. [Abstract] [Full Text] [PDF]

				J. Nagendran, V. Gurtu, D. Z. Fu, J. R.B. Dyck, A. Haromy, D. B. Ross, I. M. Rebeyka, and E. D. Michelakis A dynamic and chamber-specific mitochondrial remodeling in right ventricular hypertrophy can be therapeutically targeted J. Thorac. Cardiovasc. Surg., July 1, 2008; 136(1): 168 - 178. [Abstract] [Full Text] [PDF]

				J. Yin, J. Hoffmann, S. M. Kaestle, N. Neye, L. Wang, J. Baeurle, W. Liedtke, S. Wu, H. Kuppe, A. R. Pries, et al. Negative-Feedback Loop Attenuates Hydrostatic Lung Edema via a cGMP-Dependent Regulation of Transient Receptor Potential Vanilloid 4 Circ. Res., April 25, 2008; 102(8): 966 - 974. [Abstract] [Full Text] [PDF]

				H. Rietema, S. Holverda, H. J. Bogaard, J. T. Marcus, H. J. Smit, N. Westerhof, P. E. Postmus, A. Boonstra, and A. Vonk-Noordegraaf Sildenafil treatment in COPD does not affect stroke volume or exercise capacity Eur. Respir. J., April 1, 2008; 31(4): 759 - 764. [Abstract] [Full Text] [PDF]

				S. J. Lester, A. J. Tajik, R. A. Nishimura, J. K. Oh, B. K. Khandheria, and J. B. Seward Unlocking the Mysteries of Diastolic Function Deciphering the Rosetta Stone 10 Years Later. J. Am. Coll. Cardiol., February 19, 2008; 51(7): 679 - 689. [Abstract] [Full Text] [PDF]

				S. R. Goldsmith Type 5 Phosphodiesterase Inhibition in Heart Failure: The Next Step J. Am. Coll. Cardiol., November 27, 2007; 50(22): 2145 - 2147. [Full Text] [PDF]

				D. A. Kass, H. C. Champion, and J. A. Beavo Phosphodiesterase Type 5: Expanding Roles in Cardiovascular Regulation Circ. Res., November 26, 2007; 101(11): 1084 - 1095. [Abstract] [Full Text] [PDF]

				G. D. Lewis, R. Shah, K. Shahzad, J. M. Camuso, P. P. Pappagianopoulos, J. Hung, A. Tawakol, R. E. Gerszten, D. M. Systrom, K. D. Bloch, et al. Sildenafil Improves Exercise Capacity and Quality of Life in Patients With Systolic Heart Failure and Secondary Pulmonary Hypertension Circulation, October 2, 2007; 116(14): 1555 - 1562. [Abstract] [Full Text] [PDF]

				D. A. Kass Hypertrophied Right Hearts Get Two for the Price of One: Can Inhibiting Phosphodiesterase Type 5 Also Inhibit Phosphodiesterase Type 3? Circulation, July 17, 2007; 116(3): 233 - 235. [Full Text] [PDF]