on April 29, 2002
Circulation. 2002
Published online before print April 29, 2002, doi: 10.1161/01.CIR.0000016641.12984.DC
Published online before print April 29, 2002, doi: 10.1161/01.CIR.0000016641.12984.DC
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Submitted on December 29, 2001
From the Department of Medicine, Division of Cardiology; Vascular Biology Group; and Division of Pulmonary Medicine (D.L.), University of Alberta, Edmonton, Alberta, Canada. * To whom correspondence should be addressed. E-mail: emichela{at}cha.ab.ca.
Background—The prognosis of patients with severe pulmonary hypertension (PHT) is poor. To determine prognosis and guide therapy, an acute hemodynamic trial of selective pulmonary vasodilators, usually inhaled nitric oxide (iNO), was performed. We hypothesized that oral sildenafil, a phosphodiesterase-5 inhibitor, is a safe and effective alternative to iNO. Methods and Results—We studied 13 consecutive patients (mean±SEM, 44±2 years of age; 9 women) referred for consideration of heart-lung transplantation or as a guide to medical therapy. All but one were functional class III or IV. Patients had primary PHT (n=9), pulmonary arterial hypertension (n=2), or secondary PHT (n=2). Hemodynamics and serum cyclic guanosine-monophosphate levels (cGMP) were measured at baseline and at peak effects of iNO (80 ppm), sildenafil (75 mg), and their combination. The decrease in pulmonary vascular resistance was similar with iNO (-19±5%) and sildenafil (-27±3%), whereas sildenafil+iNO was more effective than iNO alone (-32±5%, P<0.003). Sildenafil and sildenafil+iNO increased cardiac index (17±5% and 17±4%, respectively), whereas iNO did not (-0.2±2.0%, P<0.003). iNO increased, whereas sildenafil tended to decrease, pulmonary capillary wedge pressure (+15±6 versus -9±7%, P<0.0007). Systemic arterial pressure was similar among groups and did not decrease with treatment. cGMP levels increased similarly with iNO and sildenafil, and their combination synergistically elevated cGMP (P<0.0001). Conclusions—A single oral dose of sildenafil is as effective and selective a pulmonary vasodilator as iNO. Sildenafil may be superior to iNO in that it increases cardiac output and does not increase wedge pressure. Future studies are indicated to establish whether sildenafil could be effective over a longer duration.
Revised on March 5, 2002
Accepted on March 12, 2002
Oral Sildenafil Is an Effective and Specific
Pulmonary Vasodilator in Patients With Pulmonary
Arterial Hypertension. Comparison With Inhaled Nitric
Oxide
Evangelos Michelakis MD*,
Key words: hypertension, pulmonary • nitric oxide • hemodynamics
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S. Klotz, M. C. Deng, D. Hanafy, C. Schmid, J. Stypmann, C. Schmidt, D. Hammel, and H. H. Scheld Reversible pulmonary hypertension in heart transplant candidates--pretransplant evaluation and outcome after orthotopic heart transplantation Eur J Heart Fail, October 1, 2003; 5(5): 645 - 653. [Abstract] [Full Text] [PDF]
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I. Schulze-Neick, P. Hartenstein, J. Li, B. Stiller, N. Nagdyman, M. Hubler, G. Butrous, A. Petros, P. Lange, and A. N. Redington Intravenous Sildenafil Is a Potent Pulmonary Vasodilator in Children With Congenital Heart Disease Circulation, September 9, 2003; 108(90101): II-167 - 173. [Abstract] [Full Text] [PDF]
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S. M. Lowson Nitric Oxide Signaling and Clinical Alternatives to Nitric Oxide Seminars in Cardiothoracic and Vascular Anesthesia, September 1, 2003; 7(3): 239 - 252. [Abstract] [PDF]
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 D. H. Maurice, D. Palmer, D. G. Tilley, H. A. Dunkerley, S. J. Netherton, D. R. Raymond, H. S. Elbatarny, and S. L. Jimmo Cyclic Nucleotide Phosphodiesterase Activity, Expression, and Targeting in Cells of the Cardiovascular System Mol. Pharmacol., September 1, 2003; 64(3): 533 - 546. [Abstract] [Full Text] [PDF]
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S. D. Rybalkin, C. Yan, K. E. Bornfeldt, and J. A. Beavo Cyclic GMP Phosphodiesterases and Regulation of Smooth Muscle Function Circ. Res., August 22, 2003; 93(4): 280 - 291. [Abstract] [Full Text] [PDF]
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T. Reffelmann and R. A. Kloner Effects of sildenafil on myocardial infarct size, microvascular function, and acute ischemic left ventricular dilation Cardiovasc Res, August 1, 2003; 59(2): 441 - 449. [Abstract] [Full Text] [PDF]
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T. Reffelmann and R. A. Kloner Therapeutic Potential of Phosphodiesterase 5 Inhibition for Cardiovascular Disease Circulation, July 15, 2003; 108(2): 239 - 244. [Full Text] [PDF]
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A. Sebkhi, J. W. Strange, S. C. Phillips, J. Wharton, and M. R. Wilkins Phosphodiesterase Type 5 as a Target for the Treatment of Hypoxia-Induced Pulmonary Hypertension Circulation, July 1, 2003; 107(25): 3230 - 3235. [Abstract] [Full Text] [PDF]
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 A. J Peacock Treatment of pulmonary hypertension BMJ, April 19, 2003; 326(7394): 835 - 836. [Full Text] [PDF]
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S. Mehta Sildenafil for Pulmonary Arterial Hypertension: Exciting, But Protection Required Chest, April 1, 2003; 123(4): 989 - 992. [Full Text] [PDF]
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L. Zhao, N. A. Mason, J. W. Strange, H. Walker, and M. R. Wilkins Beneficial Effects of Phosphodiesterase 5 Inhibition in Pulmonary Hypertension Are Influenced by Natriuretic Peptide Activity Circulation, January 21, 2003; 107(2): 234 - 237. [Abstract] [Full Text] [PDF]
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J. Oliver, D. J Webb, S. Patole, and J. Travadi Sildenafil for "blue babies" BMJ, November 16, 2002; 325(7373): 1174 - 1174. [Full Text]
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W. R. Franek, Y. C. Chowdary, X. Lin, M. Hu, E. J. Miller, J. A. Kazzaz, P. Razzano, J. Romashko III, J. M. Davis, P. Narula, et al. Suppression of Nuclear Factor-kappa B Activity by Nitric Oxide and Hyperoxia in Oxygen-resistant Cells J. Biol. Chem., November 1, 2002; 277(45): 42694 - 42700. [Abstract] [Full Text] [PDF]
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