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Effect of sildenafil on the acute pulmonary vasodilator response to inhaled nitric oxide in adults with primary pulmonary hypertension

2002; Elsevier BV; Volume: 90; Issue: 6 Linguagem: Inglês

10.1016/s0002-9149(02)02586-9

1879-1913

John J. Lepore, Anjli Maroo, Naveen L. Pereira, Leo C. Ginns, G. William Dec, Warren M. Zapol, Kenneth D. Bloch, Marc J. Semigran,

Heart Rate Variability and Autonomic Control

Breathing low concentrations of nitric oxide (NO) produces selective pulmonary vasodilatation and increases exercise capacity in patients with pulmonary hypertension of various etiologies, 1 Frostell C.G. Blomqvist H. Hedenstierna G. Lundberg J. Zapol W.M. Inhaled nitric oxide selectively reverses human hypoxic pulmonary vasoconstriction without causing systemic vasodilation. Anesthesiology. 1993; 78: 427-435 Crossref PubMed Scopus (401) Google Scholar , 2 Hasuda T. Satoh T. Shimouchi A. Sakamaki F. Kyotani S. Matsumoto T. Goto Y. Nakanishi N. Improvement in exercise capacity with nitric oxide inhalation in patients with precapillary pulmonary hypertension. Circulation. 2000; 101: 2066-2070 Crossref PubMed Scopus (44) Google Scholar and an acute pulmonary vasodilator response to NO inhalation has been used as a predictor of response to oral vasodilators. 3 Cockrill B.A. Kacmarek R.M. Fifer M.A. Bigatello L.M. Ginns L.C. Zapol W.M. Semigran M.J. Comparison of the effects of nitric oxide, nitroprusside, and nifedipine on hemodynamics and right ventricular contractility in patients with chronic pulmonary hypertension. Chest. 2001; 119: 128-136 Crossref PubMed Scopus (60) Google Scholar Continuous or intermittent NO inhalation has been proposed as chronic pulmonary vasodilator therapy; 4 Channick R.N. Newhart J.W. Johnson F.W. Williams P.J. Auger W.R. Fedullo P.F. Moser K.M. Pulsed delivery of inhaled nitric oxide to patients with primary pulmonary hypertension an ambulatory delivery system and initial clinical tests. Chest. 1996; 109: 1545-1549 Crossref PubMed Scopus (174) Google Scholar however, many patients with pulmonary hypertension do not have a pulmonary vasodilator response to inhaled NO, and in patients who do respond, the duration of vasodilatation after cessation of NO inhalation is brief. Inhaled NO exerts its pulmonary vasodilator effects by diffusing into pulmonary vascular smooth muscle cells and stimulating the production of cyclic guanosine 3′-5′ monophosphate, a mediator of vasodilatation. 5 Steudel W. Hurford W.E. Zapol W.M. Inhaled nitric oxide basic biology and clinical applications. Anesthesiology. 1999; 91: 1090-1121 Crossref PubMed Scopus (139) Google Scholar One approach to augment and prolong the pulmonary vasodilator effects of inhaled NO is the concomitant administration of an inhibitor of cyclic guanosine 3′-5′ monophosphate metabolism. Sildenafil is a selective inhibitor of type 5 phosphodiesterase, a phosphodiesterase isoenzyme that metabolizes cyclic guanosine 3′-5′ monophosphate specifically and is present in pulmonary vascular smooth muscle cells. 6 Corbin J.D. Francis S.H. Cyclic GMP phosphodiesterase-5 target of sildenafil. J Biol Chem. 1999; 274: 13729-13732 Crossref PubMed Scopus (467) Google Scholar Our laboratory has recently reported that sildenafil is a selective pulmonary vasodilator in lambs with experimental pulmonary hypertension. 7 Weimann J. Ullrich R. Hromi J. Fujino Y. Clark M.W. Bloch K.D. Zapol W.M. Sildenafil is a pulmonary vasodilator in awake lambs with acute pulmonary hypertension. Anesthesiology. 2000; 92: 1702-1712 Crossref PubMed Scopus (205) Google Scholar Several case reports have suggested that sildenafil has pulmonary vasodilator effects in humans, 8 Prasad S. Wilkinson J. Gatzoulis M.A. Sildenafil in primary pulmonary hypertension. N Engl J Med. 2000; 343: 1342 Crossref PubMed Scopus (313) Google Scholar , 9 Zhao L. Mason N.A. Morrell N.W. Kojonazarov B. Sadykov A. Maripov A. Mirrakhimov M.M. Aldashev A. Wilkins M.R. Sildenafil inhibits hypoxia-induced pulmonary hypertension. Circulation. 2001; 104: 424-428 Crossref PubMed Scopus (431) Google Scholar , 10 Wilkens H. Guth A. Konig J. Forestier N. Cremers B. Hennen B. Bohm M. Sybrecht G.W. Effect of inhaled iloprost plus oral sildenafil in patients with primary pulmonary hypertension. Circulation. 2001; 104: 1218-1222 Crossref PubMed Scopus (373) Google Scholar that it can augment the pulmonary vasodilator effects of inhaled NO, 11 Bigatello L.M. Hess D. Dennehy K.C. Medoff B.D. Hurford W.E. Sildenafil can increase the response to inhaled nitric oxide. Anesthesiology. 2000; 92: 1827-1829 Crossref PubMed Scopus (64) Google Scholar and that it can prevent rebound pulmonary hypertension after cessation of NO inhalation. 12 Atz A.M. Wessel D.L. Sildenafil ameliorates effects of inhaled nitric oxide withdrawal. Anesthesiology. 1999; 91: 307-310 Crossref PubMed Scopus (317) Google Scholar , 13 Mychaskiw G. Sachdev V. Heath B.J. Sildenafil (Viagra) facilitates weaning of inhaled nitric oxide following placement of a biventricular-assist device. J Clin Anesth. 2001; 13: 218-220 Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar In this report, we describe hemodynamic effects of sildenafil administered alone and in combination with inhaled NO in a series of adult patients with primary pulmonary hypertension.