Circulation. 2002;105:2398-2403
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
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Circulation. 2002;105:2398.)
© 2002 American Heart Association, Inc.
Clinical Investigation and Reports |
Oral Sildenafil Is an Effective and Specific Pulmonary Vasodilator in Patients With Pulmonary Arterial Hypertension
Comparison With Inhaled Nitric Oxide
From the Department of Medicine, Division of Cardiology; Vascular Biology Group; and Division of Pulmonary Medicine (D.L.), University of Alberta, Edmonton, Alberta, Canada.
Correspondence to Evangelos D. Michelakis, MD, Cardiology, University of Alberta, 2C2.36 Walter Mackenzie Health Sciences Centre, Edmonton, AB, Canada T6G 2B7. 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.
Key Words: hypertension, pulmonary • nitric oxide • hemodynamics
This article has been cited by other articles:
 |
|
 |
|
  A. Giardini, A. Balducci, S. Specchia, G. Gargiulo, M. Bonvicini, and F. M. Picchio Effect of sildenafil on haemodynamic response to exercise and exercise capacity in Fontan patients Eur. Heart J., July 1, 2008; 29(13): 1681 - 1687. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Bhate, M. Rossiter-Thornton, S. G. Cooper, J. Gillis, A. D. Cole, G. S. Sholler, R. B. Chard, and D. S. Winlaw Use of sildenafil and nitric oxide in the management of hypoxemia owing to pulmonary arteriovenous fistulas after total cavopulmonary connection. J. Thorac. Cardiovasc. Surg., February 1, 2008; 135(2): 446 - 448. [Full Text] [PDF]
|
|
|
|
 |
|
 D. Gamboa, D. Robbins, and Z. Saba Bleeding After Circumcision in a Newborn Receiving Sildenafil Clinical Pediatrics, December 1, 2007; 46(9): 842 - 843. [Abstract] [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]
|
|
|
|
 |
|
 Y. Kamata, M. Iwamoto, and S. Minota Consecutive use of sildenafil and bosentan for the treatment of pulmonary arterial hypertension associated with collagen vascular disease: sildenafil as reliever and bosentan as controller Lupus, November 1, 2007; 16(11): 901 - 903. [Abstract] [PDF]
|
|
|
|
 |
|
 P. Vermeersch, E. Buys, P. Pokreisz, G. Marsboom, F. Ichinose, P. Sips, M. Pellens, H. Gillijns, M. Swinnen, A. Graveline, et al. Soluble Guanylate Cyclase-{alpha}1 Deficiency Selectively Inhibits the Pulmonary Vasodilator Response to Nitric Oxide and Increases the Pulmonary Vascular Remodeling Response to Chronic Hypoxia Circulation, August 21, 2007; 116(8): 936 - 943. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Nagendran, S. L. Archer, D. Soliman, V. Gurtu, R. Moudgil, A. Haromy, C. St. Aubin, L. Webster, I. M. Rebeyka, D. B. Ross, et al. Phosphodiesterase Type 5 Is Highly Expressed in the Hypertrophied Human Right Ventricle, and Acute Inhibition of Phosphodiesterase Type 5 Improves Contractility Circulation, July 17, 2007; 116(3): 238 - 248. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Nagendran and E. Michelakis MRI: One-Stop Shop for the Comprehensive Assessment of Pulmonary Arterial Hypertension? Chest, July 1, 2007; 132(1): 2 - 5. [Full Text] [PDF]
|
|
|
|
|
|
C. T.-J. Gan, S. Holverda, J. T. Marcus, W. J. Paulus, K. M. Marques, J. G.F. Bronzwaer, J. W. Twisk, A. Boonstra, P. E. Postmus, and A. Vonk-Noordegraaf Right Ventricular Diastolic Dysfunction and the Acute Effects of Sildenafil in Pulmonary Hypertension Patients Chest, July 1, 2007; 132(1): 11 - 17. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Takaoka, J. L. Faul, and R. Doyle Current Therapies for Pulmonary Arterial Hypertension Seminars in Cardiothoracic and Vascular Anesthesia, June 1, 2007; 11(2): 137 - 148. [Abstract] [PDF]
|
|
|
|
|
|
G. D. Lewis, J. Lachmann, J. Camuso, J. J. Lepore, J. Shin, M. E. Martinovic, D. M. Systrom, K. D. Bloch, and M. J. Semigran Sildenafil Improves Exercise Hemodynamics and Oxygen Uptake in Patients With Systolic Heart Failure Circulation, January 2, 2007; 115(1): 59 - 66. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Martell, F. Blasina, F. Silvera, S. Tellechea, C. Godoy, L. Vaamonde, L. Benenatti, and W. Olivera Intratracheal Sildenafil in the Newborn With Pulmonary Hypertension Pediatrics, January 1, 2007; 119(1): 215 - 216. [Full Text] [PDF]
|
|
|
|
 |
|
 O. Uzun, J. K. Wong, V. Bhole, and O. Stumper Resolution of Protein-Losing Enteropathy and Normalization of Mesenteric Doppler Flow With Sildenafil After Fontan Ann. Thorac. Surg., December 1, 2006; 82(6): e39 - e40. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Fantozzi, O. Platoshyn, A. H. Wong, S. Zhang, C. V. Remillard, M. R. Furtado, O. V. Petrauskene, and J. X.-J. Yuan Bone morphogenetic protein-2 upregulates expression and function of voltage-gated K+ channels in human pulmonary artery smooth muscle cells Am J Physiol Lung Cell Mol Physiol, November 1, 2006; 291(5): L993 - L1004. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Mukhopadhyay, M. Sharma, S. Ramakrishnan, J. Yusuf, M. D. Gupta, N. Bhamri, V. Trehan, and S. Tyagi Phosphodiesterase-5 Inhibitor in Eisenmenger Syndrome: A Preliminary Observational Study Circulation, October 24, 2006; 114(17): 1807 - 1810. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Kiowski, H. Brunner, and C. Schalcher Sex, the heart, and heart failure. Seminars in Cardiothoracic and Vascular Anesthesia, September 1, 2006; 10(3): 256 - 258. [Abstract] [PDF]
|
|
|
|
 |
|
 Z.-K. Dai, M.-S. Tan, C.-Y. Chai, S.-H. Chou, P.-C. Lin, J.-L. Yeh, A. Y. Jeng, C.-I Chang, I.-J. Chen, and J.-R. Wu Effects of Sildenafil on Pulmonary Hypertension and Levels of ET-1, eNOS, and cGMP in Aorta-Banded Rats. Experimental Biology and Medicine, June 1, 2006; 231(6): 942 - 947. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Baquero, A. Soliz, F. Neira, M. E. Venegas, and A. Sola Oral Sildenafil in Infants With Persistent Pulmonary Hypertension of the Newborn: A Pilot Randomized Blinded Study Pediatrics, April 1, 2006; 117(4): 1077 - 1083. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. V. Evgenov, C. J. Busch, N. V. Evgenov, R. Liu, B. Petersen, G. E. Falkowski, B. Petho, A. Vas, K. D. Bloch, W. M. Zapol, et al. Inhibition of phosphodiesterase 1 augments the pulmonary vasodilator response to inhaled nitric oxide in awake lambs with acute pulmonary hypertension Am J Physiol Lung Cell Mol Physiol, April 1, 2006; 290(4): L723 - L729. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. B. Lobato, T. Beaver, J. Muehlschlegel, D. S. Kirby, C. Klodell, and A. Sidi Treatment with phosphodiesterase inhibitors type III and V: milrinone and sildenafil is an effective combination during thromboxane-induced acute pulmonary hypertension Br. J. Anaesth., March 1, 2006; 96(3): 317 - 322. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. R. Klinger, S. Thaker, J. Houtchens, I. R. Preston, N. S. Hill, and H. W. Farber Pulmonary hemodynamic responses to brain natriuretic Peptide and sildenafil in patients with pulmonary arterial hypertension. Chest, February 1, 2006; 129(2): 417 - 425. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. M. Tsai, M. W. Turrentine, B. C. Sheridan, M. Wang, A. C. Fiore, J. W. Brown, and D. R. Meldrum Differential Effects of Phosphodiesterase-5 Inhibitors on Hypoxic Pulmonary Vasoconstriction and Pulmonary Artery Cytokine Expression Ann. Thorac. Surg., January 1, 2006; 81(1): 272 - 278. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. J. Rubin Pulmonary arterial hypertension. Proceedings of the ATS, January 1, 2006; 3(1): 111 - 115. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Belmonte, C. Ticconi, S. Dolci, M. Giorgi, A. Zicari, A. Lenzi, E. A. Jannini, and E. Piccione Regulation of Phosphodiesterase 5 Expression and Activity in Human Pregnant and Non-pregnant Myometrial Cells by Human Chorionic Gonadotropin Reproductive Sciences, December 1, 2005; 12(8): 570 - 577. [Abstract] [PDF]
|
|
|
|
 |
|
 N. Galie, H. A. Ghofrani, A. Torbicki, R. J. Barst, L. J. Rubin, D. Badesch, T. Fleming, T. Parpia, G. Burgess, A. Branzi, et al. Sildenafil Citrate Therapy for Pulmonary Arterial Hypertension N. Engl. J. Med., November 17, 2005; 353(20): 2148 - 2157. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. M. Hoeper, I. Markevych, E. Spiekerkoetter, T. Welte, and J. Niedermeyer Goal-oriented treatment and combination therapy for pulmonary arterial hypertension Eur. Respir. J., November 1, 2005; 26(5): 858 - 863. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. F. Nadrous, P. A. Pellikka, M. J. Krowka, K. L. Swanson, N. Chaowalit, P. A. Decker, and J. H. Ryu Pulmonary Hypertension in Patients With Idiopathic Pulmonary Fibrosis Chest, October 1, 2005; 128(4): 2393 - 2399. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Fung, R. R. Fiscus, A. P. C. Yim, G. D. Angelini, and A. A. Arifi The Potential Use of Type-5 Phosphodiesterase Inhibitors in Coronary Artery Bypass Graft Surgery Chest, October 1, 2005; 128(4): 3065 - 3073. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Ladha, S. Bonnet, F. Eaton, K. Hashimoto, G. Korbutt, and B. Thebaud Sildenafil Improves Alveolar Growth and Pulmonary Hypertension in Hyperoxia-induced Lung Injury Am. J. Respir. Crit. Care Med., September 15, 2005; 172(6): 750 - 756. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. J. Rubin and D. B. Badesch Evaluation and Management of the Patient with Pulmonary Arterial Hypertension Ann Intern Med, August 16, 2005; 143(4): 282 - 292. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Wharton, J. W. Strange, G. M. O. Moller, E. J. Growcott, X. Ren, A. P. Franklyn, S. C. Phillips, and M. R. Wilkins Antiproliferative Effects of Phosphodiesterase Type 5 Inhibition in Human Pulmonary Artery Cells Am. J. Respir. Crit. Care Med., July 1, 2005; 172(1): 105 - 113. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. A. Dias-Junior, D. C. Souza-Costa, T. Zerbini, J. B. T. da Rocha, R. F. Gerlach, and J. E. Tanus-Santos The Effect of Sildenafil on Pulmonary Embolism-Induced Oxidative Stress and Pulmonary Hypertension Anesth. Analg., July 1, 2005; 101(1): 115 - 120. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Humpl, J. T. Reyes, H. Holtby, D. Stephens, and I. Adatia Beneficial Effect of Oral Sildenafil Therapy on Childhood Pulmonary Arterial Hypertension: Twelve-Month Clinical Trial of a Single-Drug, Open-Label, Pilot Study Circulation, June 21, 2005; 111(24): 3274 - 3280. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Ng, S. J. Finney, R. Shulman, G. J. Bellingan, M. Singer, and P. A. Glynne Treatment of pulmonary hypertension in the general adult intensive care unit: a role for oral sildenafil? Br. J. Anaesth., June 1, 2005; 94(6): 774 - 777. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. J. Lepore, A. Maroo, L. M. Bigatello, G. W. Dec, W. M. Zapol, K. D. Bloch, and M. J. Semigran Hemodynamic Effects of Sildenafil in Patients With Congestive Heart Failure and Pulmonary Hypertension: Combined Administration With Inhaled Nitric Oxide Chest, May 1, 2005; 127(5): 1647 - 1653. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. J Lee, T. B Chiao, and M. P Tsang Sildenafil for Pulmonary Hypertension Ann. Pharmacother., May 1, 2005; 39(5): 869 - 884. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Das, L. Xi, and R. C. Kukreja Phosphodiesterase-5 Inhibitor Sildenafil Preconditions Adult Cardiac Myocytes against Necrosis and Apoptosis: ESSENTIAL ROLE OF NITRIC OXIDE SIGNALING J. Biol. Chem., April 1, 2005; 280(13): 12944 - 12955. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A Rashid and D Ivy Severe paediatric pulmonary hypertension: new management strategies Arch. Dis. Child., January 1, 2005; 90(1): 92 - 98. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. M. Lowson Alternatives to nitric oxide Br. Med. Bull., November 5, 2004; 70(1): 119 - 131. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. A. Palmieri, F. Affuso, S. Fazio, and D. Lembo Tadalafil in Primary Pulmonary Arterial Hypertension Ann Intern Med, November 2, 2004; 141(9): 743 - 744. [Full Text] [PDF]
|
|
|
|
|
|
H. A. Ghofrani, R. Voswinckel, F. Reichenberger, H. Olschewski, P. Haredza, B. Karadas, R. T. Schermuly, N. Weissmann, W. Seeger, and F. Grimminger Differences in hemodynamic and oxygenation responses to three different phosphodiesterase-5 inhibitors in patients with pulmonary arterial hypertension: A randomized prospective study J. Am. Coll. Cardiol., October 6, 2004; 44(7): 1488 - 1496. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. G. Raja and S. H. Nayak Sildenafil: Emerging Cardiovascular Indications Ann. Thorac. Surg., October 1, 2004; 78(4): 1496 - 1506. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. Pauvert, S. Bonnet, E. Rousseau, R. Marthan, and J.-P. Savineau Sildenafil alters calcium signaling and vascular tone in pulmonary arteries from chronically hypoxic rats Am J Physiol Lung Cell Mol Physiol, September 1, 2004; 287(3): L577 - L583. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W.-R. Chou, P.-H. Kuo, J.-C. Shih, and P.-C. Yang A 31-Year-Old Pregnant Woman With Progressive Exertional Dyspnea and Differential Cyanosis Chest, August 1, 2004; 126(2): 638 - 641. [Full Text] [PDF]
|
|
|
|
|
|
B. P. Madden, A. Sheth, T. B. L. Ho, J. E. S. Park, and R. R. Kanagasabay Potential role for sildenafil in the management of perioperative pulmonary hypertension and right ventricular dysfunction after cardiac surgery Br. J. Anaesth., July 1, 2004; 93(1): 155 - 156. [Full Text] [PDF]
|
|
|
|
|
|
D. B. Badesch, S. H. Abman, G. S. Ahearn, R. J. Barst, D. C. McCrory, G. Simonneau, and V. V. McLaughlin Medical Therapy For Pulmonary Arterial Hypertension: ACCP Evidence-Based Clinical Practice Guidelines Chest, July 1, 2004; 126(1_suppl): 35S - 62S. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Ichinose, J. D. Roberts Jr, and W. M. Zapol Inhaled Nitric Oxide: A Selective Pulmonary Vasodilator: Current Uses and Therapeutic Potential Circulation, June 29, 2004; 109(25): 3106 - 3111. [Full Text] [PDF]
|
|
|
|
|
|
H. A. Ghofrani, J. Pepke-Zaba, J. A. Barbera, R. Channick, A. M. Keogh, M. A. Gomez-Sanchez, M. Kneussl, and F. Grimminger Nitric oxide pathway and phosphodiesterase inhibitors in pulmonary arterial hypertension J. Am. Coll. Cardiol., June 16, 2004; 43(12_Suppl_S): 68S - 72S. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. J. Lacassie, A. M. Germain, G. Valdes, M S. Fernandez, F. Allamand, and H. Lopez Management of Eisenmenger Syndrome in Pregnancy With Sildenafil and l-arginine Obstet. Gynecol., May 1, 2004; 103(5): 1118 - 1120. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. J. Webster, E. D. Michelakis, T. Davis, and S. L. Archer Use of Sildenafil for Safe Improvement of Erectile Function and Quality of Life in Men With New York Heart Association Classes II and III Congestive Heart Failure: A Prospective, Placebo-Controlled, Double-blind Crossover Trial Arch Intern Med, March 8, 2004; 164(5): 514 - 520. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. W Mikhail, S. K Prasad, W. Li, P. Rogers, A. H Chester, S. Bayne, D. Stephens, M. Khan, J.S.R Gibbs, T. W Evans, et al. Clinical and haemodynamic effects of sildenafil in pulmonary hypertension: acute and mid-term effects Eur. Heart J., March 1, 2004; 25(5): 431 - 436. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Abe, H. Shimokawa, K. Morikawa, T. Uwatoku, K. Oi, Y. Matsumoto, T. Hattori, Y. Nakashima, K. Kaibuchi, K. Sueishi, et al. Long-Term Treatment With a Rho-Kinase Inhibitor Improves Monocrotaline-Induced Fatal Pulmonary Hypertension in Rats Circ. Res., February 20, 2004; 94(3): 385 - 393. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. T. Schermuly, K. P. Kreisselmeier, H. A. Ghofrani, H. Yilmaz, G. Butrous, L. Ermert, M. Ermert, N. Weissmann, F. Rose, A. Guenther, et al. Chronic Sildenafil Treatment Inhibits Monocrotaline-induced Pulmonary Hypertension in Rats Am. J. Respir. Crit. Care Med., January 1, 2004; 169(1): 39 - 45. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. C Kukreja, R. Ockaili, F. Salloum, and L. Xi Sildenafil-induced cardioprotection in rabbits Cardiovasc Res, December 1, 2003; 60(3): 700 - 701. [Full Text] [PDF]
|
|
|
|
|