Inhaled nitric oxide as a screening agent for safely identifying responders to oral calcium-channel blockers in primary pulmonary hypertension

In a subset of patients with primary pulmonary hypertension (PPH), high doses of oral calcium-channel blockers (CCB) produce a sustained clinical and haemodynamic improvement. However, significant side-effects have been reported during acute testing with CCB. Therefore, to identify accurately patients who may benefit from long-term CCB therapy, there is a need for a safe, potent and short-acting vasodilator. The aim of this study was to compare the acute response to inhaled nitric oxide (NO) and oral high doses of CCB in 33 consecutive patients with PPH. A significant acute vasodilator response was defined by a fall in both mean pulmonary artery pressure and total pulmonary resistance by >20%. Ten patients responded acutely to NO, nine of whom responded acutely to CCB, without any complications. The 23 other patients failed to respond to NO and CCB. In these nonresponders, nine serious adverse events were observed with CCB (38%). There was no clinical or baseline haemodynamic feature predicting acute vasodilator response. Long-term oral treatment with CCB was restricted to the nine acute responders and a sustained clinical and haemodynamic improvement was observed in only six patients. In primary pulmonary hypertension, the acute response rate to high doses of calcium-channel blockers is low (27%). Serious adverse reactions to high doses of calcium-channel blockers during acute testing are frequently observed in nonresponders. It is concluded that nitric oxide may be used as a screening agent for safely identifying patients with primary pulmonary hypertension who respond acutely to calcium-channel blockers and may benefit from long-term treatment with these agents.

This article has been cited by other articles:

				Z-C. Jing, X. Jiang, Z-Y. Han, X-Q. Xu, Y. Wang, Y. Wu, H. Lv, C-R. Ma, Y-J. Yang, and J-L. Pu Iloprost for pulmonary vasodilator testing in idiopathic pulmonary arterial hypertension Eur. Respir. J., June 1, 2009; 33(6): 1354 - 1360. [Abstract] [Full Text] [PDF]

				H. A. Ghofrani and F. Grimminger Soluble guanylate cyclase stimulation: an emerging option in pulmonary hypertension therapy Eur. Respir. Rev., March 1, 2009; 18(111): 35 - 41. [Abstract] [Full Text] [PDF]

				H. A. Ghofrani, M. W. Wilkins, and S. Rich Uncertainties in the Diagnosis and Treatment of Pulmonary Arterial Hypertension Circulation, September 9, 2008; 118(11): 1195 - 1201. [Abstract] [Full Text] [PDF]

				K. Boutet, D. Montani, X. Jais, A. Yaici, O. Sitbon, G. Simonneau, and M. Humbert Review: Therapeutic advances in pulmonary arterial hypertension Therapeutic Advances in Respiratory Disease, August 1, 2008; 2(4): 249 - 265. [Abstract] [PDF]

				B. Sztrymf, F. Coulet, B. Girerd, A. Yaici, X. Jais, O. Sitbon, D. Montani, R. Souza, G. Simonneau, F. Soubrier, et al. Clinical Outcomes of Pulmonary Arterial Hypertension in Carriers of BMPR2 Mutation Am. J. Respir. Crit. Care Med., June 15, 2008; 177(12): 1377 - 1383. [Abstract] [Full Text] [PDF]

				National Pulmonary Hypertension Centres of the UK Consensus statement on the management of pulmonary hypertension in clinical practice in the UK and Ireland Heart, March 1, 2008; 94(Suppl_1): i1 - i41. [Full Text] [PDF]

				National Pulmonary Hypertension Centres of the UK Consensus statement on the management of pulmonary hypertension in clinical practice in the UK and Ireland Thorax, March 1, 2008; 63(Suppl_2): ii1 - ii41. [Full Text] [PDF]

				M. P. Coggins and K. D. Bloch Nitric Oxide in the Pulmonary Vasculature Arterioscler Thromb Vasc Biol, September 1, 2007; 27(9): 1877 - 1885. [Abstract] [Full Text] [PDF]

				J. D. Edelman Clinical Presentation, Differential Diagnosis, and Vasodilator Testing of Pulmonary Hypertension Seminars in Cardiothoracic and Vascular Anesthesia, June 1, 2007; 11(2): 110 - 118. [Abstract] [PDF]

				C. Jardim, C. E. Rochitte, M. Humbert, G. Rubenfeld, D. Jasinowodolinski, C. R. R. Carvalho, and R. Souza Pulmonary artery distensibility in pulmonary arterial hypertension: an MRI pilot study Eur. Respir. J., March 1, 2007; 29(3): 476 - 481. [Abstract] [Full Text] [PDF]

				H. A. Ghofrani, R. Voswinckel, F. Reichenberger, N. Weissmann, R. T. Schermuly, W. Seeger, and F. Grimminger Hypoxia- and non-hypoxia-related pulmonary hypertension - Established and new therapies Cardiovasc Res, October 1, 2006; 72(1): 30 - 40. [Abstract] [Full Text] [PDF]

				S. Ulrich, M. Fischler, R. Speich, V. Popov, and M. Maggiorini Chronic thromboembolic and pulmonary arterial hypertension share acute vasoreactivity properties. Chest, September 1, 2006; 130(3): 841 - 846. [Abstract] [Full Text] [PDF]

				C. G. Elliott, E. W. Glissmeyer, G. T. Havlena, J. Carlquist, J. T. McKinney, S. Rich, M. D. McGoon, M. B. Scholand, M. Kim, R. L. Jensen, et al. Relationship of BMPR2 Mutations to Vasoreactivity in Pulmonary Arterial Hypertension Circulation, May 30, 2006; 113(21): 2509 - 2515. [Abstract] [Full Text] [PDF]

				M. Humbert, O. Sitbon, A. Chaouat, M. Bertocchi, G. Habib, V. Gressin, A. Yaici, E. Weitzenblum, J.-F. Cordier, F. Chabot, et al. Pulmonary Arterial Hypertension in France: Results from a National Registry Am. J. Respir. Crit. Care Med., May 1, 2006; 173(9): 1023 - 1030. [Abstract] [Full Text] [PDF]

				A. Rabiller, X. Jais, A. Hamid, A. Resten, F. Parent, R. Haque, F. Capron, O. Sitbon, G. Simonneau, and M. Humbert Occult alveolar haemorrhage in pulmonary veno-occlusive disease Eur. Respir. J., January 1, 2006; 27(1): 108 - 113. [Abstract] [Full Text] [PDF]

				H Nunes, M Humbert, F Capron, M Brauner, O Sitbon, J-P Battesti, G Simonneau, and D Valeyre Pulmonary hypertension associated with sarcoidosis: mechanisms, haemodynamics and prognosis Thorax, January 1, 2006; 61(1): 68 - 74. [Abstract] [Full Text] [PDF]

				M. J.D. Griffiths and T. W. Evans Inhaled Nitric Oxide Therapy in Adults N. Engl. J. Med., December 22, 2005; 353(25): 2683 - 2695. [Full Text] [PDF]

				O. Sitbon, M. Humbert, X. Jais, V. Ioos, A. M. Hamid, S. Provencher, G. Garcia, F. Parent, P. Herve, and G. Simonneau Long-Term Response to Calcium Channel Blockers in Idiopathic Pulmonary Arterial Hypertension Circulation, June 14, 2005; 111(23): 3105 - 3111. [Abstract] [Full Text] [PDF]

				R. Souza, H. B. Bogossian, M. Humbert, C. Jardim, R. Rabelo, M. B. P. Amato, and C. R. R. Carvalho N-terminal-pro-brain natriuretic peptide as a haemodynamic marker in idiopathic pulmonary arterial hypertension Eur. Respir. J., March 1, 2005; 25(3): 509 - 513. [Abstract] [Full Text] [PDF]

				R. J. Roeleveld, J. T. Marcus, T. J. C. Faes, T.-J. Gan, A. Boonstra, P. E. Postmus, and A. Vonk-Noordegraaf Interventricular Septal Configuration at MR Imaging and Pulmonary Arterial Pressure in Pulmonary Hypertension Radiology, March 1, 2005; 234(3): 710 - 717. [Abstract] [Full Text] [PDF]

				Task Force members, N. Galie, A. Torbicki, R. Barst, P. Dartevelle, S. Haworth, T. Higenbottam, H. Olschewski, A. Peacock, G. Pietra, et al. Guidelines on diagnosis and treatment of pulmonary arterial hypertension: The Task Force on Diagnosis and Treatment of Pulmonary Arterial Hypertension of the European Society of Cardiology Eur. Heart J., December 2, 2004; 25(24): 2243 - 2278. [Full Text] [PDF]

				P. M. Mourani, D. D. Ivy, D. Gao, and S. H. Abman Pulmonary Vascular Effects of Inhaled Nitric Oxide and Oxygen Tension in Bronchopulmonary Dysplasia Am. J. Respir. Crit. Care Med., November 1, 2004; 170(9): 1006 - 1013. [Abstract] [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]

				M. Humbert, O. Sitbon, and G. Simonneau Treatment of Pulmonary Arterial Hypertension N. Engl. J. Med., September 30, 2004; 351(14): 1425 - 1436. [Full Text] [PDF]

				M.C. Post, S. Janssens, F. Van de Werf, and W. Budts Responsiveness to inhaled nitric oxide is a predictor for mid-term survival in adult patients with congenital heart defects and pulmonary arterial hypertension Eur. Heart J., September 2, 2004; 25(18): 1651 - 1656. [Abstract] [Full Text] [PDF]

				E Hachulla and J G Coghlan A new era in the management of pulmonary arterial hypertension related to scleroderma: endothelin receptor antagonism Ann Rheum Dis, September 1, 2004; 63(9): 1009 - 1014. [Abstract] [Full Text] [PDF]

				B. M. Tsai, M. Wang, M. W. Turrentine, Y. Mahomed, J. W. Brown, and D. R. Meldrum Hypoxic pulmonary vasoconstriction in cardiothoracic surgery: basic mechanisms to potential therapies Ann. Thorac. Surg., July 1, 2004; 78(1): 360 - 368. [Abstract] [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]

				M. Confalonieri, V. Antonaglia, U. Lucangelo, A. Gullo, M. Humbert, and G. Simonneau Sildenafil in Pulmonary Arterial Hypertension Am. J. Respir. Crit. Care Med., June 1, 2004; 169(11): 1256 - 1257. [Full Text]

				H.A. Ghofrani, G. Friese, T. Discher, H. Olschewski, R.T. Schermuly, N. Weissmann, W. Seeger, F. Grimminger, and J. Lohmeyer Inhaled iloprost is a potent acute pulmonary vasodilator in HIV-related severe pulmonary hypertension Eur. Respir. J., February 1, 2004; 23(2): 321 - 326. [Abstract] [Full Text] [PDF]

				H. H. Leuchte, M. Schwaiblmair, R. A. Baumgartner, C. F. Neurohr, T. Kolbe, and J. Behr Hemodynamic Response to Sildenafil, Nitric Oxide, and Iloprost in Primary Pulmonary Hypertension Chest, February 1, 2004; 125(2): 580 - 586. [Abstract] [Full Text] [PDF]

				M Emmel, B Keuth, and S Schickendantz Paradoxical increase of pulmonary vascular resistance during testing of inhaled iloprost Heart, January 1, 2004; 90(1): e2 - 2. [Abstract] [Full Text] [PDF]

				M. Humbert, O. Sitbon, and G. Simonneau Novel therapeutic perspectives in pulmonary arterial hypertension Eur. Respir. J., August 1, 2003; 22(2): 193 - 194. [Full Text] [PDF]

				H. Nunes, M. Humbert, O. Sitbon, J. H. Morse, Z. Deng, J. A. Knowles, C. Le Gall, F. Parent, G. Garcia, P. Herve, et al. Prognostic Factors for Survival in Human Immunodeficiency Virus-associated Pulmonary Arterial Hypertension Am. J. Respir. Crit. Care Med., May 15, 2003; 167(10): 1433 - 1439. [Abstract] [Full Text] [PDF]

				D. Chemla, V. Castelain, P. Herve, Y. Lecarpentier, and S. Brimioulle Haemodynamic evaluation of pulmonary hypertension Eur. Respir. J., November 1, 2002; 20(5): 1314 - 1331. [Abstract] [Full Text] [PDF]

				M. Humbert and R.C. Trembath Genetics of pulmonary hypertension: from bench to bedside Eur. Respir. J., September 1, 2002; 20(3): 741 - 749. [Abstract] [Full Text] [PDF]

				O. Sitbon, M. Humbert, H. Nunes, F. Parent, G. Garcia, P. Herve, M. Rainisio, and G.e. Simonneau Long-term intravenous epoprostenol infusion in primary pulmonary hypertension: Prognostic factors and survival J. Am. Coll. Cardiol., August 21, 2002; 40(4): 780 - 788. [Abstract] [Full Text] [PDF]

				E. Michelakis, W. Tymchak, D. Lien, L. Webster, K. Hashimoto, and S. Archer Oral Sildenafil Is an Effective and Specific Pulmonary Vasodilator in Patients With Pulmonary Arterial Hypertension: Comparison With Inhaled Nitric Oxide Circulation, May 21, 2002; 105(20): 2398 - 2403. [Abstract] [Full Text] [PDF]

				M. M. Hoeper, N. Galie, G. Simonneau, and L. J. Rubin New Treatments for Pulmonary Arterial Hypertension Am. J. Respir. Crit. Care Med., May 1, 2002; 165(9): 1209 - 1216. [Full Text] [PDF]

				H.A. Ghofrani, R. Wiedemann, F. Rose, N. Weissmann, R.T. Schermuly, K. Quanz, F. Grimminger, W. Seeger, and H. Olschewski Lung cGMP release subsequent to NO inhalation in pulmonary hypertension: responders versus nonresponders Eur. Respir. J., April 1, 2002; 19(4): 664 - 671. [Abstract] [Full Text] [PDF]

				M.M. Hoeper Pulmonary hypertension in collagen vascular disease Eur. Respir. J., March 1, 2002; 19(3): 571 - 576. [Abstract] [Full Text] [PDF]

				I. R. Preston, J. R. Klinger, J. Houtchens, D. Nelson, S. Mehta, and N. S. Hill Pulmonary Edema Caused by Inhaled Nitric Oxide Therapy in Two Patients With Pulmonary Hypertension Associated With the CREST Syndrome Chest, February 1, 2002; 121(2): 656 - 659. [Abstract] [Full Text] [PDF]

				W Budts, N Van Pelt, H Gillyns, M Gewillig, F Van de Werf, and S Janssens Residual pulmonary vasoreactivity to inhaled nitric oxide in patients with severe obstructive pulmonary hypertension and Eisenmenger syndrome Heart, November 1, 2001; 86(5): 553 - 558. [Abstract] [Full Text] [PDF]

				I. M. Robbins, R. J. Barst, R. N. Channick, and L. J. Rubin Pulmonary vasoreactivity in PPH J. Am. Coll. Cardiol., October 1, 2001; 38(4): 1267 - 1267. [Full Text] [PDF]

				British Cardiac Society Guidelines and Medical Pra Recommendations on the management of pulmonary hypertension in clinical practice Heart, September 1, 2001; 86(90001): i1 - 13. [Full Text] [PDF]

				B. A. Cockrill, R. M. Kacmarek, M. A. Fifer, L. M. Bigatello, L. C. Ginns, W. M. Zapol, and M. J. Semigran Comparison of the Effects of Nitric Oxide, Nitroprusside, and Nifedipine on Hemodynamics and Right Ventricular Contractility in Patients With Chronic Pulmonary Hypertension Chest, January 1, 2001; 119(1): 128 - 136. [Abstract] [Full Text] [PDF]

				R. A. Krasuski, J. J. Warner, A. Wang, J. K. Harrison, V. F. Tapson, and T. M. Bashore Inhaled nitric oxide selectively dilates pulmonary vasculature in adult patients with pulmonary hypertension, irrespective of etiology J. Am. Coll. Cardiol., December 1, 2000; 36(7): 2204 - 2211. [Abstract] [Full Text] [PDF]

				R Ziesche, V Petkov, K Wittmann, J Kopatschka, L Stiebellehner, P Schenk, P Germann, G Röder, R Ullrich, and L H Block Treatment with epoprostenol reverts nitric oxide non-responsiveness in patients with primary pulmonary hypertension Heart, April 1, 2000; 83(4): 406 - 409. [Abstract] [Full Text]

				M. FARTOUKH, M. HUMBERT, F. CAPRON, S. MAÎTRE, F. PARENT, C. LE GALL, O. SITBON, P. HERVÉ, P. DUROUX, and G. SIMONNEAU Severe Pulmonary Hypertension in Histiocytosis X Am. J. Respir. Crit. Care Med., January 1, 2000; 161(1): 216 - 223. [Abstract] [Full Text]

				A J Peacock Rare diseases bullet 5: Primary pulmonary hypertension Thorax, December 1, 1999; 54(12): 1107 - 1118. [Full Text]

				C. S Hayward, R. P Kelly, and P. S Macdonald Inhaled nitric oxide in cardiology practice Cardiovasc Res, August 15, 1999; 43(3): 628 - 638. [Abstract] [Full Text] [PDF]

				O. Sanchez, M. Humbert, O. Sitbon, and G. Simonneau Treatment of pulmonary hypertension secondary to connective tissue diseases Thorax, March 1, 1999; 54(3): 273 - 277. [Full Text]