Am. J. Respir. Crit. Care Med., Volume 164, Number 9, November 2001, 1694-1700

Coaerosolization of Phosphodiesterase Inhibitors Markedly Enhances the Pulmonary Vasodilatory Response to Inhaled Iloprost in Experimental Pulmonary Hypertension
Maintenance of Lung Selectivity

RALPH THEO SCHERMULY, ELENA KRUPNIK, HERRMANN TENOR, CHRISTIAN SCHUDT, NORBERT WEISSMANN, FRANK ROSE, FRIEDRICH GRIMMINGER, WERNER SEEGER, DIETER WALMRATH, and HOSSEIN ARDESCHIR GHOFRANI

Department of Internal Medicine, Justus-Liebig-University Giessen, D-35392 Giessen, Germany; and Byk Gulden Pharmaceuticals, Konstanz, Germany

Inhalation of aerosolized iloprost, a stable prostacyclin analog, has been suggested for treatment of primary and secondary pulmonary hypertension, but demands multiple daily inhalation maneuvers because of the short-term effect of this approach. In intact rabbits, pulmonary hypertension was induced by continuous infusion of the stable thromboxane mimetic U46619. Thereafter, the influence of aerosolized iloprost on pulmonary and systemic hemodynamics and gas exchange was investigated in the presence and absence of phosphodiesterase (PDE) inhibitors for stabilization of the second-messenger cAMP. First, dose-effect curves for pulmonary artery pressure (Ppa) decline were established for the nonspecific PDE inhibitors pentoxifylline and dipyridamole and for the dual-selective PDE3/4 inhibitor tolafentrine when being applied as sole agent, either via the intravenous or the inhalative route. Subthreshold doses for each agent and each route of administration were then combined with a standardized iloprost aerosolization maneuver, which resulted in a substantial prolongation, but not augmentation, of the lung vasodilatory response for the prostanoid. Next, higher doses of each PDE inhibitor were employed for nebulization, causing per se some pulmonary vasodilative effect, in the absence of arterial pressure decrease or impairment of gas exchange. Coaerosolization of these PDE inhibitor doses with standardized iloprost caused approximate doubling of the immediate pulmonary vasodilator response, marked prolongation of the pressure relief overtime, and a 2- to 4-fold increase in the area under the curve of pulmonary vasodilation (efficacy tolafentrine > dipyridamole > pentoxifylline). Still, systemic arterial pressure was not suppressed and gas exchange was fully maintained. We conclude that coadministration of PDE inhibitors with inhaled iloprost markedly enhances the prostanoid-induced pulmonary artery pressure decrease while maintaining the lung selectivity of the vasodilatory response, and that coaerosolization is a particularly suitable route of administration. Even nonselective clinically approved PDE inhibitors may be employed for this purpose.

This article has been cited by other articles:

				L. De Franceschi, O. S. Platt, G. Malpeli, A. Janin, A. Scarpa, C. Leboeuf, Y. Beuzard, E. Payen, and C. Brugnara Protective effects of phosphodiesterase-4 (PDE-4) inhibition in the early phase of pulmonary arterial hypertension in transgenic sickle cell mice FASEB J, June 1, 2008; 22(6): 1849 - 1860. [Abstract] [Full Text] [PDF]

				F Urdaneta, E. Lobato, T Beaver, J. Muehlschlegel, D. Kirby, C Klodell, and A Sidi Treating pulmonary hypertension post cardiopulmonary bypass in pigs: milrinone vs. sildenafil analog Perfusion, March 1, 2008; 23(2): 117 - 125. [Abstract] [PDF]

				E. Dony, Y-J. Lai, R. Dumitrascu, S. S. Pullamsetti, R. Savai, H. A. Ghofrani, N. Weissmann, C. Schudt, D. Flockerzi, W. Seeger, et al. Partial reversal of experimental pulmonary hypertension by phosphodiesterase-3/4 inhibition Eur. Respir. J., March 1, 2008; 31(3): 599 - 610. [Abstract] [Full Text] [PDF]

				B. L. Sandifer, K. L. Brigham, E. C. Lawrence, D. Mottola, C. Cuppels, and R. E. Parker Potent effects of aerosol compared with intravenous treprostinil on the pulmonary circulation J Appl Physiol, December 1, 2005; 99(6): 2363 - 2368. [Abstract] [Full Text] [PDF]

				R. Dembinski, W. Brackhahn, D. Henzler, A. Rott, R. Bensberg, R. Kuhlen, and R. Rossaint Cardiopulmonary effects of iloprost in experimental acute lung injury Eur. Respir. J., January 1, 2005; 25(1): 81 - 87. [Abstract] [Full Text] [PDF]

				P. G. Phillips, L. Long, M. R. Wilkins, and N. W. Morrell cAMP phosphodiesterase inhibitors potentiate effects of prostacyclin analogs in hypoxic pulmonary vascular remodeling Am J Physiol Lung Cell Mol Physiol, January 1, 2005; 288(1): L103 - L115. [Abstract] [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]

				R. Coimbra, A. Razuk-Filho, M. M. Yada-Langui, and M. Rocha-e-Silva Intraarterial Pulmonary Pentoxifylline Improves Cardiac Performance and Oxygen Utilization After Hemorrhagic Shock: A Novel Resuscitation Strategy Anesth. Analg., May 1, 2004; 98(5): 1439 - 1446. [Abstract] [Full Text] [PDF]

				R. T. Schermuly, K. P. Kreisselmeier, H. A. Ghofrani, A. Samidurai, S. Pullamsetti, N. Weissmann, C. Schudt, L. Ermert, W. Seeger, and F. Grimminger Antiremodeling Effects of Iloprost and the Dual-Selective Phosphodiesterase 3/4 Inhibitor Tolafentrine in Chronic Experimental Pulmonary Hypertension Circ. Res., April 30, 2004; 94(8): 1101 - 1108. [Abstract] [Full Text] [PDF]

				T. Itoh, N. Nagaya, T. Fujii, T. Iwase, N. Nakanishi, K. Hamada, K. Kangawa, and H. Kimura A Combination of Oral Sildenafil and Beraprost Ameliorates Pulmonary Hypertension in Rats Am. J. Respir. Crit. Care Med., January 1, 2004; 169(1): 34 - 38. [Abstract] [Full Text] [PDF]

				T. Kramm, B. Eberle, F. Krummenauer, S. Guth, H. Oelert, and E. Mayer Inhaled iloprost in patients with chronic thromboembolic pulmonary hypertension: effects before and after pulmonary thromboendarterectomy Ann. Thorac. Surg., September 1, 2003; 76(3): 711 - 718. [Abstract] [Full Text] [PDF]

				H. A. Ghofrani, F. Rose, R. T. Schermuly, H. Olschewski, R. Wiedemann, A. Kreckel, N. Weissmann, S. Ghofrani, B. Enke, W. Seeger, et al. Oral sildenafil as long-term adjunct therapy to inhaled iloprost in severe pulmonary arterial hypertension J. Am. Coll. Cardiol., July 2, 2003; 42(1): 158 - 164. [Abstract] [Full Text] [PDF]

				M. J. TOBIN Chronic Obstructive Pulmonary Disease, Pollution, Pulmonary Vascular Disease, Transplantation, Pleural Disease, and Lung Cancer in AJRCCM 2001 Am. J. Respir. Crit. Care Med., March 1, 2002; 165(5): 642 - 662. [Full Text] [PDF]