Am. J. Respir. Crit. Care Med., Volume 157, Number 4, April 1998, 1104-1110

Dipyridamole Potentiates Pulmonary Vasodilation Induced by Acetylcholine and Nitric Oxide in the Ovine Fetus

JAMES W. ZIEGLER, D. DUNBAR IVY, JONATHAN J. FOX, JOHN P. KINSELLA, WILLIAM R. CLARKE, and STEVEN H. ABMAN

Pediatric Heart Lung Center, Sections of Cardiology, Neonatology, and Pulmonary Medicine, Department of Pediatrics, University of Colorado School of Medicine, Denver, Colorado; Departments of Anesthesiology and Pediatrics, University of Washington School of Medicine, Seattle, Washington; and Department of Pediatrics, Section of Pediatric Cardiology, Rhode Island Hospital and Brown University, Providence, Rhode Island

Nitric oxide (NO) modulates pulmonary vascular resistance (PVR) in the normal fetus by increasing the cyclic guanosine 3',5'-monophosphate (cGMP) content of pulmonary vascular smooth muscle cells. Although several vasodilator stimuli, including acetylcholine, decrease fetal PVR through the release of endogenous NO, fetal pulmonary vasodilation is often transient despite prolonged treatment. Because cGMP is hydrolyzed and inactivated by cGMP-specific (type 5) phosphodiesterases (PDE5), we hypothesized that PDE5 activity contributes to high fetal PVR and limits the capability of the fetal pulmonary circulation to dilate or sustain vasodilation in response to cGMP-dependent stimuli. To test this hypothesis, we studied the hemodynamic effects of dipyridamole in 19 late-gestation fetal lambs. To determine whether dipyridamole-induced vasodilation is dependent upon basal NO release, we measured the response to dipyridamole before and after pretreatment with the NO synthase antagonist nitro-L-arginine (L-NA) in five fetal lambs. L-NA completely blocked dipyridamole- induced pulmonary vasodilation. To evaluate the effect of dipyridamole on pulmonary vasodilation due to the stimulated release of NO, we studied effects of prolonged intrapulmonary acetylcholine infusions, with and without concomitant administration of low-dose dipyridamole, in six fetal lambs. During prolonged (2-h) infusions, acetylcholine and dipyridamole individually caused transient pulmonary vasodilation. When administered together, pulmonary vasodilation was of greater magnitude and was sustained for the entire study period. To determine the effects of dipyridamole on endothelium-independent pulmonary vasodilation, we investigated the hemodynamic effects of inhaled NO (5 and 20 ppm) alone and in combination with dipyridamole during mechanical ventilation with low FI_O2. The combination of dipyridamole with inhaled NO resulted in a greater degree of pulmonary vasodilation than that achieved with inhaled NO alone. We conclude that dipyridamole-induced pulmonary vasodilation is dependent on endogenous (basal) NO production and that dipyridamole potentiates vasodilator responses to endothelium-dependent and -independent dilators in the ovine fetal pulmonary circulation. We speculate that PDE5 activity opposes vasodilation and maintains high PVR in the normal fetal lung.

This article has been cited by other articles:

				K. N. Farrow, B. S. Groh, P. T. Schumacker, S. Lakshminrusimha, L. Czech, S. F. Gugino, J. A. Russell, and R. H. Steinhorn Hyperoxia Increases Phosphodiesterase 5 Expression and Activity in Ovine Fetal Pulmonary Artery Smooth Muscle Cells Circ. Res., February 1, 2008; 102(2): 226 - 233. [Abstract] [Full Text] [PDF]

				K. Subramaniam and J.-P. Yared Management of Pulmonary Hypertension in the Operating Room Seminars in Cardiothoracic and Vascular Anesthesia, June 1, 2007; 11(2): 119 - 136. [Abstract] [PDF]

				S. Jaillard, B. Larrue, P. Deruelle, A. Delelis, T. Rakza, G. Butrous, and L. Storme Effects of Phosphodiesterase 5 Inhibitor on Pulmonary Vascular Reactivity in the Fetal Lamb. Ann. Thorac. Surg., March 1, 2006; 81(3): 935 - 942. [Abstract] [Full Text] [PDF]

				B. Larrue, S. Jaillard, M. Lorthioir, X. Roubliova, G. Butrous, T. Rakza, H. Warembourg, and L. Storme Pulmonary vascular effects of sildenafil on the development of chronic pulmonary hypertension in the ovine fetus Am J Physiol Lung Cell Mol Physiol, June 1, 2005; 288(6): L1193 - L1200. [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]

				L. Foubert, D. De Wolf, K. Reyntjens, Y. Van Belleghem, F. De Somer, G. Van Nooten, and E. Mortier Intermittent Nitric Oxide Combined with Intravenous Dipyridamole in a Piglet Model of Acute Pulmonary Hypertension Anesth. Analg., November 1, 2003; 97(5): 1497 - 1500. [Abstract] [Full Text] [PDF]

				S. Mehta Sildenafil for Pulmonary Arterial Hypertension: Exciting, But Protection Required Chest, April 1, 2003; 123(4): 989 - 992. [Full Text] [PDF]

				R. T. Schermuly, A. Roehl, N. Weissmann, H. A. Ghofrani, H. Leuchte, F. Grimminger, W. Seeger, and D. Walmrath Combination of nonspecific PDE inhibitors with inhaled prostacyclin in experimental pulmonary hypertension Am J Physiol Lung Cell Mol Physiol, December 1, 2001; 281(6): L1361 - L1368. [Abstract] [Full Text] [PDF]

				R. C. DUKARM, J. A. RUSSELL, F. C. MORIN III, B. J. PERRY, and R. H. STEINHORN The cGMP-specific Phosphodiesterase Inhibitor E4021 Dilates the Pulmonary Circulation Am. J. Respir. Crit. Care Med., September 1, 1999; 160(3): 858 - 865. [Abstract] [Full Text]

				J. W. ZIEGLER, D. D. IVY, J. W. WIGGINS, J. P. KINSELLA, W. R. CLARKE, and S. H. ABMAN Effects of Dipyridamole and Inhaled Nitric Oxide in Pediatric Patients with Pulmonary Hypertension Am. J. Respir. Crit. Care Med., November 1, 1998; 158(5): 1388 - 1395. [Abstract] [Full Text] [PDF]