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Ann Thorac Surg 1997;64:414-420
© 1997 The Society of Thoracic Surgeons

Original Articles: Cardiovascular

L-Arginine Prevents Cyclosporin A-Induced Pulmonary Vascular Dysfunction

Patrick Mathieu, MD, Michel Carrier, MD, Jocelyn Dupuis, MD, PhD, Jim Ryan, MD, PhD, L. Conrad Pelletier, MD

Departments of Medicine and Surgery, Montreal Heart Institute, Montreal, Quebec, Canada

Accepted for publication February 3, 1997.

Background. Cyclosporin A is known to alter endothelium-dependent responses to different agonists. Few data are available concerning the effect of cyclosporin A on the pulmonary vascular bed.

Methods. The endothelium-dependent responses to acetylcholine (20 µg), bradykinin (5 µg), and substance P (5 µg) were investigated in a dog model of left lung autoperfusion at constant flow.

Results. The vasodilator response to bradykinin and substance P was significantly decreased with cyclosporin A (20 mg) administration. The average decreases in pulmonary arterial pressure with bradykinin were 5.4 ± 1.5 mm Hg and 2.4 ± 0.4 mm Hg before and after cyclosporin A administration, respectively (p = 0.04). The average decreases in pulmonary arterial pressure with substance P were 4.4 ± 1.0 mm Hg and 1.8 ± 0.5 mm Hg before and after cyclosporin A administration, respectively (p = 0.04). The responses to acetylcholine and the endothelium-independent relaxing agent nitroglycerin were not significantly affected by cyclosporin A. The effects of cyclosporin A on endothelium-dependent responses to bradykinin and substance P were overcome by the administration of L-arginine (200 mg/kg intravenously). The decreased response to bradykinin and substance P after cyclosporin A administration was not significantly affected by indomethacin, a cyclooxygenase inhibitor. The pulmonary angiotensin-converting enzyme activity was also measured using [3H]benzoyl-phenylalanyl-glycyl-proline, an inactive angiotensin-converting enzyme substrate. There was an average [3H]benzoyl-phenylalanyl-glycyl-proline hydrolysis of 54% ± 2% and 55% ± 2% before and after cyclosporin A administration, respectively (not significant).

Conclusions. The present study suggests that cyclosporin A selectively decreases endothelium-dependent responses to bradykinin and substance P without affecting the cyclic guanosine monophosphate-dependent pathway in the canine pulmonary vascular bed. The decreased endothelium-dependent responses to bradykinin and substance P are not related to increased angiotensin-converting enzyme activity. The toxic effect of cyclosporin A on endothelium-dependent responses is reversible by the administration of L-arginine, a source of substrate for nitric oxide.






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