DIPYRIDAMOLE, A CGMP PHOSPHODIESTERASE INHIBITOR, CAUSES PULMONARY VASODILATION IN THE OVINE FETUS

Endogenous nitric oxide (NO) modulates fetal pulmonary vascular tone b y stimulating guanosine 3',5'-cyclic monophosphate (cGMP) production i n vascular smooth muscle. Because cGMP is hydrolyzed and inactivated b y phosphodiesterase enzymes, we evaluated the hemodynamic effects of t wo cGMP-specific phosphodiesterase (PDES) inhibitors, dipyridamole and zaprinast, in the near-term chronically prepared ovine fetus. Brief ( 10 min) intrapulmonary infusions of dipyridamole caused dose-dependent increases in left pulmonary artery flow and decreases in left pulmona ry arterial resistance that persisted for >40 min after termination of the infusion. Prolonged (2 h) infusions of dipyridamole caused sustai ned pulmonary vasodilation throughout the infusion period. To compare the hemodynamic effects of dipyridamole with the PDES antagonist zapri nast, we studied the responses to equimolar doses of both agents in fo ur fetuses. Zaprinast caused dose-dependent pulmonary vasodilation tha t was equivalent to that noted with equimolar doses of dipyridamole. T o determine whether adenosine is involved with dipyridamole-induced pu lmonary vasodilation, we compared the hemodynamic response to dipyrida mole before and after administration of the potent adenosine receptor (P-1) antagonist 8-phenyltheophylline (8-PT). Pretreatment with 8-PT m arkedly attenuated adenosine-induced pulmonary vasodilation but had no effect on the hemodynamic response to dipyridamole. We conclude that cGMP-specific phosphodiesterase activity is important in regulating fe tal pulmonary vascular tone. In addition, dipyridamole administration causes dose-dependent pulmonary vasodilation that is equivalent to zap rinast and not primarily due to its effects on adenosine. We speculate that dipyridamole may be useful as a pulmonary vasodilator, either al one or in combination with cGMP-dependent dilators such as inhaled NO.