DIPYRIDAMOLE POTENTIATES PULMONARY VASODILATION INDUCED BY ACETYLCHOLINE AND NITRIC-OXIDE IN THE OVINE FETUS

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 seve ral vasodilator stimuli, including acetylcholine, decrease fetal PVR t hrough the release of endogenous NO, fetal pulmonary vasodilation is o ften 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 l imits the capability of the fetal pulmonary circulation to dilate or s ustain vasodilation in response to cGMP-dependent stimuli. To test thi s 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 resp onse to dipyridamole before and after pretreatment with the NO synthas e antagonist nitro-L-arginine (L-NA) in five fetal lambs. L-NA complet ely blocked dipyridamole-induced pulmonary vasodilation. To evaluate t he effect of dipyridamole on pulmonary vasodilation due to the stimula ted release of NO, we studied effects of prolonged intrapulmonary acet ylcholine infusions, with and without concomitant administration of lo w-dose dipyridamole, in six fetal lambs. During prolonged (2-h) infusi ons, acetylcholine and dipyridamole individually caused transient pulm onary vasodilation. When administered together, pulmonary vasodilation was of greater magnitude and was sustained for the entire study perio d. To determine the effects of dipyridamole on endothelium-independent pulmonary vasodilation, we investigated the hemodynamic effects of in haled NO (5 and 20 ppm) alone and in combination with dipyridamole dur ing mechanical ventilation with low Fl(02). The combination of dipyrid amole with inhaled NO resulted in a greater degree of pulmonary vasodi lation than that achieved with inhaled NO alone. We conclude that dipy ridamole-induced pulmonary vasodilation is dependent on endogenous (ba sal) NO production and that dipyridamole potentiates vasodilator respo nses to endothelium-dependent and -independent dilators in the ovine f etal pulmonary circulation. We speculate that PDE5 activity opposes va sodilation and maintains high PVR in the normal fetal lung.