Dipyridamole, a cGMP phosphodiesterase inhibitor, causes pulmonary vasodilation in the ovine fetus

Abstract

Endogenous nitric oxide (NO) modulates fetal pulmonary vascular tone by stimulating guanosine 3',5'-cyclic monophosphate (cGMP) production in vascular smooth muscle. Because cGMP is hydrolyzed and inactivated by phosphodiesterase enzymes, we evaluated the hemodynamic effects of two cGMP-specific phosphodiesterase (PDE5) 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 pulmonary arterial resistance that persisted for > 40 min after termination of the infusion. Prolonged (2 h) infusions of dipyridamole caused sustained pulmonary vasodilation throughout the infusion period. To compare the hemodynamic effects of dipyridamole with the PDE5 antagonist zaprinast, we studied the responses to equimolar doses of both agents in four fetuses. Zaprinast caused dose-dependent pulmonary vasodilation that was equivalent to that noted with equimolar doses of dipyridamole. To determine whether adenosine is involved with dipyridamole-induced pulmonary vasodilation, we compared the hemodynamic response to dipyridamole before and after administration of the potent adenosine receptor (P1) antagonist 8-phenyltheophylline (8-PT). Pretreatment with 8-PT markedly 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 fetal pulmonary vascular tone. In addition, dipyridamole administration causes dose-dependent pulmonary vasodilation that is equivalent to zaprinast and not primarily due to its effects on adenosine.(ABSTRACT TRUNCATED AT 250 WORDS)

Inhibition of cyclic 3'-5'-guanosine monophosphate-specific phosphodiesterase selectively vasodilates the pulmonary circulation in chronically hypoxic rats.

“…Recent data suggest that the richest relative source of PDE5 is the lung and pulmonary vasculature (20), suggesting this enzyme as a potential pharmacological target for pulmonary vasodilation. This concept is supported by reports that Zaprinast, a cGMP-specific PDE inhibitor, can vasodilate the neonatal pulmonary circulation (8,21).…”

“…In addition to PDE5 inhibition, dipyridamole is an adenosine reuptake inhibitor. As adenosine may directly and indirectly stimulate cyclic nucleotide production, this property of dipyridamole may complicate interpretation of its effects (21). We therefore used a newly described PDE5 inhibitor, E4021, which has an IC 50 for PDE5 which is 3.5 nM (vs. 450nM for Zaprinast) and has no detectable inhibition of PDE1, PDE3, and PDE4 (24).…”

Pharmacotherapy for meconium aspiration

“…In experimental models it has been shown to augment and prolong the response of NO in post-cardiac surgery patients. 36 However, augmentation response is not consistent and in some pediatric studies decrease in pulmonary vascular resistance of >20% is noted in only half the treated cases. Dipyridamole has been shown to help in attenuating the rebound phenomenon seen after discontinuation of INO therapy in pediatric patients.…”

“…Intravenous administration showed, in a fetal lamb model, to decrease pulmonary arterial resistance as well as a potentiation of inhaled NO-mediated pulmonary vasodilatation. [36][37][38] The concern with intravenous administration was that at moderate-to-high doses systemic vasodilatation was noted. Aerosolized drug therapy has been shown to have less systemic side effects, preferential delivery to better ventilated areas of the lungs and a potentiation of the INO effect.…”

Intravenous Dipyridamole Enhances the Effects of Inhaled Nitric Oxide and Prevents Rebound Pulmonary Hypertension in Piglets

“…Another putative mechanism of vasodilation by dipyridamole includes inhibition of adenosine re-uptake (35). However, the evidence that pulmonary vasodilation by dipyridamole is not altered by adenosine receptor blockers such as theophylline but is exerted through an effect on cGMP metabolism (15,32), and the fact that i.v. dipyridamole can prevent rebound PHT, suggest that cGMP concentrations in pulmonary vascular smooth muscle cells are increased by dipyridamole.…”