Dipyridamole, a cGMP phosphodiesterase inhibitor, causes pulmonary vasodilation in the ovine fetus.
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)
Ziegler
J W
JW
Department of Pediatrics, Children's Hospital, Denver, Colorado, USA.
Ivy
D D
DD
Fox
J J
JJ
Kinsella
J P
JP
Clarke
W R
WR
Abman
S H
SH
D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000818:Animals; D001160:Arterioles / Q000187:drug effects / Q000196:embryology; D004176:Dipyridamole / Q000494:pharmacology*; D005333:Fetus / Q000502:physiology*; D006439:Hemodynamics / Q000187:drug effects; D011651:Pulmonary Artery / Q000187:drug effects / Q000196:embryology*; D058915:Purinergic P1 Receptor Antagonists; D011688:Purinones / Q000494:pharmacology; D018047:Receptors, Purinergic P1 / Q000187:drug effects; D012756:Sheep; D013806:Theophylline / Q000031:analogs & derivatives / Q000494:pharmacology; D013997:Time Factors; D014655:Vascular Resistance; D014664:Vasodilation / Q000187:drug effects*
D058915:Purinergic P1 Receptor Antagonists; D011688:Purinones; D018047:Receptors, Purinergic P1; D004176:Dipyridamole; D013806:Theophylline; C028322:8-phenyltheophylline; D015106:3',5'-Cyclic-GMP Phosphodiesterases; C011145:zaprinast