Intravenous dipyridamole enhances the effects of inhaled nitric oxide and prevents rebound pulmonary hypertension in piglets.
Inhaled nitric oxide (NO) is increasingly used in the treatment of pulmonary hypertension, despite its potential toxicity and the risk of life-threatening rebound pulmonary hypertension upon its discontinuation. We investigated whether i.v. dipyridamole, a cGMP phosphodiesterase inhibitor, increased the effects of inhaled NO and prevented rebound pulmonary hypertension. In 14 anesthetized and mechanically ventilated piglets, pulmonary hypertension was induced with U-46619, a thromboxane A(2) analogue. Response to NO and rebound pulmonary hypertension were evaluated without and with i.v. dipyridamole. Low-dose dipyridamole (10 micro g/kg/min) increased cardiac output and augmented the effects of inhaled NO on pulmonary vascular resistance, with marginal additive effect on mean pulmonary artery pressure. Pulmonary vascular resistance decreased from 904 to 511 (20 parts per million NO) (p < 0.0005) and 358 dyne s cm(-5) (20 parts per million NO + dipyridamole) (p < 0.001 versus NO alone), and mean pulmonary artery pressure decreased from 29.0 to 20.5 (p < 0.0001) and 19.3 mm Hg (NS versus NO), respectively. Mean arterial pressure decreased from 85 to 74 mm Hg (dipyridamole + NO) (p < 0.01). High-dose dipyridamole (100 micro g/kg/min) with inhaled NO reduced pulmonary vascular resistance to 334 dyne s cm(-5) but also decreased mean arterial pressure to 57 mm Hg. Eight piglets developed rebound pulmonary hypertension. Two died of acute right ventricular failure and, in five, rebound pulmonary hypertension was prevented by low-dose dipyridamole. In conclusion, low-dose i.v. dipyridamole augments the effects of inhaled NO on right ventricular afterload with moderate changes in systemic hemodynamics, and can prevent rebound pulmonary hypertension.
Foubert
Luc
L
Department of Anesthesia, Division of Cardiac Anesthesia, University Hospital Ghent, Gent, Belgium. Luc.Foubert@olvz-aalst.be
De Wolf
Daniël
D
Mareels
Katty
K
Van Belleghem
Yves
Y
Reyntjens
Koen
K
Mortier
Eric
E
Van Nooten
Guido
G
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000037:antagonists & inhibitors; D000280:Administration, Inhalation; D000818:Animals; D006152:Cyclic GMP / Q000097:blood; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D004176:Dipyridamole / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D004357:Drug Synergism; D006976:Hypertension, Pulmonary / Q000188:drug therapy / Q000201:enzymology / Q000517:prevention & control*; D007275:Injections, Intravenous; D009569:Nitric Oxide / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D010727:Phosphoric Diester Hydrolases / Q000502:physiology; D012008:Recurrence; D013375:Substance Withdrawal Syndrome / Q000517:prevention & control*; D013552:Swine; D014655:Vascular Resistance / Q000187:drug effects
D010726:Phosphodiesterase Inhibitors; D009569:Nitric Oxide; D004176:Dipyridamole; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D010727:Phosphoric Diester Hydrolases; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D006152:Cyclic GMP