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

摘要

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 A2 analogue. Response to NO and rebound pulmonary hypertension were evaluated without and with i.v. dipyridamole. Low-dose dipyridamole (10 μg/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 ?5 (20 parts per million NO + dipyridamole) (p versus NO alone), and mean pulmonary artery pressure decreased from 29.0 to 20.5 (p versus NO), respectively. Mean arterial pressure decreased from 85 to 74 mm Hg (dipyridamole + NO) (p ?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.Abbreviations: CO, cardiac output; MAP, mean arterial pressure; MPAP, mean pulmonary artery pressure; NO, nitric oxide; NO2, nitrogen dioxide; PDE 5, phosphodiesterase type 5; PHT, pulmonary hypertension; ppm, parts per million; PVR, pulmonary vascular resistance; SVR, systemic vascular resistance