Effects of zaprinast and dissolved nitric oxide on the pulmonary circulation of fetal sheep.

Abstract

This study was designed to determine indirectly if the changes in ovine fetal pulmonary vascular tone caused by i.v. injections of nitric oxide-containing solutions are mediated by cGMP. We first characterized the dose-response relationship of bolus intrapulmonary injections of zaprinast (a cGMP-selective phosphodiesterase inhibitor) and nitric oxide solutions. Injections of nitric oxide solutions as well as zaprinast solutions resulted in dose-dependent decreases in pulmonary arterial pressure that were greater than reductions in systemic arterial pressure. We also evaluated the effects of simultaneous infusions of zaprinast and U46619 (a thromboxane mimetic) on the response to bolus injections of 1.0 micrograms of acetylcholine, 100 ng of endothelin-1, and 10.0 microL of ethanol saturated with nitric oxide. Zaprinast was infused at a rate of 1.5 mg/min, and the concentration of U46619 was titrated to raise mean left pulmonary arterial pressure (LPAP) to the steady state level that was present before infusing zaprinast. All bolus injections reduced left pulmonary arterial pressure more than they reduced mean systemic arterial pressure. However, neither the response magnitudes nor the response durations were affected by simultaneous infusions of zaprinast and U46619. We therefore suggest that modulation of fetal pulmonary vascular tone by endogenously produced nitric oxide may involve mechanisms other than raising smooth muscle cytoplasmic cGMP concentrations.