A stable preparation of pulmonary hypertension in sheep was developed using a continuous infusion of the vasoconstrictor U46619, a stable endoperoxide thromboxane A2-mimetic. Using this model, the pulmonary and systemic effects of nitroglycerin, sodium nitroprusside, hydralazine, and prostaglandin E1 were compared at doses producing equivalent reductions in systemic blood pressure. Although all four drugs decreased pulmonary artery pressure and resistance, different drug hemodynamic profiles were found. Prostaglandin E1 demonstrated the greatest pulmonary specificity and resulted in the largest decrease in pulmonary artery pressure (from 33 ± 1 to 23 ± 1 mmHg). Nitroglycerin and sodium nitroprusside demonstrated intermediate pulmonary specificity and did not affect cardiac output. Hydralazine demonstrated the least pulmonary specificity and resulted in a large decrease in systemic vascular resistance, with only a moderate decrease in pulmonary artery pressure and resistance. Rational selection of pulmonary vasodilators for clinical application will vary depending on baseline heart rate and rhythm, pulmonary artery pressure, systemic artery pressure, and cardiac output.