Combined therapy with zaprinast and inhaled nitric oxide abolishes hypoxicpulmonary hypertension

Objective: To determine whether the combination of the phosphodiesterase 5 inhibitor zaprinast and inhaled nitric oxide (NO) decreases hypoxic pulmona ry hypertension in the rat. Design: Prospective, experimental study. Setting: Animal laboratory of a university medical center. Subjects: Male Sprague-Dawley rats. interventions: Anesthetized rats were m echanically ventilated and instrumented for measurement of mean systemic ar terial pressure, pulmonary arterial pressure, and cardiac output. In group 1, four acute hypoxic challenges (F10(2) = 0.17 for 5 mins) were performed: initial, during 40 ppm inhaled NO, immediately after discontinuation of 5 mins of inhaled NO, and final. In group 2 rats, an initial hypoxic challeng e was performed and rats then received zaprinast (3 mg/kg bolus followed by 0.3 mg/kg/min infusion). Four hypoxic challenges analogous to group 1 were then performed during zaprinast administration. Measurements and Main Results: Initial hypoxic challenge produced similar i ncreases in pulmonary arterial pressure in both groups. In group 1, inhaled NO either only before or only during hypoxia decreased the pulmonary hyper tensive response to bypoxia. In group 2, zaprinast administration did not a lter hemodynamics. Zaprinast alone decreased the pulmonary hypertensive res ponse to hypoxia. The combination of zaprinast and inhaled NO (either befor e or during hypoxia) abolished the pulmonary hypertensive response to hypox ia. Conclusions: Treatment with inhaled NO for 5 mins before but not during hyp oxia is as effective as inhaled NO during hypoxia. Inhaled NO and zaprinast both decrease the pulmonary hypertensive response to hypoxia, and the comb ination abolishes the response. The combination of a phosphodiesterase 5 in hibitor and inhaled MO may have clinical applicability in the treatment of pulmonary hypertension.