Tezosentan, a combined parenteral endothelin receptor antagonist, produces pulmonary vasodilation in lambs with acute and chronic pulmonary hypertension

Abstract

Objective: To investigate the hemodynamic effects of tezosentan in the intact lamb both at rest and during acute and chronic pulmonary hypertension.

Design: Prospective, randomized experimental study.

Setting: University-based research laboratory.

Subjects: Lambs with and without pulmonary hypertension.

Interventions: Six newborn lambs were instrumented to measure vascular pressures and left pulmonary blood flow. The hemodynamic effects of tezosentan (0.5, 1.0, 5.0 mg/kg, intravenously) were studied at rest and during U46619-induced pulmonary hypertension. Following in utero placement of an aortopulmonary vascular graft, nine additional lambs with increased pulmonary blood flow and chronic pulmonary hypertension (shunt) were also studied at 1 wk (n = 5) and 8 wks (n = 4) of age.

Measurements and main results: At rest, tezosentan had no significant effect on any of the variables. During acute U46619-induced pulmonary hypertension, tezosentan caused a dose-dependent decrease in pulmonary arterial pressure (from 5.9% +/- 4.7 to 16.0% +/- 10.7; p < .05) and pulmonary vascular resistance (from 6.2% +/- 8.0 to 21% +/- 8.8; p < .05). Mean systemic arterial pressure was unchanged. In 1- and 8-wk-old shunt lambs with increased pulmonary blood flow, tezosentan (1 mg/kg) produced potent nonselective pulmonary vasodilation.

Conclusions: Tezosentan, a combined endothelin receptor antagonist optimized for parenteral use, induces potent selective pulmonary vasodilation during acute U46619-induced pulmonary hypertension and potent nonselective vasodilation in chronic pulmonary hypertension secondary to increased pulmonary blood flow. In general, the hemodynamic effects of bolus doses of tezosentan occurred within 60 secs of administration and lasted approximately 5-10 mins. The hemodynamic profile of intravenous tezosentan may make it a useful adjunct therapy for acute pulmonary hypertensive disorders and warrants further study.