PREVENTION OF COMPLEMENT-INDUCED PULMONARY-HYPERTENSION AND IMPROVEMENT OF RIGHT-VENTRICULAR FUNCTION BY SELECTIVE THROMBOXANE RECEPTOR ANTAGONISM

The effect of complement activation on the pulmonary vascular system a nd on right ventricular function was studied in sheep (n = 12) by inje ction of cobra venom factor. Animals were instrumented for measurement of pulmonary flow, mean pulmonary artery pressure, right ventricular stroke work, arterial blood gases, and systemic vascular resistance. B lood was sampled from the left atrium and pulmonary artery to measure thromboxane B-2, the metabolite of thromboxane A(2), by radioimmunoass ay. After baseline measurements, animals were randomly assigned to rec eive a selective thromboxane receptor antagonist SQ30741 as a 10 mg/kg bolus with an infusion of 10 mg/kg per hour or else to receive vehicl e. Cobra venom factor was then injected (30 U/kg) in all animals, and data were recorded at 15, 30, 60, 90, and 120 minutes. In control anim als there was a 2.4-fold increase in mean pulmonary artery pressure an d a 76 % increase in right ventricular stroke work at 15 minutes from baseline (p < 0.05); these values remained elevated for 30 minutes and returned to baseline by 1 hour with no change in systemic vascular re sistance. Arterial oxygenation decreased by 124 % at 15 minutes and re mained depressed through the experiment, but in treated animals oxygen tension remained unchanged from baseline. Thromboxane B-2 increased 9 5 % from baseline in the control group and 1.5 fold in treated animals and followed a similar time course as the functional measurements (p < 0.05). A pulmonary vascular thromboxane B-2 gradient of approximatel y 1000 pg/ml was measured at 15 and 30 minutes in both control and tre ated groups. (p < 0.05) We conclude that after complement activation i n this model pulmonary hypertension and decreased oxygen tension are m ediated by thromboxane release from the pulmonary vascular bed. This i ncreased afterload causes a stress on the right ventricle as demonstra ted by the increased right ventricular stroke work. Selective thrombox ane receptor antagonism may be a beneficial therapy for pulmonary hype rtension in patients after cardiopulmonary bypass.