IRL2500, A Selective ETB Antagonist for Endothelin-Induced Vasodilatation in the Pulmonary Vascular Bed in Rats

Introduction: Endothelins (ET-1 and ET-2) have vasoactive effects mediated by receptors (ETA & ETB). The objective of the present study was to determine the effect of endothelins and their antagonists on the pulmonary vascular bed in vivo. To accomplish this, we employed the unique rat model and studied the pulmonary vascular beds of intact-chest animal under conditions of constant pulmonary blood flow. Methods: Twenty-five rats were anesthetized with pentobarbital, and a specially designed balloon catheter was placed into rat's the pulmonary artery via the right jugular vein. The right lower lobe of the lung was perfused at constant flow (14 ± 0.6 ml/min) with blood removed from a cannulated carotid artery. The baseline pulmonary arterial pressure was 12.8 ± 1.1 mmHg. In order to demonstrate vasodilator responses to testing agents, the pulmonary arterial pressure was elevated to 34.8 ± 1.4 mmHg by continuous infusion of U46619, a thromboxane-like substance. The effect of various endothelin agonists and antagonists were then studied. Results: Intrapulmonary arterial injections of ET-1, IRL1620 (ETB agonist) and ET-3 produced dose-dependent vasodilator responses in the pulmonary vascular bed. At a dose of 1µg, ET-1, IRL1620 and ET-3 caused decreases in pulmonary arterial pressure of 8.1 ± 0.4 mmHg, 8.2 ± 0.3 mmHg and 7.9 ± 0.3 mmHg respectively (all significantly different from baseline, n=5, p<0.05). After pretreatment with IRL2500 (ETB antagonist, 10mg/kg, i.v.), the vasodilator responses to ET-1, IRL1620 and ET-3 at the same dose were 0.9 ± 0.1mmHg, 2.1 ± 0.3 mmHg and 1.8 ± 0.3 mmHg respectively (n=5, not significantly differ from the baseline). This data suggests that IRL2500 can block the vasodilator responses to ET-1, IRL1620 and ET-3 in the lung. Data from a different group of animal demonstrate that the vasodilator responses to ET-1, IRL1620 and ET-3 are not altered significantly by pretreatment with BQ123 (an ETA antagonist) (n=5) Conclusions: Using a new rat model, these results indicate that ET-1, IRL1620 and ET-3 dilate the pulmonary vascular bed by activation of the ETB receptor. The present data also suggest that IRL2500, as a specific ETB antagonist can be a useful pharmacological tool to study the pulmonary vascular regulation in rats. This new intact rat preparation appears to be valuable in carrying out cardiopulmonary studies in vivo.