Importance of local production of endothelin-1 and of the ETB receptor in the regulation of pulmonary vascular tone

Interaction between locally released endothelin-1 (ET-1) and the endothelial ETB receptor could modulate pulmonary vascular tone. We evaluated pulmonary ET-1 clearance and ET-1-ETB receptor interaction in the modulation of pulmonary vascular tone. Controls and rats with Monocrotaline (MCT)-induced pulmonary hypertension (PH) were studied. Lungs were isolated and perfused under constant pressure. The effect of the selective ETB antagonist BQ-788 (10(-12)-10(-8) mole) on perfusion flow rate and I-125-ET-1 extraction was determined. Baseline I-125-ET-1 extraction was reduced from 62+/-5% in controls to 49+/-10% in PH (P=0.012). BQ-788 inhibited extraction with a higher half-inhibitory dose in the MCT group (-Log ID50 = 8.9 +/-0.4 vs. 9.5+/-0.1, P= 0.03). BQ-788 induced a mild reduction in perfusion flow rate of 0.7 +/- 0.3 ml/min in controls. In the MCT group, this occurred at a lower dose and was more pronounced with a maximal reduction of 3.3 +/- 0.7 ml/min (P<0.01 vs. control). ET-1 was undetectable in the effluent at baseline but was present in similar concentrations in both groups after ETB blockade. Addition of 2 pg/ml ET-1 to lung perfusate did not modify pulmonary ET-1 clearance or the effect of BQ788 on perfusion flow rate in control lungs. In normal rat lungs, the ETB receptor plays a minor regulatory role on vascular tone. In MCT hypertension however, despite a reduction in ETB mediated extraction, luminal production of ET-1 attenuates the increase in pulmonary vascular tone. (C) 2000 Academic Press.