Characterization and distribution of endothelin receptors in the pulmonarycirculation: Investigation of isolated, perfused, and ventilated rabbit lungs

The aim of the study was to investigate the distribution of 2 subtypes of e ndothelin-receptors, mediating the effects of endothelin-1 (ET-1) in the pu lmonary circulation. Until now, it is still unclear, whether ETA receptors or ETB receptors or even both are localized in pulmonary vessels. The exper iments were performed on 72 isolated and ventilated rabbit lungs that were perfused with a cell- and plasma-free buffer solution. The arterial pressur e and the lung weight gain were continuously registered. Intermittently per fusate samples were taken for determination of thromboxane A(2) (TXA(2)) an d prostacyclin (PGI(2)). The injection of ET-1 (10(-8) M, n = 6) resulted i n a biphasic increase in pulmonary arterial pressure (PAP) that was accompa nied by the generation of TXA(2) and PGI(2). Pretreatment with the ETA-rece ptor antagonist LU135252 (10(-6) M, n = 6) suppressed the pressure response after ET-1 application (P < 0.01 at 120 min) and reduced the generation of TXA(2) (P < 0.05 at 120 min) and PGI(2) (P < 0.05 at 120 min). Pretreatmen t with the cyclooxygenase inhibitor diclofenac (10 mu g/mL; n = 6) also red uced the PAP increase after ET-1 injection. In contrast to this, the pulmon ary vascular pressure reaction after ET-1 application was elevated, when ET B-receptor antagonist BQ788 (10(-6) M; n = 6) was given. Furthermore, the P GI(2) to TXA(2) ratio was shifted from 2.3 to 0.9, reflecting a predominanc e of vasoconstrictive TXA(2). The simultaneous application of LU135252 and BQ788 significantly reduced the PAP increase after ET-1 application, but no beneficial effects were observed compared with the application of LU135252 solely. The injection of the ETB-receptor agonist sarafotoxin S6c (S6c; 10 (-8) M, n = 6) also induced an increase in PAP that was not attenuated by p retreatment with the ETB-receptor antagonist BQ788 (10(-6) M, n = 6). LU135 252 (n = 6) as well as the application of LU135252 in combination with BQ78 8 (n = 6) failed to suppress the pressure response after S6c, whereas the c yclooxygenase inhibitor diclofenac (10 mu g/mL, n = 6) alone and in combina tion with LU135252 and BQ788 (n = 6) was able to prevent the PAP increase a fter S6c injection (P < 0.001), The results demonstrate that the ET-1-induc ed increase in pulmonary vascular resistance is mainly mediated via ETA rec eptors, whereas ETB receptors seem to mediate vasodilation, which was shown by an imbalance of TXA(2) and PGI(2) generation. On the other hand, the ET B-receptor agonist S6c induced vasoconstriction, which was only attenuated by the cyclooxygenase inhibitor diclofenac. From the current results we con clude that, apart from vasoconstrictor ETA receptors, at least 2 ETB-recept or subtypes are expressed in the pulmonary circulation, one mediating vasoc onstriction, which was not blocked by BQ788, and one mediating vasodilation , which was influenced by BQ788.