Endothelin plays a role in contractions of isolated pig pulmonary vessels induced by diaspirin cross-linked hemoglobin

The current studies were undertaken to investigate the role of endothelin-1 (ET-1) and its receptors in contractions of isolated pulmonary vessels of the pig induced by diaspirin cross-linked hemoglobin (DCLHb). Second-order pulmonary arteries (PAs) and veins (PVs) were isolated from pigs, cut into rings (4 to 5 mm), and mounted at optimal passive tension in 37 degrees C K rebs-filled tissue baths bubbled with 95% 0(2)/5% CO2. Isometric tension wa s recorded continuously. In paired rings, concentration responses to ET-1 ( 10(-10) to 10(-7) mol/L), DCLHb (10(-9) to 3 x 10(-6) mol/L), and N-nitro-L -arginine (LNA) (10(-6) to 5 x 10(-5) mol/L) in the presence and absence of the ETA receptor antagonist BQ123 (3 x 10(-5) mol/L) were determined. PVs and PAs with intact endothelium and rings from which the endothelium was re moved (denuded) were pretreated with the ETB receptor antagonist BQ788 to d etermine the contribution of ETB receptors to ET-1, DCLHb, and LNA response s. ET-1, DCLHb, and LNA caused concentration-dependent increases in tension in all vessels. In the presence of BQ123, the 50% effective concentration (EC50) of ET-1 was significantly increased (by 5-fold to 10-fold) in all ve ssels. DCLHb concentration responses were significantly attenuated-in the P Vs by 45% and in the PAs by 79%-during treatment with BQ123. BQ123 attenuat ed LNA responses in PVs by 35% and in PAs by 87%. Treatment with BQ788 had no effect on endothelium-intact PVs or PAs but significantly increased ET-1 EC50 (log of the molar concentration) from -9.0 +/- 0.22 to -7.8 +/- 0.05 in denuded PAs. The ET-1 EC50 was significantly decreased in denuded PAs (- 9.0 +/- 0.22) as compared with responses in endothelium-intact PAs (-8.1 +/ - 0.18), DCLHb concentration responses were attenuated by 71% and LNA respo nses by 80% during antagonism with BQ788 in the intact PAs only. These data demonstrate that ET-1 plays a role in DCLHb-induced contractions in the PA and PV. The contributions of ET are mediated by both ETA and ETB receptors in the PA but only by ETA receptors in the PV. These results suggest that the vasoconstrictor actions of DCLHb, which have previously been shown to d epend on its interference with endothelium-generated NO, may also involve E T. This may reflect the importance of the interaction of these two endothel ium-generated physiologic antagonists in the pulmonary circulation.