Abstract

The endothelin (ET) receptor that mediates vasoconstriction of the isolated rabbit pulmonary resistance artery was characterized using selective ET receptor agonists and antagonists. We also examined changes in ET-induced vasoconstriction brought about by left ventricular dysfunction using the rabbit coronary ligation model. The rank order of potency for contraction was sarafotoxin S6c (S6c) > ET-1 = ET-3, which is characteristic of an ET_B-like receptor. The combined ET_A/ET_B receptor antagonist SB209670 (1 μM) antagonized responses to ET-1 and S6c with estimated pK_b values of 6.8 ± 0.2 and 7.8 ± 0.2, respectively. BQ788 (1 μM) antagonized responses to S6c and ET-3 (but not ET-1) with estimated pK_b values of 7.1 ± 0.2 and 6.6 ± 0.1, respectively. The ET_A receptor antagonist FR139317 (1 μM), either alone or in combination with BQ788, did not inhibit responses to ET-1. The profile of the ET-1 response was not altered by left ventricular dysfunction. In control rabbits, the inhibitor of nitric oxide synthaseN^ω-nitro-L-arginine methyl ester (100 μM) had no significant effect on the potency of either ET-1 or S6c. In the coronary-ligated rabbits, however, it significantly increased the potency (10–15-fold) of both ET-1 and S6c. These results suggest that the ET receptor that mediates contraction in rabbit pulmonary resistance arteries has the characteristics of an ET_B-like receptor. The responses to ET-1 are not altered by LVD but may be modified by increased release of nitric oxide.