Endothelins Contract Guinea-Pig Pulmonary Artery And Enhance Its Adrenergic Response Via Et(A) Receptors

1. This study has pharmacologically characterized endothelin (ET) receptor suhtype(s) mediating contraction and enhancement of adrenergic contraction in guinea-pig pulmonary artery, Isometric tension of the isolated endothelium-denuded ring preparations was measured in the presence of indomethacin (10(-5) mol/L) and N-G-nitro-L-arginine methyl ester (L-NAME; 3 x 10(-4) mol/L) to exclude a mechanism via endothelium, cyclo-oxygenase-generated eicosanoids and nitric oxide.2. In the additional presence of tetrodotoxin (TTX; 3 x 10(-7) mol/L), ET-1 (10(-11)-10(-7) mol/L) concentration-dependently contracted the preparations. The rank order of potency to contract the preparations among ET receptor agonists was ET-1, sarafotoxin (STX) 6b > ET-3 > IRL 1620, STX 6c, BQ-123 (7 x 10(-7)-7 x 10(-6) mol/L) concentration-dependently shifted the concentration-contraction curve for ET-1 to the right in a parallel manner. Pretreatment with STX 6c (3 x 10(-7) mol/L for 30 min) did not significantly desensitize contractions to ET-1, ET-3 or IRL 1620 (P > 0.05; t-test, 10 d.f.).3. ET-1 (10(-10)-10(-9) mol/L) and STX 6b (10(-9)-10(-8) mol/L) significantly enhanced the electrical field stimulation-induced contraction in a BQ-123-sensitive manner (P < 0.05; t-test, 24-38 d.f.), while ET-3 (10(-11)-10(-8) mol/L) and STX 6c (10(-11)-10(-7) mol/L) did not affect contractions. ET-1 (10(-11) mol/L) significantly enhanced contractions to exogenous noradrenaline in the presence of TTX (3 x 10(-7) mol/L) (P < 0.05; t-test, 16 d.f.).4. These data indicate that the BQ-123-sensitive ETA receptor mediates both contraction and enhancement of adrenergic contractions in the guinea-pig pulmonary artery.