ENDOTHELINS CONTRACT GUINEA-PIG PULMONARY-ARTERY AND ENHANCE ITS ADRENERGIC RESPONSE VIA ET(A) RECEPTORS

1. This study has pharmacologically characterized endothelin (ET) rece ptor suhtype(s) mediating contraction and enhancement of adrenergic co ntraction in guinea-pig pulmonary artery, Isometric tension of the iso lated endothelium-denuded ring preparations was measured in the presen ce of indomethacin (10(-5) mol/L) and N-G-nitro-L-arginine methyl este r (L-NAME; 3 x 10(-4) mol/L) to exclude a mechanism via endothelium, c yclo-oxygenase-generated eicosanoids and nitric oxide. 2. In the addit ional presence of tetrodotoxin (TTX; 3 x 10(-7) mol/L), ET-1 (10(-11)- 10(-7) mol/L) concentration-dependently contracted the preparations. T he rank order of potency to contract the preparations among ET recepto r agonists was ET-1, sarafotoxin (STX) 6b > ET-3 > IRL 1620, STX 6c, B Q-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 paralle l manner. Pretreatment with STX 6c (3 x 10(-7) mol/L for 30 min) did n ot 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 stimu lation-induced contraction in a BQ-123-sensitive manner (P < 0.05; t-t est, 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) sign ificantly enhanced contractions to exogenous noradrenaline in the pres ence of TTX (3 x 10(-7) mol/L) (P < 0.05; t-test, 16 d.f.). 4. These d ata indicate that the BQ-123-sensitive ETA receptor mediates both cont raction and enhancement of adrenergic contractions in the guinea-pig p ulmonary artery.