Endothelins contract guinea-pig pulmonary artery and enhance its adrenergic response via ET(A) receptors.
1. This study has pharmacologically characterized endothelin (ET) receptor subtype(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) concentrations-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 ET(A) receptor mediates both contraction and enhancement of adrenergic contractions in the guinea-pig pulmonary artery.
Matsuda
H
H
Department of Cardiovascular Dynamics, National Cardiovascular Center Research Institute, Osaka, Japan.
Kawaguchi
A
A
Uematsu
M
M
Ohmori
F
F
Nagata
S
S
Miyatake
K
K
D000818:Animals; D002395:Catecholamines / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000494:pharmacology*; D005260:Female; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D010446:Peptide Fragments / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology; D011651:Pulmonary Artery / Q000187:drug effects*; D017466:Receptors, Endothelin / Q000819:agonists / Q000145:classification* / Q000187:drug effects*; D014661:Vasoconstriction / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014757:Viper Venoms / Q000494:pharmacology
D002395:Catecholamines; D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D010446:Peptide Fragments; D010456:Peptides, Cyclic; D017466:Receptors, Endothelin; D014662:Vasoconstrictor Agents; D014757:Viper Venoms; C057354:sarafotoxins s6; C074308:sovateltide; C072247:cyclo(Trp-Asp-Pro-Val-Leu)