Antagonism of Prostanoid-Induced Vascular Contraction by 13-Azaprostanoic Acid (13-APA)

Abstract

Isometric contractions in vitro of helically cut strips of canine mesenteric arteries (O.D. [outside diameter] = 0.6-1 mm) were recorded in the presence of 10 .mu.M indomethacin. PGF2.alpha., [prostaglandin F2.alpha.] PGE2, U-46619 (TXA2 [thromboxane A2] mimetic), norepinephrine, 5-hydroxytryptamine and KCl produced dose-related contractions. The EC50 [median effective concentration] values of the prostanoids in the control period were: PGF2.alpha., 7.3 .+-. 0.7 .times. 10-7 M; PGE2, 2.1 .+-. 0.2 .times. 10-6 M; and U-46619, 4.1 .+-. 1.0 .times. 10-10 M. Exposure to 13-azaprostanoic acid (13-APA), 5 .times. 10-5 M and 2 .times. 10-4 M for 20 min caused parallel and dose-related shifts to the right of the dose-response curves generated by all 3 prostanoids without affecting the contractile responses to KCl, norepinephrine, or 5-hydroxytryptamine or relaxation induced by PGI2 [prostacyclin]. 13-APA, at the concentrations used, had no agonist activity. Small contractions (10-15%) seen on the addition of 13-APA to the baths were related to the alcohol content of the solvent. Dose ratios (with/without antagonist) at the EC50 level were in the presence of 5 .times. 10-5 M 13-APA, PGF2.alpha., 2.7 .+-. 0.3; PGE2, 3.5 .+-. 0.9; U-46619, 5.2 .+-. 0.9; in the presence of 2 .times. 10-4 M 13-APA, PGF2.alpha., 17.1 .+-. 3; PGE2 > 50; and U-46619, 23.3 .+-. 5.7. 13-APA is evidently a specific antagonist of these prostanoids with no agonist activity of its own.