Characterization of FR 172357, a new non-peptide bradykinin B-2 receptor antagonist, in human, pig and rabbit preparations

FR 172357, a new non-peptide antagonist of the kinin B-2 receptor was teste d in three isolated vessels, the human umbilical vein, the rabbit jugular v ein, and the pig coronary artery, to evaluate its antagonistic activities a gainst bradykinin. FR 172357 displaced to the right the concentration-respo nse curves of bradykinin. The displacements were parallel to the controls w ithout reduction of the maximum effect in the human umbilical vein and in t he rabbit jugular vein, but not in the pig coronary artery. Schild plots co nfirmed that FR 172357 acts as a competitive antagonist in the human umbili cal vein (pA(2) 8.65) and in the rabbit jugular vein (pA(2) 9.07), and as a non-competitive antagonist in the pig coronary artery (pK(B) 10.14). FR 17 2357 is selective for the kinin B-2 receptor since it does not influence th e effects of Lys-des-Arg(9)-bradykinin in the human umbilical vein, in the rabbit aorta, and in the pig renal vein. It is specific because it does not affect the contractions induced by angiotensin II, noradrenaline, 5-hydrox ytryptamine, or endothelin-1 in the human umbilical vein. It, however, inte racts with the tachykinin NK1 receptor of the rabbit jugular vein and pig c oronary artery. Compared to other bradykinin B-2 receptor antagonists, FR 1 72357 emerges as a very potent compound, which may represent a choice for e xperimental (and clinical?) applications. (C) 1999 Elsevier Science B.V. Al l rights reserved.