Receptors for bradykinin in intestinal and uterine smooth muscle

Abstract

An attempt has been made to characterize receptors for bradykinin (BK) in two smooth muscle preparations (cat ileum and rat uterus) sensitive to BK. Studies have shown that contractions of the two isolated organs produced by BK result from a direct action of this peptide on specific receptors. Since (a) experimental dose–response curves of BK in the two preparations are superimposed to the theoretical ones calculated with the equation of Clark (Clark, A. J. 1937. General pharmacology. Verlag von J. Springer, Berlin), (b) ratios between doses producing 16 and 84% of maximum effect correspond to 1:28 (cat ileum) and 1:19 (rat uterus), and (c) relations stimulus–effect are linear and with a slope of 1.0 (cat ileum) and 1.1 (rat uterus), we choose to interpret these findings with the approach proposed by Clark (1937) and elaborated by Ariens (Ariens, E. J. 1964. Molecular pharmacology. Academic Press Inc., London).Studies on the structure–activity relationships performed with fragments and analogues of BK do not allow for a precise distinction of groups responsible for affinity or for the activation of receptors, and actually show that 1-Arg, 4-Gly, 5-Phe, 8-Phe, and 9-Arg are essential for the interaction. Analogues more potent than BK were obtained by replacing 8-Phe with Tyr(Me) and Trp, while 8-Cha BK keeps full activity. When tested for antagonism, all the analogues and the fragments are inactive; some of these compounds were found to potentiate the activity of BK in the rat uterus.Cyproheptadine (CH), dihydrochlorprothixene (DHCP), phenylalanine-octyl ester (POE), and β-phenylanaline-hexyl ester (β-PHE), as well as 5-Tyr(Me),8-Tyr(Me) BK, and 8-Leu-OMe Octa BK were tested for antagonism. CH, DHCP, POE, and β-PHE (at concentrations ranging from 10−6 to 10−5 M) reduce the myotropic effects of BK in the two preparations. The antagonism is nonspecific for BK, since the effects of other agonists acting on receptors different from those of BK are also reduced. Maximal responses to BK as well as to the other stimulants are significantly diminished, indicating that the antagonism is of the noncompetitive type. 5-Tyr(Me),8-Tyr(Me) BK and 8-Leu-OMe Octa BK did not exert any antagonistic action.Evidence is presented in favour of the interpretation that the receptors for BK in the two preparations are of the same type, and differ from the receptor of the rabbit aorta.