PHARMACOLOGICAL EVIDENCE FOR A SINGLE BRADYKININ B-2 RECEPTOR IN THE GUINEA-PIG

1 The present study addresses the possibility of the existence of diff erent kinin B-2 receptor subtypes in the guinea-pig by evaluating the affinity of peptide and nonpeptide receptor antagonists. For this purp ose, jugular vein rings, ileum segments, lung parenchymal and trachea strips were set up in organ baths for isometric tension measurements. The experiments were conducted in the presence of indomethacin (3 mu M ), atropine (10 mu M) and captopril (10 mu M). 2 BK contracted jugular vein (JV), ileum (GPI), parenchyma (LP) and trachea (GPT) with an EC( 50), of 13.2+/-1.4 nM (n=27), 11.2+/-2.1 (n=26), 23.6+/-6.3 nM (n=26) and 33.0+/-6.5 (n=27), respectively. Thiorphan, a neutral endopeptidas e (EC 3.4.24.11) inhibitor and MERGETPA (DL-2-mercaptomethyl-3-guanidi noethyrthiopropanoic acid), a carboxypeptidase inhibitor, had no effec t on the BK-induced contractions of JV, GPI and LP. In the GPT, thiorp an potentiated the contractile response to BK and was thus added in th e corresponding experiments. 3 The peptide B-2 receptor antagonist, Ho e 140 and the nonpeptide compound, WIN 64338, behaved as noncompetitiv e antagonists against contractile responses to cumulative BK in the fo ur tissues although Hoe 140 appeared as a competitive inhibitor in the GPT only. In order to compare the inhibitory potency of these compoun ds between tissues, pK(B) values were determined. Mean values of pK(B) for Hoe 140 were 8.05+/-0.07, 8.43+/-0.11, 8.13+/-0.18 and 8.52+/-0.2 5 in the JV, GPI, GPT and LP, respectively. WIN 64338 gave mean pK(B) values of 6.89+/-0.10, 7.57+/-0.12, 7.36+/-0.12 and 7.51+/-0.28 in the JV, GPI, LP and GPT, respectively. 4 D-Arg [Hyp(3), D-Phe(7), Leu(8)] BK and D-Arg [Hyp(3), D-Phe(7)]BK (NPC 567) inhibited in a competitive fashion the concentration-response curves to BK. Values of pA(2) for each compound were not significantly different in the four tissues and were between 5,81 and 6.31 for D-Arg [Hyp(3), D-Phe(7), Leu(8)]BK and between 5.55 and 5.65 for NPC 567. 5 We conclude that the contractile response to BK in guinea-pig vascular, intestine and hmg tissue is me diated by a unique B-2 receptor. Thus, our results do not support the existence of a B-3 receptor in the trachea and we suggest that the pre viously reported B-2B receptor subtype simply represents the guineapig isoform.