PHARMACOLOGICAL PROFILES OF THE HUMAN AND RABBIT B-1 RECEPTORS

Twenty-two peptides related to kinins were used (i) to examine some ch emical features required for the human and rabbit B-1 receptor activat ion or blockade and (ii) to establish the existence of a correlation b etween the pharmacological spectrum of the B-1 receptor obtained on th e rabbit aorta (rbA) and the human umbilical vein (hUV). The apparent affinities of these peptides were measured in vitro using classical bi oassays and are expressed in terms of pD(2) (for agonists) or pA(2) va lues (for antagonists). Selectivity for the B-1 receptor was demonstra ted by testing the peptides against the effect of bradykinin (BK) on t he hUV and the rabbit jugular vein (rbJV), two preparations containing B-2 receptor-mediating vasoconstriction. The results show that (i) ly syl-peptide agonists and antagonists demonstrate higher affinities tha n nonlysyl compounds on human and rabbit B-1 receptors, (ii) peptides containing hydrophobic D-residues (e.g., Tic, beta Nal, Hyp(trans-prop yl), Igl) in position 7 are suitable for B-1 receptor antagonism, and (iii) the additive substitution of an Oic residue in position 8 leads to nonselective kinin receptor antagonists. Moreover, a high (r=0.92) and positive (regression slope=0.99+/-0.09) correlation between the af finities measured for the kinin analogues in two B-1 receptor bioassay systems has been revealed. Based on the similarity of pharmacological profiles observed in the rabbit and human B-1 receptors, we suggest t hat the B-1 receptor domain in which peptide agonists and antagonists interact may be similar in these two species.