Studies on the angiotensin-converting enzyme and the kinin B2 receptor in the rabbit jugular vein:: modulation of contractile response to bradykinin

The rabbit jugular vein (rbJV) was used as a bioassay system to validate some early and new hypothetical interactions between the angiotensin-converting enzyme (ACE) and the B-2 receptor, which may be influenced by ACE inhibitors (ACE-I). These involve the potentiation of the contractile effect of bradykinin (BK) and BK analogues, which are inactivated by ACE (e.g., [Hyp(3), Tyr(Me-8)]-BK (R556)), the prevention of BK-induced B-2 receptor desensitisation, and the restoration of receptor sensitivity in tissues desensitised with B-2 receptor agonists. Enzymatic degradation studies performed in vitro and in vivo revealed that BK and R556 are readily degraded by rabbit ACE whereas [Phe(8)psi(CH2-NH)Arg(9)]-BK (R379) is totally resistant. BK, R556, and R379 contracted endothelium-denuded veins with similar potencies (pEC(50) range 8.10-8.50). Tissues pretreated with ACE-I showed an increase in pEC(50) values for BK and R556 but not for R379. ACE-I (captopril, enalaprilat) were unable to prevent B-2 receptor desensitisation induced by BK (1 muM). ACE-I partially restored B-2 receptor-mediated contraction in tissues initially exposed to BK but not to R379. These effects were antagonised by HOE 140 (0.1 muM) but were unaffected by AcLys[Dbeta-Nal(7), Ile(8)]-desArg(9)BK (R715) (1 muM) or by Losartan (1 muM). In conclusion, the potentiation of BK and its analogues relates exclusively on prevention of their metabolism, B-2 receptor desensitisation is not affected by ACE-I, and restoration of tissue responsiveness to BK by ACE-I may be attributed to changes in BK concentrations in the vicinity of the B-2 receptor.