Studies on the angiotensin-converting enzyme and the kinin B2receptor in the rabbit jugular vein: modulation of contractile response to bradykinin

Abstract

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 B2receptor, 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., [Hyp3, Tyr(Me8)]-BK (R556)), the prevention of BK-induced B2receptor desensitisation, and the restoration of receptor sensitivity in tissues desensitised with B2receptor agonists. Enzymatic degradation studies performed in vitro and in vivo revealed that BK and R556 are readily degraded by rabbit ACE whereas [Phe8ψ(CH2-NH)Arg9]-BK (R379) is totally resistant. BK, R556, and R379 contracted endothelium-denuded veins with similar potencies (pEC50range 8.10–8.50). Tissues pretreated with ACE-I showed an increase in pEC50values for BK and R556 but not for R379. ACE-I (captopril, enalaprilat) were unable to prevent B2receptor desensitisation induced by BK (1 µM). ACE-I partially restored B2receptor-mediated contraction in tissues initially exposed to BK but not to R379. These effects were antagonised by HOE 140 (0.1 µM) but were unaffected by AcLys[Dβ-Nal7, Ile8]-desArg9BK (R715) (1 µM) or by Losartan (1 µM). In conclusion, the potentiation of BK and its analogues relates exclusively on prevention of their metabolism, B2receptor 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 B2receptor.Key words: B2receptor, angiotensin-converting enzyme, inhibitor, BK, jugular vein, rabbit.