Gobeil Fernand, Hallé Stéphanie, Blais Paul-André, Regoli Domenico
Department of Pharmacology, Medical School, Université de Sherbrooke, QC, Canada.
Can J Physiol Pharmacol. 2002 Feb;80(2):153-63. doi: 10.1139/y02-014.
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 B2 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., [Hyp3, Tyr(Me8)]-BK (R556)), the prevention of BK-induced B2 receptor desensitisation, and the restoration of receptor sensitivity in tissues desensitised with B2 receptor agonists. Enzymatic degradation studies performed in vitro and in vivo revealed that BK and R556 are readily degraded by rabbit ACE whereas [Phe8psi(CH2-NH)Arg9]-BK (R379) is totally resistant. BK, R556, and R379 contracted endothelium-denuded veins with similar potencies (pEC50 range 8.10-8.50). Tissues pretreated with ACE-I showed an increase in pEC50 values for BK and R556 but not for R379. ACE-I (captopril, enalaprilat) were unable to prevent B2 receptor desensitisation induced by BK (1 microM). ACE-I partially restored B2 receptor-mediated contraction in tissues initially exposed to BK but not to R379. These effects were antagonised by HOE 140 (0.1 microM) but were unaffected by AcLys[Dbeta-Nal7, Ile8]-desArg9BK (R715) (1 microM) or by Losartan (1 microM). In conclusion, the potentiation of BK and its analogues relates exclusively on prevention of their metabolism, B2 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 B2 receptor.
兔颈静脉（rbJV）被用作生物测定系统，以验证血管紧张素转换酶（ACE）与B2受体之间一些早期和新的假设性相互作用，这些相互作用可能受ACE抑制剂（ACE-I）影响。这些相互作用包括缓激肽（BK）和BK类似物收缩作用的增强，它们可被ACE灭活（例如，[Hyp3, Tyr(Me8)]-BK（R556））、防止BK诱导的B2受体脱敏，以及恢复用B2受体激动剂脱敏的组织中的受体敏感性。体外和体内进行的酶降解研究表明，BK和R556很容易被兔ACE降解，而[Phe8psi(CH2-NH)Arg9]-BK（R379）则完全耐受。BK、R556和R379使去内皮静脉收缩的效力相似（pEC50范围为8.10 - 8.50）。用ACE-I预处理的组织中，BK和R556的pEC50值增加，但R379的pEC50值未增加。ACE-I（卡托普利、依那普利拉）无法预防BK（1 microM）诱导的B2受体脱敏。ACE-I部分恢复了最初暴露于BK但未暴露于R379的组织中B2受体介导的收缩。这些作用被HOE 140（0.1 microM）拮抗，但不受AcLys[Dbeta-Nal7, Ile8]-desArg9BK（R715）（1 microM）或氯沙坦（1 microM）影响。总之，BK及其类似物效力的增强仅与防止它们的代谢有关，B2受体脱敏不受ACE-I影响，ACE-I使组织对BK反应性恢复可能归因于B2受体附近BK浓度的变化。
