Potentiation of kinin analogues by ramiprilat is exclusively related to their degradation

The potentiation of kinin actions represents a cardioprotective property of ACE inhibitors. Although a clear contribution to this effect is related to the inhibition of bradykinin (BK) breakdown, the high efficacy of potentia tion and the ability of ACE inhibitors to provoke a B-2-receptor-mediated r esponse even after receptor desensitization has also triggered hypotheses c oncerning additional mechanisms of kinin potentiation. The application of k inin analogues with enhanced metabolic stability for the demonstration of d egradation-independent mechanisms of potentiation, however, has yielded inc onsistent results. Therefore, the relation between the susceptibility of B- 2-agonists to ACE and the potentiation of their actions by ACE inhibitors w as investigated with the use of minimally modified kinin derivatives that v aried in their degree of ACE resistance. The B-2-agonists 13K, D-Arg-[Hyp(3 )]-BK, [Hyp,(3) Tyr(Me)(8)]-BK, [Delta Phe(5)]-BK, [D-NMF7]-BK, and [Phe(8) psi (CH2-NH)Arg(9)]-BK were tested for degradation by purified rabbit ACE a nd for their potency in contracting the endothelium-denuded rabbit jugular vein in the absence and presence of ramiprilat. Purified ACE degraded D-Arg -[Hyp,(3)]-BK and [Hyp,(3) Tyr(Me)(8)]-BK at 81% and 71% of BK degradation activity, respectively, whereas other peptides were highly ([Delta Phe(5)]- BK) or completely ([D-NMF7]-BK, [Phe(8)psiP(CH2-NH)Arg(9)]-BK) resistant. T he EC50 of BK-induced venoconstriction (1.15 +/-0.2 nmol/L) was reduced by a factor of 5.7 in the presence of ramiprilat. Likewise, D-Arg-[Hyp 3]-BK a nd [Hyp,3 Tyr(Me)8]-BK were both significantly potentiated by a factor of 4 .4, whereas the activities of the other agonists were not affected. Ramipri lat exerted no influence on the maximum contraction induced by any of the a gonists. It is concluded that the potentiation of kinin analogues during AC E inhibition correlates quantitatively with the susceptibility of each subs tance to degradation by ACE. As such, no evidence of degradation-independen t potentiating actions of ACE inhibitors could be obtained.