Potentiation by ACE inhibitors of the dilator response to bradykinin in the coronary microcirculation: interaction at the receptor level

Abstract

1 To examine the possibility that angiotensin-converting enzyme (ACE) inhibitors modulate the action of bradykinin at the receptor level, their effect on the dilator response to bradykinin was studied in the isolated saline-perfused heart of the rabbit. 2 Continuous infusion of bradykinin (10 nM were unable to elicit a significant change in CPP or PGI2 release while ramiprilat and another ACE inhibitor, quinaprilat, were still active in the presence of these substrates. 6 To reveal the potential B2-receptor action of ramiprilat, its effect on the constrictor response to bradykinin was studied in the rabbit isolated jugular vein. Ramiprilat (0.1 M), but not RA-octyl (1 pM), potentiated the endothelium-independent, B2-receptor-mediated constrictor response to bradykinin, but not that to the thromboxane-mimetic U46619 (9,11-dideoxy-lla,9a-epoxymethano-prostaglandin F2.).Moreover, ramiprilat but not RA-octyl caused a concentration-dependent, B2-receptor antagonistsensitive increase in tone when administered alone. 7 These findings suggest that an interaction of ACE inhibitors with the B2-receptor or its signal transduction pathway rather than an accumulation of bradykinin within the vascular wall is responsible for the restoration of the endothelial response to bradykinin (dilatation, PGI2 release) in the coronary vascular bed of the rabbit.

Potentiation of the Vascular Response to Kinins by Inhibition of Myocardial Kininases

“…11,13 However, this effect can be related to a direct resensitizing influence on receptor regulation only if the desensitized receptor will not respond to increasing BK doses, a prerequisite that has not been established in previous studies. In contrast, the present study demonstrated a maintained reactivity to high BK concentrations in the desensitized state that can be interpreted as a stimulation-dependent loss of BK potency.…”

“…11,13 This effect was reproduced in the rat heart, in which the vasodilatory effect of BK (0.2 mol/L) ceased during a 30-minute application (78Ϯ8% loss of vasodilation, half-maximum desensitization after 20Ϯ3 minutes, nϭ5) but was completely restored on subsequent treatment with ramiprilat (250 nmol/L; Figure 3). Consistent with previous studies, 11,13 this resensitization was abolished by the B 2 antagonist icatibant (HOE140, 1 mol/L) administered 2 minutes before ramiprilat (data not shown). The same experiment performed with the stable agonist FR190997 (0.1 mol/L) induced an equivalent course of desensitization, but the subsequent application of ramiprilat was ineffective (Figure 3).…”

“…These findings do not reflect the potentiation properties of ACE inhibitors reported with stabilized kinin derivatives in earlier studies. [11][12][13][14] 8 ]BK, which have so far been exclusively used for such investigations, has not yet been demonstrated. As such, the failure of ramiprilat and mercaptoethanol to potentiate the effects of B6014 and FR190997 in this study excludes these experimental imponderabilities and demonstrates the absence of degradation-independent actions of the ACE inhibitor.…”

“…In the rat heart, the influence of kininase inhibitors on local kinin concentrations has been established in tracer transit studies that demonstrated a marked increase in kinin concentrations during ACE inhibition specifically in an extravascular distribution compartment. 6 Additional observations have been made suggesting that some of the kinin potentiation properties of ACE inhibitors might be related to mechanisms independent of the inhibition of kinin degradation; for example, (1) ACE inhibitors act as kinin mimetics under conditions in which kinin breakdown should be negligible, 10 (2) ACE inhibitors can enhance the effects of degradation-resistant BK analogs, [11][12][13][14] (3) ACE inhibitors show structure-related differences in their kinin potentiation activities, 15 and (4) ACE inhibitors can provoke a kinin-mediated response even when B 2 receptors have been desensitized through kinin pretreatment. 11,13 The last phenomenon is addressed further here as "receptor resensitization."…”

Reinventing the ACE inhibitors: some old and new implications of ACE inhibition

“…These findings demonstrate that ACEis selectively potentiate the B 2 -receptor-mediated vascular effects of bradykinin independently of their ACE-inhibiting properties, and this might be related to differences in molecular structure. 154,155 ACEis also induce cross-talk between the transmembrane protein ACE and the B 2 -kinin receptor, probably by formation of a heterodimer. This protects high-affinity receptors, blocks receptor desensitization and decreases internalization, thereby potentiating BK beyond blocking its hydrolysis.…”