Co-solubilization of bradykinin B2 receptors and angiotensin-converting enzyme from guinea pig lung membranes

Lach, Estelle; Mousli, Marc; Haddad, El-Bdaoui; Landry, Yves; Gies, Jean-Pierre

doi:10.1016/0005-2736(94)90238-0

Cited by 8 publications

(8 citation statements)

References 24 publications

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“…Properties shared by B 2 -receptors and ACE include a similar susceptibility of both proteins to solubilization 23 and their presence within caveolae. 9,24 A recent investigation has illustrated the functional significance of a colocalization of B 2 -receptors and ACE within the membrane.…”

Section: Discussionmentioning

confidence: 99%

Potentiation of Kinin Analogues by Ramiprilat Is Exclusively Related to Their Degradation

et al. 2001

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Abstract-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 potentiation and the ability of ACE inhibitors to provoke a B 2 -receptor-mediated response even after receptor desensitization has also triggered hypotheses concerning additional mechanisms of kinin potentiation. The application of kinin analogues with enhanced metabolic stability for the demonstration of degradation-independent mechanisms of potentiation, however, has yielded inconsistent results. Therefore, the relation between the susceptibility of B 2 -agonists to ACE and the potentiation of their actions by ACE inhibitors was investigated with the use of minimally modified kinin derivatives that varied in their degree of ACE resistance. ]-BK were both significantly potentiated by a factor of 4.4, whereas the activities of the other agonists were not affected. Ramiprilat exerted no influence on the maximum contraction induced by any of the agonists. It is concluded that the potentiation of kinin analogues during ACE inhibition correlates quantitatively with the susceptibility of each substance to degradation by ACE. As such, no evidence of degradation-independent potentiating actions of ACE inhibitors could be obtained. Key Words: bradykinin Ⅲ angiotensin-converting enzyme Ⅲ receptors, bradykinin Ⅲ kinins Ⅲ rabbits P otentiation of kinin actions is a well-known property of angiotensin I-converting enzyme inhibitors, an effect attributed to a protection of kinins against ACE enzymatic degradation. This mechanism contributes to the therapeutic spectrum of ACE inhibitors in vivo. A variety of experimental studies have demonstrated that enhancement of kinin effectiveness is responsible for beneficial influences of ACE inhibitors on the cardiovascular system, such as reduction of infarct size, inhibition of myocardial hypertrophy and fibrosis, and protection against the development of hypertension (reviewed by Linz et al 1 ). The contribution of endogenous kinins to the vasodilatory effect of an ACE inhibitor has recently been demonstrated in humans as well. 2 Such kininmediated effects can arise because of the high extent to which ACE inhibitors potentiate the effectiveness of kinins. In volunteers, ACE inhibitor treatment sensitized the blood pressure response to injected bradykinin (BK) by a factor of Ϸ40. 3 However, attempts to correlate this intriguing effect with BK accumulation have failed because (1) plasma kinin levels increase only modestly after ACE inhibition, 4 and (2) kinin potentiation by ACE inhibitors is also observed in experimental models in which kinin degradation should be negligible (eg, in superfused vessels 5 ).This fact, and the observation that after desensitization by prolonged kinin exposure an ACE inhibitor can reestablish a B 2 -receptor-mediated response in the continued presence of the desensitizing kinin concentration (a phenomenon addressed as "receptor re...

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Section: Discussionmentioning

confidence: 99%

Potentiation of Kinin Analogues by Ramiprilat Is Exclusively Related to Their Degradation

et al. 2001

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“…Even within the cell surface, a colocalization of B 2 receptors and ACE has been suggested. 19 Because stimulated B 2 receptors and internalized BK have been found to be associated with caveolae, 20,21 these vesicles may also be involved in the formation of a compartment in which kinin levels are highly sensitive to kininase inhibition.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2000

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Abstract-Inhibitors of angiotensin I-converting enzyme (ACE) are very efficacious in the potentiation of the actions of bradykinin (BK) and are able to provoke a B 2 receptor-mediated vasodilation even after desensitization of this receptor. Because this activity cannot be easily explained only by an inhibition of kinin degradation, direct interactions of ACE inhibitors with the B 2 receptor or its signal transduction have been hypothesized. To clarify the significance of degradation-independent potentiation, we studied the vasodilatory effects of BK and 2 degradation-resistant B 2 receptor agonists in the isolated rat heart, a model in which ACE and aminopeptidase P (APP) contribute equally to the degradation of BK. Coronary vasodilation to BK and to a peptidic (B6014) and a nonpeptidic (FR190997) degradation-resistant B 2 agonist was assessed in the presence or absence of the ACE inhibitor ramiprilat, the APP inhibitor mercaptoethanol, or both. Ramiprilat or mercaptoethanol induced leftward shifts in the BK dose-response curve (EC 50 ϭ3.4 nmol/L) by a factor of 4.6 or 4.9, respectively. Combined inhibition of ACE and APP reduced the EC 50 of BK to 0.18 nmol/L (ie, by a factor of 19) but potentiated the activity of B6014 (EC 50 ϭ1.9 nmol/L) only weakly without altering that of FR190997 (EC 50 ϭ0.34 nmol/L). Desensitization of B 2 receptors was induced by the administration of BK (0.2 mol/L) or FR190997 (0.1 mol/L) for 30 minutes; the vascular reactivity to ramiprilat or increasing doses of BK was tested thereafter. After desensitization with BK, but not FR190997, an additional application of ramiprilat provoked a B 2 receptor-mediated vasodilation. High BK concentrations were still effective at the desensitized receptor. The process of desensitization was not altered by ramiprilat. These results show that in this model, all potentiating actions of ACE inhibitors on kinin-induced vasodilation are exclusively related to the reduction in BK breakdown and are equivalently provoked by APP inhibition. The desensitization of B 2 receptors is overcome by increasing BK concentrations, either directly or through the inhibition of ACE. These observations do not suggest any direct interactions of ACE inhibitors with the B 2 receptor or its signal transduction but point to a very high activity of BK degradation in the vicinity of the B 2 receptor in combination with a stimulation-dependent reduction in receptor affinity. (Hypertension. 2000;35:32-37.)Key Words: bradykinin Ⅲ angiotensin-converting enzyme Ⅲ receptor, bradykinin Ⅲ rats Ⅲ heart I nhibitors of angiotensin I-converting enzyme (ACE) have been proved to be clinically effective against diseases such as hypertension, congestive heart failure, and myocardial infarction. Through their main mechanism of action (ie, inhibition of the peptidase ACE), ACE inhibitors not only prevent the activation of angiotensin I but also eliminate a degradation pathway for the vasodilatory peptide bradykinin (BK) and thus increase the availability and effectiveness of kinins. The results...

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“…In the absence of Mg 2+ there was only a minimal reduction of binding activity upon addition of guanosine nucleotides. This dependence on divalent cations may explain the observed lack of reduction of [ 3 H]BK binding to guinea pig lung membranes by GTP analogs (Trifilieff et al, 1994), since Mg 2+ was not included in the incubation buffer in these studies. As suggested by Keravis et al (1991), the regulation of receptors by G proteins may vary depending on differences in species or tissues.…”

Section: Discussionmentioning

confidence: 96%

“…In other studies, a change in affinity of B2 kinin receptors (Burch and Axelrod, 1987;Leeb-Lundberg and Mathis, 1990;Liao and Homcy, 1993) or changes in both affinity and receptor number (Mathis and Leeb-Lundberg, 1991) were reported. By contrast, guanosine nucleotides were reported to inhibit [ 3 H]BK binding to the human B2 kinin receptor expressed in COS-7 cells (Hess et al, 1992), while no effect of these nucleotides was observed on BK binding to receptors in guinea pig lung (Trifilieff et al, 1994).…”

Section: Introductionmentioning

confidence: 89%

Guanosine Nucleotides Regulate B2 Kinin Receptor Affinity of Agonists But Not of Antagonists: Discussion of a Model Proposing Receptor Precoupling to G Protein

Faußner

Roscher²

2000

Biological Chemistry

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Co-solubilization of bradykinin B2 receptors and angiotensin-converting enzyme from guinea pig lung membranes

Cited by 8 publications

References 24 publications

Potentiation of Kinin Analogues by Ramiprilat Is Exclusively Related to Their Degradation

Potentiation of Kinin Analogues by Ramiprilat Is Exclusively Related to Their Degradation

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

Guanosine Nucleotides Regulate B2 Kinin Receptor Affinity of Agonists But Not of Antagonists: Discussion of a Model Proposing Receptor Precoupling to G Protein

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