© 1997 American Heart Association, Inc.
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Potentiation of the Actions of Bradykinin by Angiotensin I–Converting Enzyme Inhibitors
The Role of Expressed Human Bradykinin B2 Receptors and Angiotensin –Converting Enzyme in CHO Cells
From the Departments of Pharmacology (R.D.M., F.T., F.N., B.M., E.G.E.), Anesthesiology (R.D.M., E.G.E.), and Anatomy and Cell Biology (R.P.B.), University of Illinois College of Medicine at Chicago, and the Department of Anesthesiology (S.F.R), Cook County Hospital, Chicago, Ill.
Correspondence to Ervin G. Erdös, MD, Department of Pharmacology (M/C 868), University of Illinois at Chicago, 835 S Wolcott Ave, Chicago, IL 60612.
Abstract Part of the beneficial effects of angiotensin I–converting enzyme (ACE) inhibitors are due to augmenting the actions of bradykinin (BK). We studied this effect of enalaprilat on the binding of [3H]BK to Chinese hamster ovary (CHO) cells stably transfected to express the human BK B2 receptor alone (CHO-3B) or in combination with ACE (CHO-15AB). In CHO-15AB cells, enalaprilat (1 µmol/L) increased the total number of low-affinity [3H]BK binding sites on the cells at 37°C, but not at 4°C, from 18.4±4.3 to 40.3±11.9 fmol/106 cells (P<.05; Kd, 2.3±0.8 and 5.9±1.3 nmol/L; n=4). Enalaprilat preserved a portion of the receptors in high-affinity conformation (Kd, 0.17±0.08 nmol/L; 8.1±0.9 fmol/106 cells). Enalaprilat decreased the IC50 of [Hyp3-Tyr(Me)8]BK, the BK analogue more resistant to ACE, from 3.2±0.8 to 0.41±0.16 nmol/L (P<.05, n=3). The biphasic displacement curve of the binding of [3H]BK also suggested the presence of high-affinity BK binding sites. Enalaprilat (5 nmol to 1 µmol/L) potentiated the release of [3H]arachidonic acid and the liberation of inositol 1,4,5-trisphosphate (IP3) induced by BK and [Hyp3-Tyr(Me)8]BK. Moreover, enalaprilat (1 µmol/L) completely and immediately restored the response of the B2 receptor, desensitized by the agonist (1 µmol/L [Hyp3-Tyr(Me)8]BK); this effect was blocked by the antagonist, HOE 140. Finally, enalaprilat, but not the prodrug enalapril, decreased internalization of the receptor from 70±9% to 45±9% (P<.05, n=7). In CHO-3B cells, enalaprilat was ineffective. ACE inhibitors in the presence of both the B2 receptor and ACE enhance BK binding, protect high-affinity receptors, block receptor desensitization, and decrease internalization, thereby potentiating BK beyond blocking its hydrolysis.
Key Words: kininase II • receptor desensitization • receptor internalization • peptidase • tachyphylaxis
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