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(Hypertension. 2002;39:619.)
© 2002 American Heart Association, Inc.

Scientific Contributions

Neprilysin Inhibitors Potentiate Effects of Bradykinin on B2 Receptor

Peter A. Deddish; Branislav M. Marcic; Fulong Tan; Herbert L. Jackman; Zhenlong Chen; Ervin G. Erdös

From the Departments of Pharmacology (P.A.D., B.M.M., F.T., H.L.J., Z.C., E.G.E.) and Anesthesiology (E.G.E.), University of Illinois College of Medicine at Chicago.

Correspondence to Peter A. Deddish, PhD, Department of Pharmacology (M/C 868), University of Illinois-Chicago, 835 S. Wolcott Ave., Chicago, IL 60612. E-mail pdeddish{at}uic.edu

Some beneficial effects of angiotensin-I–converting enzyme (ACE, kininase II) inhibitor therapy are attributed to enhancing the activity of bradykinin on its B₂ receptor. Independent of inhibition of bradykinin hydrolysis, ACE inhibitors enhance the action of bradykinin on its B₂ receptor by inducing crosstalk between ACE and the receptor. We investigated whether inhibitors of another kininase II-type enzyme, neprilysin (neutral endopeptidase 24.11; NEP), could augment bradykinin effects unrelated to blocking its breakdown using a NEP-resistant bradykinin analog as ligand. We used transfected Chinese hamster ovary (CHO) cells stably expressing human B₂ receptor and NEP (CHO/NEP-B₂) or only B₂ (CHO/B₂) as control and human pulmonary fibroblasts (IMR90), expressing B₂, but more NEP than ACE. NEP inhibitor phosphoramidon (100 nmol/L), or omapatrilat, which inhibits both NEP and ACE, did not potentiate bradykinin in CHO/B₂ cells. In IMR90 cells, 10 nmol/L bradykinin elevated [Ca²⁺]_i and desensitized the receptor. Adding either 100 nmol/L omapatrilat or phosphoramidon resensitized the receptor to the ligand, which was abolished by receptor blocker HOE 140. Arachidonic acid release by bradykinin from CHO/NEP-B₂ cells was also augmented by 100 nmol/L phosphoramidon or omapatrilat about 3-fold, and again, the inhibitors resensitized the desensitized B₂ receptor. The inhibitors did not potentiate bradykinin when soluble rNEP was added to the medium of CHO/B₂ cells. Similar to ACE, NEP inhibitors potentiated bradykinin independent of inhibiting inactivation. Consequently, omapatrilat could augment bradykinin effects on B₂, when either ACE or NEP is expressed close to receptor on cell membrane.

Key Words: G proteins • calcium • arachidonic acids • angiotensin-converting enzyme • receptors, bradykinin • fibroblasts

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