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(Circulation. 1998;97:2268-2273.)
© 1998 American Heart Association, Inc.

Basic Science Reports

Mechanism of ß-Adrenergic Receptor Upregulation Induced by ACE Inhibition in Cultured Neonatal Rat Cardiac Myocytes

Roles of Bradykinin and Protein Kinase C

Hidetoshi Yonemochi, MD; Seikoh Yasunaga, MD; Yasusi Teshima, MD; Tetsu Iwao, MD; Kumiko Akiyoshi, MD; Mikiko Nakagawa, MD; Tetsunori Saikawa, MD; ; Morio Ito, MD

From the Department of Laboratory Medicine (H.Y., T.I., M.N., M.I.) and the First Department of Internal Medicine (S.Y., Y.T., K.A., T.S.), Oita (Japan) Medical University.

Correspondence to Hidetoshi Yonemochi, MD, Department of Laboratory Medicine, Oita Medical University, Idaigaoka 1–1, Hasama-machi, Oita 879–55, Japan. E-mail yonemo{at}pios.oita-med.ac.jp

Background—Although bradykinin is thought to contribute to the effects of ACE inhibitors on the cardiovascular system, its precise role remains to be elucidated. Evidence suggests that bradykinin might be important in the upregulation of ß-adrenergic receptors (ß-ARs) induced by ACE inhibitors, and the role of bradykinin in this effect has now been investigated with cultured neonatal rat cardiac myocytes.

Methods and Results—The density of ß-ARs on the myocyte surface was determined with a binding assay with [³H]CGP-12177. Incubation of cultured myocytes for 24 hours with the ACE inhibitor captopril (1 µmol/L) increased ß-AR density by 35% and enhanced the response of cells to isoproterenol but not to forskolin. Neither an angiotensin-II type 1 (AT₁) receptor antagonist, CV-11974, nor angiotensin-I affected ß-AR density. However, the bradykinin B₂ receptor antagonist Hoe 140 abolished the effect of captopril on ß-AR upregulation in a dose-dependent manner. The protein kinase C inhibitor staurosporine (20 nmol/L) but neither indomethacin nor L-NAME also inhibited captopril-induced upregulation of ß-ARs. Exogenous bradykinin increased the spontaneous beating frequency of cultured myocytes and Hoe 140 abolished this effect. Bradykinin level in the medium increased 1.4-fold by the treatment of cultured myocytes with captopril for 24 hours.

Conclusions—The results suggest that captopril enhances ß-AR responsiveness by inducing ß-AR upregulation and that the latter effect is mediated by activation of bradykinin B₂ receptors and protein kinase C. These observations also offer insight into the different roles of ACE inhibitors and AT₁ receptor antagonists in the treatment of heart failure.

Key Words: bradykinin • receptors, adrenergic, beta • angiotensin • myocytes

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