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(Circulation. 2000;101:2625.)
© 2000 American Heart Association, Inc.

Basic Science Reports

Rapid Electrical Stimulation of Contraction Reduces the Density of ß-Adrenergic Receptors and Responsiveness of Cultured Neonatal Rat Cardiomyocytes

Possible Involvement of Microtubule Disassembly Secondary to Mechanical Stress

Hidetoshi Yonemochi, MD; Seikoh Yasunaga, MD; Yasushi Teshima, MD; Naohiko Takahashi, MD; Mikiko Nakagawa, MD; Morio Ito, MD; Tetsunori Saikawa, MD

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

Correspondence to Hidetoshi Yonemochi, MD, Department of Laboratory Medicine, Oita Medical University, Idaigaoka 1-1, Hasama-machi, Oita 879-5593, Japan. E-mail yonemo{at}pios.oita-med.ac.jp

Background—Although tachycardia is commonly present in patients with congestive heart failure, its role in the development of congestive heart failure remains unclear. We studied the effect of rapid electrical stimulation of contraction on ß-adrenergic receptor (ß-AR) signal pathway in cultured cardiomyocytes of neonatal rats.

Methods and Results—Contraction of cardiomyocytes was induced by electrical stimulation at 50 V with twice the threshold pulse width. ß-ARs were identified by [³H]CGP-12177 and [³H]dihydroalprenolol. Electrical stimulation reduced cell-surface but not total ß-AR density; the effect was dependent on pacing frequency (a reduction of 11%, 28%, and 18% in cells paced at 2.5, 3.0, and 3.3 Hz, respectively). This reduction was apparent at 3 hours, in contrast to reduced ß-AR density after exposure to isoproterenol (ISP) for 1 hour. The fraction and inhibition constant of ß-AR binding agonist with high affinity were not affected by rapid electrical stimulation. In cardiomyocytes paced at 3.0 Hz for 24 hours, the response to ISP decreased compared with unpaced cells, 142% versus 204% of baseline with 1 µmol/L ISP, whereas the responses to forskolin or acetylcholine were not different. Treatment of cardiomyocytes with 2,3-butanedione monoxime (10 mmol/L) or taxol (10 µmol/L) inhibited the rapid pacing–induced reduction in ß-AR density.

Conclusions—Our results suggest that contractile activity is involved in regulation of cardiac function by modulating the ß-AR system independently of hemodynamic and neurohormonal factors. This may help to elucidate the role of mechanical stress in the development of heart failure.

Key Words: receptors, adrenergic, beta • electrical stimulation • contractility • heart failure • microtubule

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