Rapid electrical stimulation of contraction reduces the density of beta-adrenergic receptors and responsiveness of cultured neonatal rat cardiomyocytes. Possible involvement of microtubule disassembly secondary to mechanical stress

• Published in: Circulation (New York, N.Y.) Vol. 101; no. 22; pp. 2625 - 2630
• Main Authors: Yonemochi, H, Yasunaga, S, Teshima, Y, Takahashi, N, Nakagawa, M, Ito, M, Saikawa, T
• Format: Journal Article
• Language: English
• Published: United States 06-06-2000
• Subjects: Acetylcholine - pharmacology; Adrenergic beta-Agonists - metabolism; Adrenergic beta-Agonists - pharmacology; Adrenergic beta-Antagonists - metabolism; Adrenergic beta-Antagonists - pharmacology; Animals; Animals, Newborn; Antineoplastic Agents, Phytogenic - pharmacology; Cells, Cultured; Colforsin - pharmacology; Diacetyl - analogs & derivatives; Diacetyl - pharmacology; Dihydroalprenolol - metabolism; Dihydroalprenolol - pharmacology; Down-Regulation - physiology; Electric Stimulation; Enzyme Inhibitors - pharmacology; Heart Failure - metabolism; Isoproterenol - pharmacology; Microtubules - metabolism; Muscle Fibers, Skeletal - chemistry; Muscle Fibers, Skeletal - cytology; Muscle Fibers, Skeletal - metabolism; Myocardial Contraction - drug effects; Myocardial Contraction - physiology; Myocardium - chemistry; Myocardium - cytology; Myocardium - metabolism; Pacemaker, Artificial; Paclitaxel - pharmacology; Propanolamines - metabolism; Propanolamines - pharmacology; Radioligand Assay; Rats; Rats, Wistar; Receptors, Adrenergic, beta - metabolism; Space life sciences; Stress, Mechanical; Tritium; Vasodilator Agents - pharmacology
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/01.CIR.101.22.2625

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 beta-adrenergic receptor (beta-AR) signal pathway in cultured cardiomyocytes of neonatal rats.
Contraction of cardiomyocytes was induced by electrical stimulation at 50 V with twice the threshold pulse width. beta-ARs were identified by [(3)H]CGP-12177 and [(3)H]dihydroalprenolol. Electrical stimulation reduced cell-surface but not total beta-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 beta-AR density after exposure to isoproterenol (ISP) for 1 hour. The fraction and inhibition constant of beta-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 micromol/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 micromol/L) inhibited the rapid pacing-induced reduction in beta-AR density.
Our results suggest that contractile activity is involved in regulation of cardiac function by modulating the beta-AR system independently of hemodynamic and neurohormonal factors. This may help to elucidate the role of mechanical stress in the development of heart failure.