Beta-adrenergic stimulation disassembles microtubules in neonatal rat cultured cardiomyocytes through intracellular Ca2+ overload.
Catecholamine cardiotoxicity is attributable in part to Ca2+ overload. To test whether the cytoskeletal structures of microtubules in cardiomyocytes are reversibly injured by catecholamine through excessive Ca2+ influx, morphological changes in the microtubules of neonatal rat myocytes were studied by immunohistochemical technique during exposure to norepinephrine (NE). In intact myocytes, microtubules appeared as a filamentous network throughout the cytoplasm and around the nucleus. NE exposure (10 mumol/L) for > 30 minutes elicited microtubular disassembly in a duration-dependent fashion without any irreversible change in sarcomere structure, and this abnormality recovered within 24 hours after cessation of stimulation. Microtubular disruption scores obtained by semiquantitative assessment were significantly increased in a dose-dependent manner (10.8 +/- 4.0 in the control condition, 23.4 +/- 4.7 at 60 minutes with 10 mumol/L NE), whereas they were significantly attenuated by pretreatment with propranolol (100 mumol/L; score, 11.8 +/- 3.3) but not with phentolamine (100 mumol/L; score, 26.4 +/- 4.8). Isoproterenol (1 mumol/L) and denopamine (10 mumol/L) mimicked the effects of NE, but phenylephrine did not, indicating that NE-induced microtubular disassembly is mediated by beta 1-adrenergic receptor stimulation. This beta-adrenergic receptor-mediated insult was significantly attenuated by a decrease in Ca2+ concentration in the medium from 2 to 0.5 mmol/L and by pretreatment with diltiazem (1 mumol/L). In contrast, microtubular disassembly was induced by an increase in Ca2+ concentration in the medium and an administration of the Ca2+ ionophore A23187, even without beta-adrenergic receptor stimulation. Involvement of intracellular hypoxia and activation of Ca(2+)-calmodulin-dependent kinase or Ca(2+)-dependent neutral protease were excluded from possible mechanisms; however, inhibition of tubulin polymerization by excessive Ca2+ influx during beta-adrenergic receptor stimulation may be primarily involved. We conclude that microtubular structures that support cellular integrity are reversibly injured by beta-adrenergic receptor stimulation through excessive Ca2+ influx.[1]References
- Beta-adrenergic stimulation disassembles microtubules in neonatal rat cultured cardiomyocytes through intracellular Ca2+ overload. Hori, M., Sato, H., Kitakaze, M., Iwai, K., Takeda, H., Inoue, M., Kamada, T. Circ. Res. (1994) [Pubmed]
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