Activation of Connexin-43 Hemichannels Can Elevate [Ca2+]iand [Na+]iin Rabbit Ventricular Myocytes During Metabolic Inhibition

Author： Li F.   Sugishita K.   Su Z.   Ueda I.   Barry W.H.  

Publisher： Academic Press

ISSN： 0022-2828

Source： Journal of Molecular and Cellular Cardiology, Vol.33, Iss.12, 2001-12, pp. : 2145-2155

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Abstract

ATP depletion due to ischemia or metabolic inhibition (MI) causes Na+and Ca2+accumulation in myocytes, which may be in part due to opening of connexin-43 hemichannels. Halothane (H) has been shown to reduce conductance of connexin-43 hemichannels and to protect the heart against ischemic injury. We therefore investigated the effect of halothane on [Ca2+]iand [Na+]iin myocytes during MI. Isolated rabbit left ventricular myocytes were loaded with 4μ m fluo-3 AM for 30 min, or with 5 μ m sodium green AM for 60 min at 37°C. After washing, the myocytes were exposed to: (1) Normal HEPES solution; (2) MI solution (2 m m NaCN, 20 m m 2-deoxy- d -glucose and 0-glucose); or (3) MI+H (0.95 m m, 4.7 m m) for 60 min. Propidium iodide (PI, 25 μ m) was added to all samples before data acquisition. The fluorescence intensity was measured by flow cytometry with 488 nm excitation and 530 nm emission for fluo-3 or sodium green, and 670 nm for PI. The [Ca2+]iand [Na+]iwere then calculated by calibration. In some experiments, the effect of 10 μm tetrodotoxin (TTX) and 20 μ m nifedipine (NIF) were studied. Metabolic inhibition for 60 min caused a significant increase in [Ca2+]iand [Na+]iin myocytes when compared to controls, which was significantly reduced by halothane in a dose-dependent fashion. In the presence of TTX and NIF, halothane also significantly reduced the rise in the [Ca2+]iand [Na+]iin myocytes subjected to MI. 1-heptanol, another gap junction blocker, had similar effects. Thus, halothane reduced [Ca2+]iand [Na+]ioverload produced by MI in myocytes. This effect is not solely due to block of voltage-gated Na+and Ca2+channels, and is likely mediated by inhibiting the opening of connexin-43 hemichannels.

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