Characteristics of two slow inactivation mechanisms and their influence on the sodium channel activity of frog ventricular myocytes.
Inactivation of the fast Na+ current of heart muscle occurs in two kinetically distinct phases: a fast process operating on a millisecond time scale and a considerably slower process, the kinetic properties of which have not been explored fully. In this study, we analysed the slow inactivation process in isolated frog ventricular myocytes using the whole-cell variation of the patch-clamp method. Slow inactivation of the Na+ current followed a double-exponential time course, corresponding to slow and ultraslow components of Na+ channel inactivation. The individual time constants were 2-7 s (slow component) and 40-560 s (ultraslow component). Recovery from these slow inactivation processes also followed a double-exponential time course, but was characterized by significantly briefer time constants than those for the inactivation process. The relationship between transmembrane potential and steady-state slow or ultraslow inactivation was well described by the Boltzmann equation. The membrane potential at which half the Na+ channels are inactivated (V1/2) and the slope factor were estimated to be -48.1 and 13.6 mV, respectively, for the slow component alone. Under conditions in which the slow and ultraslow inactivation components were both present, these parameters were -53.1 and 8.7 mV respectively. When the fast and the two slow inactivation processes occurred concomitantly, the resultant steady-state inactivation curves were shifted to more negative potentials and the slope factor was decreased. Treatment with 1 mM Cd2+ externally did not affect the time course of slow inactivation, but produced a 3-7 mV depolarizing shift in its steady-state voltage dependency by virtue of cadmium's known effect on the cell surface potential. This study has thus identified two components of slow Na+ inactivation in heart muscle, operating on a time scale of seconds (slow inactivation) and minutes (ultraslow inactivation).
Department of Physiology, Hiroshima University School of Medicine Kasumi 1-2-3, Minami-ku, Hiroshima 734-8551, Japan.
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T
Furue
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M
Yakehiro
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K
Yamaoka
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K
Sumii
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Seyama
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D002104:Cadmium / Q000494:pharmacology; D002118:Calcium / Q000494:pharmacology; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D006352:Heart Ventricles / Q000166:cytology*; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008954:Models, Biological; D009206:Myocardium / Q000166:cytology* / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D011892:Rana catesbeiana; D015222:Sodium Channels / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology*; D019789:Tetraethylammonium / Q000494:pharmacology; D013997:Time Factors
D000318:Adrenergic beta-Agonists; D015222:Sodium Channels; D002104:Cadmium; D019789:Tetraethylammonium; D002118:Calcium