Use-dependent facilitation and depression of L-type Ca2+ current in guinea-pig ventricular myocytes:: modulation by Ca2+ and isoprenaline

被引:10
作者
Bates, SE [1 ]
Gurney, AM [1 ]
机构
[1] Univ Strathclyde, Strathclyde Inst Biomed Sci, Dept Physiol & Pharmacol, Glasgow G4 0NR, Lanark, Scotland
基金
英国惠康基金;
关键词
calcium; Ca-channel; membrane currents; myocytes;
D O I
10.1016/S0008-6363(99)00216-3
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Objective: An increase in stimulation frequency can facilitate or depress cardiac Ca2+ current (I-Ca). The aim was to examine the Ca2+ dependence of these effects, to determine if facilitation is sustained, and to elucidate the mechanism by which isoprenaline modulates facilitation. Methods: We examined the effects of increasing the stimulation frequency for 1 min, from 0.05 to 1 Hz, on I-Ca recorded from guinea-pig ventricular myocytes, using the whole-cell, voltage-clamp technique. Results: 1 Hz stimulation caused a facilitation of I-Ca that peaked in 5 s and was followed by depression towards the basal level. Metabolic inhibitors or replacement of extracellular Ca2+ with Ba2+ abolished facilitation without affecting depression, implying that they are independent processes and that facilitation required ATP and Ca2+. Subtraction of the depression observed in either condition, from the response to 1 Hz stimulation recorded under control conditions, revealed that I-Ca facilitation was well maintained during 1 Hz stimulation. Increased intracellular Ca2+ buffering reduced both phases of the response. Furthermore, varying the extracellular Ca2+ concentration ([Ca2+](o)) revealed a Ca2+-dependent enhancement of depression and a bell-shaped dependence of facilitation on [Ca2+](o). Facilitation increased with [Ca2+](o) up to 1 mM, then declined at higher concentrations due to partial masking by the overlapping depression. Isoprenaline produced concentration-dependent inhibition of facilitation and enhancement of depression when pipettes contained 2 mM EGTA, but not BAPTA. For an equivalent increase in I-Ca amplitude, the effects of isoprenaline and elevated [Ca2+](o) on the response to 1 Hz stimulation were quantitatively the same. Conclusions: Facilitation is sustained during increased activity, but appears transient due to overlapping depression. Both responses are promoted by increased submembrane [Ca2+]. Isoprenaline appears to modulate facilitation and depression as a consequence of increased Ca2+ influx, rather than cAMP-dependent phosphorylation. The apparent block of facilitation by isoprenaline may result from masking by the enhanced depression. (C) 1999 Elsevier Science B.V. All rights reserved.
引用
收藏
页码:381 / 389
页数:9
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