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Department of Cardiac Medicine, National Heart and Lung Institute, Imperial College, London SW3 6LY, United Kingdom

Address correspondence to K.T. MacLeod, Department of Cardiac Medicine, National Heart and Lung Institute, Imperial College, Dovehouse Street, London SW3 6LY, UK. Fax: (44) 20 7351 8145; E-mail: k.t.macleod{at}ic.ac.uk

The putative voltage-sensitive release mechanism (VSRM) was investigated in rabbit cardiac myocytes at 37°C with high resistance microelectrodes to minimize intracellular dialysis. When the holding potential was adjusted from -40 to -60 mV, the putative VSRM was expected to operate alongside CICR. Under these conditions however, we did not observe a plateau at positive potentials of the cell shortening versus voltage relationship. The threshold for cell shortening changed by -10 mV, but this resulted from a similar change of the threshold for activation of inward current. Cell shortening under conditions where the putative VSRM was expected to operate was blocked in a dose dependent way by nifedipine and CdCl₂ and blocked completely by NiCl₂. "Tail contractions" persisted in the presence of nifedipine and CdCl₂ but were blocked completely by NiCl₂. Block of early outward current by 4-aminopyridine and 4-acetoamido-4'-isothiocyanato-stilbene-2,2'-disulfonic acid (SITS) demonstrated persisting inward current during test depolarizations despite the presence of nifedipine and CdCl₂. Inward current did not persist in the presence of NiCl₂. A tonic component of cell shortening that was prominent during depolarizations to positive potentials under conditions selective for the putative VSRM was sensitive to rapidly applied changes in superfusate [Na⁺] and to the outward Na⁺/Ca²⁺ exchange current blocking drug KB-R7943. This component of cell shortening was thought to be the result of Na⁺/Ca²⁺ exchange–mediated excitation contraction coupling. Cell shortening recorded under conditions selective for the putative VSRM was increased by the enhanced state of phosphorylation induced by isoprenaline (1 µM) and by enhancing sarcoplasmic reticulum Ca²⁺ content by manipulation of the conditioning steps. Under these conditions, cell shortening at positive test depolarizations was converted from tonic to phasic. We conclude that the putative VSRM is explained by CICR with the Ca²⁺ "trigger" supplied by unblocked L-type Ca²⁺ channels and Na⁺/Ca²⁺ exchange.

Key Words: EC coupling • L-type Ca²⁺ channels • VSRM • CICR

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