Dual effects of tetracaine on spontaneous calcium release in rat ventricular myocytes.
1. Confocal microfluorometry was used to study the effects of tetracaine on spontaneous Ca2+ release from the sarcoplasmic reticulum (SR) in isolated rat ventricular myocytes. 2. At low concentrations (0.25-1.25 mM), tetracaine caused an initial inhibition of spontaneous release events (Ca2+ sparks) and Ca2+ waves, which was followed by a gradual increase in Ca2+ release activity. The frequency and magnitude of sparks were first decreased and then increased with respect to control levels. At high concentrations (> 1.25 mM), tetracaine abolished all forms of spontaneous release. 3. Exposure of the myocytes to tetracaine resulted in a gradual increase in the SR Ca2+ load as indexed by changes in the magnitude of caffeine-induced Ca2+ transients. 4. In cardiac SR Ca(2+)-release channels incorporated into lipid bilayers, tetracaine (> 0.25 mM) induced a steady inhibition of channel activity. Addition of millimolar Ca2+ to the luminal side of the channel caused an increase in channel open probability under control conditions as well as in the presence of various concentrations of tetracaine. 5. We conclude that the primary effect of tetracaine on SR Ca(2+)-release channels is inhibition of channel activity both in vitro and in situ. The ability of tetracaine to reduce spark magnitude suggests that these events are not due to activation of single channels or non-reducible clusters of channels and, therefore, supports the multichannel origin of sparks. We propose that the paradoxical late potentiation of release by submaximal concentrations of tetracaine is caused by a gradual increase in SR Ca2+ load and subsequent activation of the Ca(2+)-release channels by Ca2+ inside the SR.
Györke
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S
Department of Physiology, Texas Tech University Health Science Center, Lubbock 79430, USA. physg@ttuhsc.edu
Lukyanenko
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Györke
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I
D000779:Anesthetics, Local / Q000494:pharmacology*; D000818:Animals; D002110:Caffeine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism* / Q000493:pharmacokinetics; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D004594:Electrophysiology; D006352:Heart Ventricles / Q000737:chemistry / Q000166:cytology / Q000378:metabolism; D008051:Lipid Bilayers / Q000378:metabolism; D018613:Microscopy, Confocal; D008861:Microsomes / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D018485:Muscle Fibers, Skeletal / Q000737:chemistry / Q000187:drug effects* / Q000648:ultrastructure; D009206:Myocardium / Q000737:chemistry / Q000166:cytology* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012508:Sarcolemma / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D013748:Tetracaine / Q000494:pharmacology*
D000779:Anesthetics, Local; D015220:Calcium Channels; D000697:Central Nervous System Stimulants; D008051:Lipid Bilayers; D013748:Tetracaine; D002110:Caffeine; D002118:Calcium