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Effects of Ca2+ channel blockers on Ca2+ loading induced by metabolic inhibition and hyperkalemia in cardiomyocytes
1Department of Biomedical and Therapeutic Sciences, University of Illinois College of Medicine at Peoria, 61605, USA.
Abstract:
The effects of the L-type (nifedipine and verapamil) and the T-type (mibefradil) Ca2+ channel blockers on the increase in intracellular Ca2+ concentration ([Ca2+]i) induced by NaCN metabolic inhibition and hyperkalemia were examined in chicken cardiomyocytes using fluorescence imaging with Fura-2. NaCN induced a slow and sustained rise in [Ca2+]i, which was not affected by pretreating the cells for 5 min with nifedipine, verapamil, or mibefradil at 100 nM or 10 microM. Pretreatment of the cells with 10 microM nifedipine, verapamil, or mibefradil for 5 min remarkably inhibited the K+-induced increase in [Ca2+]i. These inhibitory effects diminished after 48-h pretreatment with nifedipine or verapamil but not with mibefradil. Ryanodine also induces an increase in [Ca2+]i, and this effect was enhanced by 48-h pretreatment of the cells with 10 microM verapamil but not with 10 microM mibefradil. We conclude that the NaCN-induced increase in [Ca2+]i is independent of the Ca2+ influx though the L-type or T-type Ca2+ channels. Chronic inhibition of the L-type Ca2+ channels but not T-type channels may enhance the ryanodine receptor-mediated Ca2+ release, which may be responsible for the development of tolerance to their inhibitory effects on K+-induced increase in [Ca2+]i.
Insights
Calcium channel blockers like nifedipine and verapamil did not affect NaCN-induced calcium increases in chicken heart cells. However, chronic use of these blockers may alter calcium release mechanisms.
Area of Science:
- Cardiovascular Physiology
- Cellular Electrophysiology
- Pharmacology
Background:
- Intracellular calcium concentration ([Ca2+]i) is critical for cardiomyocyte function.
- L-type and T-type calcium channels play roles in regulating [Ca2+]i.
- Metabolic inhibition (NaCN) and hyperkalemia can alter [Ca2+]i.
Purpose of the Study:
- To investigate the effects of L-type (nifedipine, verapamil) and T-type (mibefradil) calcium channel blockers on NaCN-induced and hyperkalemia-induced [Ca2+]i increases in chicken cardiomyocytes.
- To explore the impact of chronic calcium channel blocker pretreatment on these responses and ryanodine-induced calcium release.
Main Methods:
- Primary chicken cardiomyocytes were used.
- Fluorescence imaging with Fura-2 measured intracellular Ca2+ concentration ([Ca2+]i).
- Cells were pretreated with varying concentrations and durations of nifedipine, verapamil, and mibefradil before stimulation with NaCN or high potassium (K+).
Main Results:
- Short-term (5 min) pretreatment with nifedipine, verapamil, or mibefradil did not affect the [Ca2+]i rise induced by NaCN.
- Short-term pretreatment with these blockers significantly inhibited the K+-induced increase in [Ca2+]i.
- Chronic (48 h) pretreatment with nifedipine or verapamil diminished their inhibitory effects on K+-induced [Ca2+]i, while mibefradil did not. Chronic verapamil enhanced ryanodine-induced [Ca2+]i.
Conclusions:
- The NaCN-induced increase in [Ca2+]i is independent of L-type or T-type calcium channel influx.
- Chronic inhibition of L-type calcium channels, but not T-type, may enhance ryanodine receptor-mediated Ca2+ release.
- This enhancement might explain the development of tolerance to the inhibitory effects of chronic L-type channel blockers on K+-induced [Ca2+]i increases.