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Effect of calcium channel antagonists on calcium uptake and release by isolated rat cardiac mitochondria
W C Buss1, D D Savage, J Stepanek
1Department of Pharmacology, University of New Mexico, School of Medicine, Albuquerque 87131.
Abstract:
The effects of calcium channel antagonists on Ca2+ uptake and Na+-induced Ca2+ release were studied in isolated rat cardiac mitochondria. Diltiazem, nitrendipine and nimodipine were more effective inhibitors of Na+-induced Ca2+ release (IC50 = 19-100 microM) than of Ca2+ uptake (IC50 = 0.2-1 mM). Nitrendipine and nimodipine had virtually identical IC50 values for inhibiting Ca2+ uptake, but nitrendipine was 3-4 times more potent than nimodipine at inhibiting Na+-induced Ca2+ release. If these calcium channel antagonists achieve intracellular concentrations in the range of 10(-5)-10(-4) M, our results suggest that calcium channel antagonists would preferentially inhibit mitochondrial calcium release more than mitochondrial calcium uptake.
Insights
Calcium channel antagonists inhibit mitochondrial calcium release more effectively than uptake. This suggests potential therapeutic benefits by modulating mitochondrial calcium handling in cardiac conditions.
Area of Science:
- Biochemistry
- Cardiovascular Pharmacology
- Mitochondrial Physiology
Background:
- Mitochondrial calcium (Ca2+) handling is crucial for cardiac function and energy production.
- Dysregulation of mitochondrial Ca2+ can contribute to heart disease.
- Calcium channel antagonists (CCAs) are widely used cardiovascular drugs, but their direct effects on mitochondria are less understood.
Purpose of the Study:
- To investigate the impact of specific CCAs on Ca2+ uptake and Na+-induced Ca2+ release in isolated rat cardiac mitochondria.
- To compare the inhibitory potencies of diltiazem, nitrendipine, and nimodipine on these mitochondrial Ca2+ transport processes.
Main Methods:
- Isolated rat cardiac mitochondria were used as the experimental model.
- The effects of CCAs on Ca2+ uptake and Na+-induced Ca2+ release were quantified.
- Inhibitory concentrations (IC50) were determined for each drug and process.
Main Results:
- Diltiazem, nitrendipine, and nimodipine were more potent inhibitors of Na+-induced Ca2+ release (IC50 = 19–100 µM) compared to Ca2+ uptake (IC50 = 0.2–1 mM).
- Nitrendipine and nimodipine showed similar efficacy in inhibiting Ca2+ uptake.
- Nitrendipine was 3–4 times more potent than nimodipine in inhibiting Na+-induced Ca2+ release.
Conclusions:
- CCAs preferentially inhibit mitochondrial Ca2+ release over Ca2+ uptake at relevant intracellular concentrations (10^-5–10^-4 M).
- These findings suggest a direct mitochondrial mechanism for CCAs that could influence cardiac function.
- The differential effects highlight potential therapeutic strategies targeting mitochondrial Ca2+ handling in cardiovascular diseases.