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T- and L-type Ca2+-channel antagonists reduce contractility in guinea pig cardiac myocytes
S Hoischen1, K Brixius, R H Schwinger
1Klink III für Innere Medizin der Universität zu Köln, Germany.
Abstract:
The aim of this study was to investigate the influence of L- and T-type Ca2+-channel blockade on myocardial contractility in guinea pig cardiomyocytes. Left ventricular myocardium from guinea pig contains both L- and T-type Ca2+ channels. The T-type Ca2+ influx was inhibited with mibefradil (1-100 microM), a novel compound with a threefold higher affinity for T- compared with L-type Ca2+ channels. In comparison, L-type Ca2+ influx was reduced by the benzodiazepine diltiazem (1-100 microM). The effect of mibefradil and diltiazem on electrically driven (0.5 Hz) isolated cardiomyocytes (n = 12) was studied in a concentration-dependent manner. The change of the contraction amplitude (percentage of cell shortening) was continuously recorded with an one-dimensional high-speed camera. Both mibefradil and diltiazem concentration-dependently reduced (p < 0.05 vs. control) the contraction amplitude in isolated myocytes from guinea pig. The concentration at which the contraction amplitude of guinea pig cardiomyocytes was reduced by 50% (EC50) was 31.6 microM for diltiazem and 6.3 microM for mibefradil, indicating that the T-type Ca2+-channel blocker mibefradil is more potent in reducing contractility in guinea pig cardiac myocytes in comparison with the L-type Ca2+-channel antagonist diltiazem. Mean values for cell shortening in percentage +/- SEM for mibefradil (0, 1, 10, 100 microM) were 100%, 78 +/- 9.2%, 36 +/- 5.4%, and 24 +/- 3.6%. The corresponding values for diltiazem were 100%, 92 +/- 12.5%, 79 +/- 8.9%, and 35 +/- 2.6%. In contrast, the increase of the extracellular Ca2+ concentration (2-7.5 mM) resulted in a significant increase of the contraction amplitude (+213 +/- 14%). Therefore, blockade of the Ca2+ influx through voltage-dependent T- or L-type Ca2+ channels decreases contraction in isolated cardiac myocytes from guinea pigs containing L- and T-type Ca2+ channels.
Insights
This study shows that blocking T-type calcium channels with mibefradil more potently reduces guinea pig heart cell contraction than blocking L-type channels with diltiazem. Both calcium channel blockers decreased myocardial contractility.
Area of Science:
- Cardiovascular Physiology
- Molecular Cardiology
- Pharmacology
Background:
- Cardiac contractility is regulated by calcium (Ca2+) influx through voltage-dependent channels.
- Both L-type and T-type Ca2+ channels are present in guinea pig ventricular myocardium.
- Understanding the specific roles of these channels is crucial for developing targeted cardiac therapies.
Purpose of the Study:
- To investigate the differential effects of L-type and T-type Ca2+ channel blockade on myocardial contractility.
- To compare the potency of mibefradil (T-type blocker) and diltiazem (L-type blocker) in reducing guinea pig cardiomyocyte contraction.
Main Methods:
- Isolated guinea pig cardiomyocytes were subjected to electrical stimulation (0.5 Hz).
- Concentration-dependent effects of mibefradil and diltiazem on cell shortening (contraction amplitude) were measured.
- Extracellular Ca2+ concentration was manipulated to assess its impact on contractility.
Main Results:
- Both mibefradil and diltiazem significantly reduced cardiomyocyte contraction in a concentration-dependent manner.
- Mibefradil demonstrated higher potency, with a 50% reduction in contraction amplitude (EC50) at 6.3 microM, compared to 31.6 microM for diltiazem.
- Increased extracellular Ca2+ concentration significantly enhanced contraction amplitude (+213%).
Conclusions:
- Blockade of T-type Ca2+ channels by mibefradil is more effective in reducing guinea pig cardiac myocyte contractility than L-type channel blockade by diltiazem.
- Both T- and L-type Ca2+ channel influx play significant roles in regulating myocardial contractility.
- These findings highlight the distinct contributions of different calcium channel subtypes to cardiac function.