Acute alcohol ingestion and chronic alcoholism are associated with cardiac arrhythmias and a depression of contractility. These myocardial effects may be directly induced by ethanol or indirectly mediated through its metabolic product, acetaldehyde. Ethanol exerts biphasic, concentration-dependent effects on cardiac electromechanical function. Low concentrations potentiate contraction whereas, high concentrations produce contractile depression, arrhythmias, membrane depolarization, and attenuates action potential amplitude and duration. Mechanisms underlying ethanol-induced myocardial dysfunction are unknown. In normal cardiac muscle, contraction is preceded by an electrical event that elevates intracellular calcium which allows interaction of contractile proteins to promote cell shortening. Contractile dysfunction of cardiac muscle in chronic alcoholism may be due to ethanol or acetaldehyde-induced alterations in electrical activity and/or intracellular calcium regulation. The objective of this investigation is to determine the cellular mechanism(s) underlying ethanol-induced arrhythmias and contractile depression. A key hypothesis addressed is that acetaldehyde itself may exert a direct toxic effect on cardiac muscle causing myocardial dysfunction. The experiments proposed are designed in a dose-response format using clinically relevant concentrations of ethanol and acetaldehyde. Separate effects of acute and chronic ethanol and acetaldehyde exposure on sinus node automaticity and membrane potentials will be determined using single microelectrode recording. In addition, effects on papillary muscle electromechanical function will also be determined using single microelectrode recording in combination with measurement of isometric tension. Effects of ethanol and acetaldehyde on intracellular calcium concentration and membrane ionic currents will be determined using the fluorescent dye fura-2 and patch clamp techniques, respectively. Use of these methods will provide both a complete description of how ethanol and acetaldehyde affect excitation-contraction coupling and insight as to the cellular mechanisms underlying ethanol-induced myocardial dysfunction.
| Morales, J A; Ram, J L; Song, J et al. (1997) Acetaldehyde inhibits current through voltage-dependent calcium channels. Toxicol Appl Pharmacol 143:70-4 |
