Heart failure after myocardial infarction: altered excitation-contraction coupling.

BACKGROUND: Heart failure (HF) frequently follows the occurrence of myocardial infarction (MI). Questions about how HF develops and what cellular defects contribute to this dysfunction led to this study. Methods and Results-- MI was induced in rats by coronary artery ligation. Clinical examination of the post-MI (PMI) surviving animals indicated that they were in overt HF by all measures. Cellular examination of the cardiomyocytes by patch-clamp and confocal [Ca(2+)](i) imaging methods indicated that cellular function was significantly compromised. At the single-cell level, [Ca(2+)](i) transient amplitudes were reduced and contractions were decreased and slowed, although Ca(2+) current (I(Ca)) remained unchanged. The excitation-contraction coupling (ECC) gain function measured as Delta[Ca(2+)](i)/I(Ca) was significantly decreased. Ouabain, a cardiotonic steroid that blocks the Na(+),K(+)-ATPase and activates Ca(2+) entry via cardiac Na(+) channels, largely alleviated this defect. CONCLUSIONS: After MI, I(Ca) becomes less able to trigger release of Ca(2+) from the sarcoplasmic reticulum. This failure of ECC is a major factor contributing to the development of contractile dysfunction and HF in PMI animals. The improved ECC gain, enhanced Ca(2+) entry, and augmented Ca(2+) signaling due to cardiotonic steroids contribute to the beneficial effects of these agents.

Comparison of the effects of caffeine and other methylxanthines on [Ca2+]i in rat ventricular myocytes.

1. The effects of caffeine and other methylxanthines were investigated on intracellular calcium concentration ([Ca2+]i) and contraction in rat isolated ventricular myocytes. The use of the fluorescent indicator, Indo-1, allowed simultaneous measurement of [Ca2+]i and the intracellular concentration of the methylxanthines. 2. Rapid application of caffeine (10 mM) produced a transient rise of [Ca2+]i which decayed to resting levels. This was accompanied by a transient contraction which decayed to a level above baseline. The addition of theophylline also produced a transient increase of [Ca2+]i. However, following the initial transient, contraction decayed before redeveloping to a maintained level. 3. Direct measurements showed that [caffeine]i rose more quickly than did [theophylline]i. The slower rise of [theophylline]i was associated with a delay in the increase of [Ca2+]i. At lower concentrations of the methylxanthines, theophylline was less effective than caffeine at initiating Ca release. The rate of entry of theobromine was similar to that of theophylline. 4. Isocaffeine did not produce a rise of [Ca2+]i. The rate of rise of [isocaffeine]i was much slower than that of either caffeine or theophylline. 5. Measurements of the oil:water partition coefficient showed that the order of relative partitioning into oil was: caffeine > theophylline > theobromine > isocaffeine. This is similar to the order of rate of entry into the cell. 6. We conclude that many of the differences in the effects of these methylxanthines can be attributed to differences in membrane permeability due to differences in oil:water partition.