Mechanisms of L-Type Ca 2+ Current Downregulation in Rat Atrial Myocytes During Heart Failure

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Abstract
Abstract— Downregulation of the L-type Ca2+ current (ICa) is an important determinant of the electrical remodeling of diseased atria. Using a rat model of heart failure (HF) due to ischemic cardiopathy, we studied ICa in isolated left atrial myocytes with the whole-cell patch-clamp technique and biochemical assays. ICa density was markedly reduced (1.7±0.1 pA/pF) compared with sham-operated rats (S) (4.1±0.2 pA/pF), but its gating properties were unchanged. Calcium channel α1C-subunit quantities were not significantly different between S and HF. The β-adrenergic agonist isoproterenol (1 μmol/L) had far greater stimulatory effects on ICa in HF than in S (2.5- versus 1-fold), thereby suppressing the difference in current density. Dialyzing cells with 100 μmol/L cAMP or pretreating them with the phosphatase inhibitor okadaic acid also increased ICa and suppressed the difference in density between S and HF. Intracellular cAMP content was reduced more in HF than in S. The phosphodiesterase inhibitor 3-isobutyl-1-methyl-xanthine had a greater effect on ICa in HF than in S (76.0±11.2% versus 15.8±21.2%), whereas the inhibitory effect of atrial natriuretic peptide on ICa was more important in S than in HF (54.1±4.8% versus 24.3±8.8%). Cyclic GMP extruded from HF myocytes was enhanced compared with S (55.8±8.0 versus 6.2±4.0 pmol · mL−1). Thus, ICa downregulation in atrial myocytes from rats with heart failure is caused by changes in basal cAMP-dependent regulation of the current and is associated with increased response to catecholamines.