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(Circulation Research. 2001;89:607.)
© 2001 American Heart Association, Inc.

Cellular Biology

Mechanisms of L-Type Ca²⁺ Current Downregulation in Rat Atrial Myocytes During Heart Failure

Christophe Boixel, Walter Gonzalez, Liliane Louedec, Stéphane N. Hatem

From INSERM Unité 460, Faculté de Médecine Xavier Bichat, Paris, France.

Correspondence to Dr Stéphane Hatem, INSERM Unité 460, Faculté de Médecine Xavier Bichat, 16 rue Henri Huchard, 75018, Paris, France. E-mail hatem{at}bichat.inserm.fr

Abstract — Downregulation of the L-type Ca²⁺ current (I_Ca) 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 I_Ca in isolated left atrial myocytes with the whole-cell patch-clamp technique and biochemical assays. I_Ca 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 _1C-subunit quantities were not significantly different between S and HF. The ß-adrenergic agonist isoproterenol (1 µmol/L) had far greater stimulatory effects on I_Ca 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 I_Ca 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 I_Ca in HF than in S (76.0±11.2% versus 15.8±21.2%), whereas the inhibitory effect of atrial natriuretic peptide on I_Ca 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, I_Ca 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.

Key Words: heart failure • L-type Ca²⁺ current • atrial fibrillation • rat atrial myocytes

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