Journal
CIRCULATION RESEARCH
Volume 89, Issue 7, Pages 607-613Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/hh1901.096702
Keywords
heart failure; L-type Ca2+ current; atrial fibrillation; rat atrial myocytes
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Downregulation of the L-type Ca2+ current (Ic,) 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 Ic, 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 alpha (1C)-subunit quantities were not significantly different between S and HF. The beta -adrenergic agonist isoproterenol (1 mu mol/L) had far greater stimulatory effects on I-Ca in HF than in S (2.5- versus I-fold), thereby suppressing the difference in current density. Dialyzing cells with 100 mu mol/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 Ic, in HF than in S (76.0 +/- 11.2% versus 15.8 +/- 21.2%), whereas the inhibitory effect of atrial natriuretic peptide on Ic, 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.
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