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 a
ssays. Ica density was markedly reduced (1.7 +/- 0.1 pA/pF) compared with s
ham-operated rats (S) (4.1 +/- 0.2 pA/pF), but its gating properties were u
nchanged. Calcium channel alpha (1C)-subunit quantities were not significan
tly 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 phospha
tase inhibitor okadaic acid also increased I-Ca and suppressed the differen
ce in density between S and HF. Intracellular cAMP content was reduced more
in HF than in S. The phosphodiesterase inhibitor 3-isobutyl-1-methyl-xanth
ine 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 atri
al myocytes from rats with heart failure is caused by changes in basal cAMP
-dependent regulation of the current and is associated with increased respo
nse to catecholamines.