Abstract
Infarct-induced heart failure is usually associated with cardiac hypertrophy and decreased -adrenergic responsiveness. However, conflicting results have been reported concerning the density of L-type calcium current (I Ca(L)), and the mechanisms underlying the decreased -adrenergic inotropic response. We determined I Ca(L) density, cytoplasmic calcium ([Ca2+]i) transients, and the effects of -adrenergic stimulation (isoproterenol) in a model of postinfarction heart failure in rats. Left ventricular myocytes were obtained by enzymatic digestion 8-10 weeks after infarction. Electrophysiological recordings were obtained using the patch-clamp technique. [Ca2+]i transients were investigated via fura-2 fluorescence. -Adrenergic receptor density was determined by [ H]-dihydroalprenolol binding to left ventricle homogenates. Postinfarction myocytes showed a significant 25% reduction in mean I Ca(L) density (5.7 0.28 vs 7.6 0.32 pA/pF) and a 19% reduction in mean peak [Ca2+]i transients (0.13 0.007 vs 0.16 0.009) compared to sham myocytes. The isoproterenol-stimulated increase in I Ca(L) was significantly smaller in postinfarction myocytes (Emax: 63.6 4.3 vs 123.3 0.9% in sham myocytes), but EC50 was not altered. The isoproterenol-stimulated peak amplitude of [Ca2+]i transients was also blunted in postinfarction myocytes. Adenylate cyclase activation through forskolin produced similar I Ca(L) increases in both groups. -Adrenergic receptor density was significantly reduced in homogenates from infarcted hearts (Bmax: 93.89 20.22 vs 271.5 31.43 fmol/mg protein in sham myocytes), while Kd values were similar. We conclude that postinfarction myocytes from large infarcts display reduced I Ca(L) density and peak [Ca2+]i transients. The response to -adrenergic stimulation was also reduced and was probably related to -adrenergic receptor down-regulation and not to changes in adenylate cyclase activity.
Highlights
After myocardial infarction, the acute loss of myocytes leads to an increased load to the heart and to the onset of a cascade of biochemical signaling processes that induce the remodeling of the infarcted zone and of the remote noninfarcted myocardium
According to the inclusion criteria established, the model of myocardial infarction used in this paper corresponds to cardiac hypertrophy and heart failure induced by a
Indicated that the equilibrium dissociation constants were the same for both membrane preparations, suggesting a noninteracting single population of DHA binding sites in both postinfarction and sham myocytes. This is the first study in which calcium current densities, intracellular calcium transients and binding to ß-adrenergic receptors were evaluated simultaneously in a welldefined model of cardiac hypertrophy
Summary
The acute loss of myocytes leads to an increased load to the heart and to the onset of a cascade of biochemical signaling processes that induce the remodeling of the infarcted zone and of the remote noninfarcted myocardium. Heart failure is often the final result of this process after large infarcts [1,2]. The decrease in the mechanical performance in this model includes the loss of myocardium caused by the infarct, and decreased contractility and response to ßadrenergic stimulation of the remaining hypertrophied myocardium [3,5,8,10]. The mechanisms underlying the reductions of inotropism and the response to ßadrenergic stimulation are not completely understood
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