Coronary artery stenosis in rats affects β-adrenergic receptor signaling in myocytes

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Abstract
Objective: The purpose of this study was to determine whether the early chronic ischemic cardiomyopathy produced by non-occlusive coronary artery constriction was characterized by alterations in the regulation of β-adrenoreceptor (β-AR) signaling. Methods: Coronary artery narrowing was surgically induced in rats and the animals sacrified at 7 and 14 days. The changes in the biochemical properties of the multiple components of the β-AR pathway were examined in enzymatically dissociated myocytes. Results: Coronary stenosis, involving an average 55% reduction in luminal diameter, was associated with left ventricular failure and right ventricular dysfunction at both time intervals. A decrease in the quantity of β-AR was detected at 7 days and preceded the loss of high-affinity binding sites. This regulatory modification was characterized by a reduction in β1 and β2 receptors and a shift in the isoproterenol dose response curve indicating a functional correlation between the decrease in β-AR and attenuated inotropic support of the myocardium. The percentage of β-AR binding agonist with high affinity decreased significantly at 14 days along with a further reduction in the density of β1 and β2 receptors. Reconstitution studies with cyc−S49 lymphoma cells did not detect an impairment of Gsα functional activity, but the quantity of Giα was increased at both intervals. Finally, activation of the catalytic unit of adenylyl cyclase by forskolin and GTP was not altered by coronary stenosis, however, basal cyclic AMP in myocytes was depressed at 14 days. Conclusions: Coronary stenosis induces distinct and progressive modifications in the β-AR signaling cascade which may contribute to the impaired ventricular performance in this model of myocardial ischemia.

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