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Coronary artery stenosis in rats affects beta-adrenergic receptor signaling in myocytes
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 beta-adrenoreceptor (beta-AR) signaling.
Methods:
Coronary artery narrowing was surgically induced in rats and the animals sacrificed at 7 and 14 days. The changes in the biochemical properties of the multiple components of the beta-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 beta-AR was detected at 7 days and preceded the loss of high-affinity binding sites. This regulatory modification was characterized by a reduction in beta 1 and beta 2 receptors and a shift in the isoproterenol dose response curve indicating a functional correlation between the decrease in beta-AR and attenuated inotropic support of the myocardium. The percentage of beta-AR binding agonist with high affinity decreased significantly at 14 days along with a further reduction in the density of beta 1 and beta 2 receptors. Reconstitution studies with cyc S49 lymphoma cells did not detect an impairment of Gs alpha functional activity, but the quantity of Gi alpha 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 beta-AR signaling cascade which may contribute to the impaired ventricular performance in this model of myocardial ischemia.
Insights
Early coronary stenosis in rats alters beta-adrenoreceptor (beta-AR) signaling, decreasing receptor quantity and impairing myocardial function. These changes contribute to ventricular dysfunction in ischemic cardiomyopathy.
Area of Science:
- Cardiovascular Physiology
- Molecular Cardiology
- Pharmacology
Background:
- Chronic ischemic cardiomyopathy can result from coronary artery disease.
- Beta-adrenoreceptor (beta-AR) signaling is crucial for cardiac function.
- Understanding beta-AR regulation in ischemia is vital for therapeutic development.
Purpose of the Study:
- To investigate alterations in beta-AR signaling regulation during early chronic ischemic cardiomyopathy.
- To determine the biochemical changes in the beta-AR pathway following non-occlusive coronary artery constriction.
Main Methods:
- Surgically induced coronary artery narrowing in rats.
- Biochemical analysis of beta-AR pathway components in myocytes at 7 and 14 days post-surgery.
- Assessed receptor density, binding affinity, and adenylyl cyclase activity.
Main Results:
- Coronary stenosis led to ventricular failure and dysfunction.
- Decreased beta-AR quantity and high-affinity binding sites were observed, preceding functional impairment.
- Downregulation of beta 1 and beta 2 receptors correlated with reduced inotropic support; Gi alpha increased, while Gs alpha and adenylyl cyclase activity remained unchanged.
Conclusions:
- Coronary stenosis induces progressive modifications in the beta-AR signaling cascade.
- These beta-AR pathway alterations contribute to impaired ventricular performance in this model of myocardial ischemia.
- Findings highlight the role of beta-AR dysregulation in the pathophysiology of ischemic cardiomyopathy.