Abnormalities in β-Adrenergic Signal Transduction with Myocardial Decompensation and Failure
The progression of changes in β-adrenergic receptor signalling was studied over several time points during the development of pacing-induced heart failure in long-term instrumented, conscious dogs. Animals were paced at 240 beats per minute for one month and data were averaged at 1 day, 1 week, and 3–4 weeks after pacing. The rate of change in left ventricular pressure (LV dP/dt) was decreased at 1 day, LV end-diastolic pressure and heart rate were increased at 1 week, but heart failure occurred only after 3–4 weeks of pacing. Circulating levels of norepinephrine were elevated after 1 day of pacing, and tissue levels of norepinephrine were reduced only after 3–4 weeks of pacing. High-affinity β-adrenergic receptors and adenylyl cyclase activity decreased after one day of pacing. β1-adrenergic receptor density decreased after one week of pacing. Gs functional activity was not reduced, but Giα2 rose after 3–4 weeks of pacing. Thus, β-adrenergic receptor signal transduction is significantly altered early, i. e., 1 day after the initiation of rapid ventricular pacing, prior to the development of heart failure. Changes occurring at 1 day after rapid ventricular pacing include increases in plasma catecholamines, uncoupling of the β-adrenergic receptor from adenylyl cyclase, and a decrease in adenylyl cyclase activity. After more prolonged pacing there is a decrease in β1-adrenergic receptors, decreases in myocardial tissue catecholamines, and increases in Giα2. Therefore, physiological changes in β-adrenergic receptor function during the initial development of heart failure appear to be mediated by different mechanisms than those changes that occur later as heart failure becomes manifest.
KeywordsHeart Failure Adenylyl Cyclase Plasma Catecholamine Adenylyl Cyclase Activity Rapid Ventricular Pace
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