Role of high affinity β-adrenergic receptor, β-arrestin, and β-adrenergic receptor kinase during the development of heart failure

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To examine the function of intracellular β-adrenergic receptor signal pathway during the development of pacing-induced heart failure, hemodynamic measurements were made with nine mongrel dogs fully awake. Signaling components were also measured using a crude cardiac sarcolemmal preparation. Furthermore, we assessed the relationship between the physiologic hemodynamic parameters and the biochemical components. Three dogs were paced for 1 d, two dogs were paced for 1 wk, and two dogs were paced for 6-7 wk. The data from dogs after 1 d, 1 wk, and 6-7 wk of pacing were compared with two sham-operated dogs. Left ventricular dP/dt in response to the acute challenges to isoproterenol was significantly decreased at 1 d and was depressed further at 1 and 6-7 wk of pacing. Both the fraction of β-adrenergic receptors binding agonist with high affinity and adenylyl cyclase activity decreased after 1 d of pacing. Ryanodine receptor decreased after 1 d of pacing, but not depressed furthermore. There were no significant changes in the total β-adrenergic receptor density, and the functional activity of Gs. β-adrenergic receptor kinase and β-arrestin did not estimated because of technical failure. Blunt responsiveness to isoproterenol derived mainly from the loss of high affinity cardiac β-adrenergic receptors. High affinity β-adrenergic receptor appears to be the most crucial change in the physiological deteriorations during the initial development of heart failure.