Role of Adrenergic Activity, Alpha-Receptor, and Beta-Receptor in Progression of Chronic Heart Failure

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We investigated serial changes in myocardial norepinephrine content and myocardial adrenergic receptors during the development of cardiomyopathy and heart failure in Syrian hamsters and their age-matched healthy controls. We found that in the pre-hypertrophic stage, myocardial norepinephrine content and densities of alpha_1-, beta-adrenergic receptors were significantly higher in the cardiomyopathic hamsters than in the controls. However, in the early heart failure stage, beta-receptor density was 28% lower than that of the age-matched controls, though alpha_1-receptor density remained 55% higher. Norepinephrine-stimulated phosphatidylinositide hydrolysis in the cardiomyopathic hamster in the hypertrophic stage was twice that in the controls, indicating that the increase in alpha_1-adrenergic receptors are coupled with the intracellular signal transduction. Furthermore, selective alpha_1-adrenoceptor blockade by bunazosin in the cardiomyopathic hamsters from 70 to 170 days of age reduc … More ed myocardial hypertrophy and focal myocardial necrosis. We also studied the effects of alpha_1-adrenoceptor stimulation on intracellular pH and Ca^<2+> concentration ([Ca^<2+>]) in rat cardiomyocytes using fluorescence dyes. Norepinephrine stimulation increased intracellular pH in BCECF-loaded cardiomyocytes. The alkalinization was inhibited by prazosin and phentolamine, but not by yohimbine. The increase in intracellular pH was abolished without extracellular Na^+ or in the presence of hexamethylene-amiloride, a specific Na^+/H^+ exchange inhibitor, indicating that the alkalinization was mediated by Na^+/H^+ exchange. alpha_1-Adrenergic stimulation also increased intracellular [Ca^<2+>] in fura-2 loaded cardiomyocytes. The increase in intracellular [Ca^<2+>] occurrd following intracellular alkalinization and was abolished without extracellular Ca^<2+> or Na^+. The increase in intracellular [Ca^<2+>] was inhibited by hexamethylene-amiloride. These results suggest that alpha_1-receptor stimulation activates Na^+/H^+ exchange, followed by an increase in intracellular [Ca^<2+>] throuh the consequent Na^+/Ca^+ exchange. Thus, we conclude that alpha_1-adrencergic activity plays an important role through Ca^<2+> overload in progression of cardiac hypertrophy and myocardial damage in chronic heart failure. Less