Yoshitaka Miyazaki

Role of adrenergic receptor systems in canine left ventricular hypertrophy

Although the sympathetic nervous system and catecholamines have been postulated to play an important role in the development of myocardial hypertrophy, the precise mechanism is still ill-defined. We therefore investigated myocardial norepinephrine and the adrenergic receptor systems in two experimental canine models for cardiac hypertrophy; in 12 dogs with surgical cardiac denervation, and in 12 dogs with chronic infusion of a subhypertensive dose of norepinephrine at a rate of 0.04 mg/kg/day. After two months both models induced myocardial hypertrophy, indicated by significant increases in the heart weight, left ventricular wall thickness and cell diameter, as compared with 14 sham-operated control dogs. Cardiac denervation remarkably depleted myocardial norepinephrine while plasma norepinephrine remained unchanged. Both alpha 1- and beta-receptors were up-regulated, with Bmax increasing by 124% and 49%, respectively. The decrease in myocardial cyclic AMP content was relatively small as compared with the marked depletion in myocardial norepinephrine, probably compensated by augmentation of beta-receptor system activity. Chronic norepinephrine infusion also reduced myocardial norepinephrine content possibly due to stimulation of presynaptic alpha 2-receptor inhibiting norepinephrine synthesis and release. The number of alpha 1- and beta-receptors also increased by 97% and 30%, respectively, while myocardial cyclic AMP content remained unchanged. These observations indicate that neither direct stimulation of norepinephrine on the myocardial cell nor increased cyclic AMP is the mechanism for cardiac hypertrophy. A greater increase in the alpha 1-receptor, rather than in the beta-receptors, in both models implies that a disproportional augmentation of the alpha 1-receptor system may play an important role in the development of myocardial hypertrophy.