Catecholamine-induced cardiac hypertrophy: significance of proto-oncogene expression

Abstract

The effect of beta- and alpha-adrenergic stimulation on cardiovascular function and development of cardiac hypertrophy was studied in rats by measuring the heart weight/body weight and cardiac RNA/DNA ratios. Beta-receptor stimulation with isoproterenol over 3 days induced an increase in the biosynthesis of cardiac adenine nucleotides, myocardial protein synthesis, and the heart weight/body weight ratio. The isoproterenol-induced metabolic effects were prevented by simultaneous beta-adrenergic blockade with propranolol. Alpha-adrenergic stimulation with norfenephrine for 3 days induced an increase in heart rate, total peripheral resistance, the myocardial RNA/DNA, and left ventricular weight/body weight ratio. The calcium antagonist verapamil prevented the hemodynamic changes but did not influence the development of cardiac hypertrophy. The alpha-adrenergic blocker prazosin reversed the norfenephrine-induced functional changes and prevented cardiac hypertrophy. Norepinephrine was infused into isolated perfused working rat hearts to elucidate some molecular biological changes that precede the development of cardiac hypertrophy. It increased transiently and sequentially the mRNA of c-fos and c-myc. This enhancement occurred at about the same time as that induced by elevation of pre- and afterload but was more pronounced. These findings were compared with those obtained in other studies assessing the effects of catecholamines on proto-oncogene expression. Combination of norepinephrine with pre- and afterload elevation induced the c-fos mRNA signal to appear earlier, to be more pronounced, and to persist for a longer period of time. Similar results were obtained in regard to the c-myc mRNA. These findings indicate that the combination of two hypertrophy-inducing stimuli which may cause a higher degree of cardiac hypertrophy in vivo induce an earlier, more pronounced, and longer lasting expression of the proto-oncogenes c-fos and c-myc.