Cardiac hypertrophy induced by alpha- and beta-adrenergic receptor stimulation

The aim of the study was to examine whether stimulation of alpha- and beta-adrenergic receptors in intact rats induces cardiac hypertrophy and to characterize the metabolic alterations that precede or accompany the process of hypertrophy. Cardiac beta-adrenergic receptors were stimulated with a single subcutaneous injection of 25 mg/kg isoproterenol. This led to an increase in the cardiac cAMP level which was followed by the sequential enhancement of adenine nucleotide biosynthesis and protein synthesis. The increase in adenine nucleotide and protein synthesis induced by isoproterenol was prevented by propranolol (50 mg/kg) within the first 5 hours. Norepinephrine, given as a continuous intravenous infusion of 0.2 mg/kg for 3 days, induced an increase in heart rate, mean aortic pressure and total peripheral resistance. Cardiac output was slightly reduced. The cardiac RNA/DNA ratio and the left ventricular weight/body weight ratio were significantly increased by about 40%. Simultaneous intravenous administration of the alpha-receptor blocker prazosin (0.1 mg/kg/h) and of the beta-receptor blocker metoprolol (1 mg/kg/h) reversed the functional changes and attenuated the increase in the RNA/DNA ratio induced by norepinephrine. The left ventricular weight/body weight ratio was within the range of the control values. Selective stimulation of alpha-adrenergic receptors by continuous intravenous infusion of norfenephrine (2 mg/kg/h) for 3 days increased heart rate and total peripheral resistance, while cardiac output was significantly lower. The RNA/DNA and left ventricular weight/body weight ratios were increased. Prazosin attenuated the increase in the RNA/DNA ratio induced by norfenephrine and prevented the development of cardiac hypertrophy. In the isolated perfused working rat heart, norepinephrine (3 x 10(-8) M) increased the expression of the proto-oncogenes c-fos and c-myc after 30 and 60 minutes, respectively. This increase occurred at about the same time as that induced by volume overload (increase of preload from 8 to 16 cm H2O) and pressure overload (increase of afterload from 80 to 100 cm H2O), but was more pronounced. In intact rats, norepinephrine elicited an increase in the mRNA and activity of glucose-6-phosphate dehydrogenase, the first and regulating enzyme of the oxidative pentose phosphate pathway, in a time-dependent manner. It is suggested that this may be part of a long-term homeostatic mechanism to keep the cardiac adenine nucleotide level in the normal range.