To examine whether stimulation of c-adrenergic receptors may affect the oxidative pentose phosphate pathway (PPP) in the rat heart, norepinephrine (NE) and the c-adrenergic agonist norfenephrine were used. NE was administered as a continuous intravenous infusion in awake rats for 3 days. It stimulated the activity of cardiac glucose-6-phosphate dehydrogenase (G-6-PD), the first and regulating enzyme of the oxidative PPP, in a dose-dependent manner. With the highest dose (0.2 mg * kg`* hr-'), there was also a time-dependent enhancement. The increase observed after 48 hours was attenuated partially by the (3-receptor blocker metoprolol and the a!-receptor blocker prazosin. It was entirely abolished when both drugs were administered. Carvedilol, a j3-adrenergic blocker and vasodilator with eel-blocking activity (0.5 mg * kg`* hr-1), prevented the NE-induced increase in cardiac G-6-PD activity, in functional parameters (heart rate, left ventricular systolic pressure, and left ventricular dP/dtmax), and in the heart weight/body weight ratio. The ae-adrenergic stimulator norfenephrine increased myocardial G-6-PD activity; prazosin prevented this stimulation. NE and norfenephrine also elevated the available pool of cardiac 5-phosphoribosyl-1-pyrophosphate. G-6-PD activity was enhanced in cardiac myocytes freshly isolated from the left ventricle of rats that had received NE infusion for 3 days (12.3±1.4 units/g protein) compared with control rats (1.5±0.4 units/g protein). The activity of 6-phosphogluconate dehydrogenase, one of the enzymes in the oxidative PPP, was elevated only moderately from 12.7±0.7 to 19.1± 1.4 units/g protein. Combined aand f3-receptor blockade with carvedilol attenuated these effects. Using Northern blot analysis, we showed that G-6-PD mRNA was elevated in a time-dependent manner in hearts of NE-treated rats, reaching a 2.6-fold increase after 3 days. This increase was abolished with carvedilol. The 6-phosphogluconate dehydrogenase mRNA was only slightly and unspecifically enhanced. These results indicate that both crand j3-adrenergic receptors contribute to the stimulation of the oxidative PPP by predominant elevation of G-6-PD mRNA. (Circulation Research 1992;71:451-459) KEY WoRDs * adenine nucleotide metabolism * carvedilol * molecular biology * catecholamines * glucose-6-phosphate dehydrogenase * 6-phosphogluconate dehydrogenase * rat heart function C atecholamines have multiple effects on the function, metabolism, and morphology of the heart. Specifically, stimulation of 83-adrenergic receptors is known to induce a positive chronotropic and inotropic effect, to increase via cAMP glycogenolysis and lipolysis,1 to shift the isomyosin from V3 to the V1 form,2 and to induce cardiac hypertrophy.3 Recently, a new metabolic effect has been found in that f3-adrenergic stimulation increased the activity of cardiac glucose-6-phosphate dehydrogenase (G-6-PD), the first and rate-limiting enzyme of the oxidative pentose phosphate pathway (PPP).4 This pathway is the link between carbohydrate and fatt...

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Pressure and volume overload have effects on the expression of c-fos and c-myc mRNA that are similar to those obtained with noradrenaline stimulation which induced the most pronounced signals. Our time course studies showed that c-fos mRNA always rose before c-myc mRNA. This common sequential induction pattern may have important signal function in the processes that trigger the development of cardiac hypertrophy.

Catecholamines and thyroid hormones have a similar influence on heart function and metabolism, but this may occur in a differential manner and to a different extent. In this study, the effects of norepinephrine (NE) and of triiodothyronine (T3) were studied in regard to the function of the left (LV) and right ventricle (RV) and to the oxidative pentose phosphate pathway (PPP). NE was applied in rats as continuous i.v. infusion (0.2 mg/kg/h) for three days. T3 was given as daily s.c. injections (0.2 mg/kg) for the same period of time. LV and RV function was measured in the closed-chest trapanal-anesthetized animals using special Millar ultraminature catheter pressure transducers. NE induced an increase in heart rate, in mean arterial pressure, and in total peripheral resistance (TPR). The cardiac RNA/DNA and the left ventricular weight/body weight ratios were increased by about 40%. These effects were prevented by simultaneous alpha- and beta-receptor blockade with prazosin and metoprolol, respectively, but not by verapamil which abolished the hemodynamic effects. RVSP was significantly elevated by NE in a dose-dependent manner. The functional effects of T3 on the LV were not as pronounced as those induced by NE. Heart rate and LV dp/dtmax were increased by T3, and this increase was prevented by concomitant beta-receptor blockade with metoprolol. In contrast to NE, T3 induced an increase in cardiac output and a concomitant decrease in TPR. The RNA/DNA ratio was elevated and cardiac hypertrophy had developed after treatment for three days with T3. These changes were not affected by beta-receptor blockade with metoprolol. RVSP was increased by T3 to a lesser extent than with NE. In metabolic terms it turned out that only NE, but not T3 had a stimulating effect on the cardiac PPP. NE increased the mRNA and activity of glucose-6-phosphate dehydrogenase (G-6-PD), the first and regulating enzyme of this pathway. However, there was no effect of T3 on G-6-PD activity nor on 6-phosphogluconate dehydrogenase activity, one of the following enzymes in the pathway within the first 5 days of T3 treatment. These results demonstrate that the functional effects of T3 were not as pronounced as or even different from those of NE, and that T3 lacked a stimulating effect on the cardiac PPP.

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