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The dynamics of cardiac adenine and uracil nucleotides, following a subcutaneous injection of isoproterenol, was studied on the rat in vivo. The effect of continuous supply of adenosine, uridine, or ribose on the level of ATP and UTP was investigated on control rats and on isoproterenol-treated animals. The precursors were administered by continuous infusion (1 ml.h-1) into the superior caval vein. 1. ATP and UTP levels were decreased within one hour after a single dose of isoproterenol (5 mg.kg-1) (Fig. 1). 2. Then, the level of ATP rose slowly toward the control value. The normal level was not reached within 48 h (Fig. 1). 3. On the contrary, the initial drop in UTP concentration was followed by a rapid restoration. The control value was reached in 3 h, and then the UTP pool was increased to 180% of the normal level, 12 h after isoproterenol application. 4. As previously shown by other authors, the restoration of ATP was accelerated by a continuous supply of adenosine (37 micromoles per hour) or ribose (170 micromoles per hour) (Fig. 2). 5. The infusion of ribose (170 micromoles per hour) or uridine (41 micromoles per hour) completely suppressed the initial decrease in UTP level caused by beta-receptor stimulation. The further enlargement of the UTP pool was greatly enhanced by ribose or uridine (Fig. 3). 6. The infusion of adenosine was also positive on UTP regeneration. On the contrary, uridine had no effect on the ATP pool (Fig. 3). 7. When supplied to non-treated animals, all precursors caused an enhancement of the UTP level. Adenosine and ribose increased the ATP pool (Fig. 2 and 3). These results contribute to the comparison of the efficiency of the various pathways of cardiac nucleotide synthesis. They show that both de novo synthesis and salvage pathways are limited by the amount of precursors. The increase in UTP synthesis caused by ribose is consistent with the theory put forward for purines (ZIMMER et GERLACH, 1974) that phosphoribosyl-pyrophosphate availability limits the efficiency of de novo synthesis of nucleotides; it demonstrates that this concept is also true for de novo synthesis of pyrimidine nucleotides.

Mechanical performance and tissue content of high-energy phosphates were studied in working rat hearts, isolated from normal rats, or from daily subcutaneously injected with isoproterenol for one day or seven days (5 mg/kg b.w.) and atrially perfused. Isoproterenol pretreatment led to a significant decrease in myocardial content of ATP, ADP. After 75-min perfusion, the content of ATP, ADP, AMP and CP was significantly lower in pretreated hearts than in untreated. On the other hand, isoproterenol-treated hearts exhibited higher aortic pressure, oxygen consumption, left ventricular systolic pressure and d (L.V.P.) max/dt and heart work. It is suggested from these findings that isoproterenol pretreatment of rats improve cardiac work and decrease efficiency in ISO.24 h group and improve cardiac work and efficiency in ISO.7 days group.

14C adenine was supplied to isolated Rat heart retrograde perfused. The experiment was continued by aortic or atrial perfusion and the evolution of the specific radioactivity of ATP was estimated. Aortic perfusion did not reduce ATP content and the specific radioactivity decreased, expressing the turnover of adenine nucleotides. On the contrary, working heart perfusion provoked a breakdown of ATP and an increase of ATP specific radioactivity. When myocardial ATP was decreased prior to the perfusion with isoproterenol, the incorporation of 14C adenine was enhanced, a further aortic perfusion induced a greater decrease of ATP specific activity than in controls. Atrial perfusion did not change the concentration and the specific activity of ATP. These data seem to provide experimental evidences for a compartmentalization of myocardial ATP.

5 hrs after a single sub-cutaneous injection of the drug in a dose of 5 mg/kg, the ATP concentration was reduced by 15%, the incorporation of 14C adenine was augmented by 20% and the turnover of ATP was accelerated: the reduction of specific radioactivity attained 16%, 75 mn after the period of marquage, instead of 7% in the control hearts. When the drug was added to the perfusion fluid, there was no supplementary reduction of the ATP concentration and the action on the nucleotide turnover only existed if the ATP level was reduced by a pretreatment: the reduction of specific radioactivity then attained 24% after 75 min. of perfusion.