Norman R. Alpert

LACTATE PRODUCTION AND REMOVAL AND THE REGULATION OF METABOLISM

For the past 40 years, blood levels of lactate or of lactate and pyruvate have been used as an index of the extent of anaerobic stress to which a whole animal has been subjected or to which individual organs of that animal have been subjected. Furthermore, the removal of this lactate or lactate and pyruvate is considered to be closely associated with or causally related to the increased metabolism occurring during the recovery processes. The development of these ideas will be reviewed, along with experiments which suggest the purely accidental nature of correlations which have been reported. Finally, experiments on tissue slices will be reported which implicate regulatory systems other than lactate or lactate and pyruvate. During exercise, oxygen consumption increases. Following the exercise there is a gradual return to control levels. In the initial phases of the work plasma lactate rises. When the work has ceased the lactate disappears a t a rate similar to the decrement in oxygen consumption.’ This general relationship is seen in FIGURE 1. During the period of exercise the muscles go into debt for oxygen despite the substantial increase in metabolism. The debt occurs because the cardiac output is not adequate to supply the oxygen necessary for the energy requirements of the muscle. The energy which would have been made available by the oxygen missed is supplied by anaerobic energy production provided from the breakdown of glucose or glycogen to lactate. Lactate accumulation is the security for the debt and forces the repayment.’ In the recovery process, the excess consumption is used to oxidize part of the lactate, thus providing the energy for the resynthesis of the remaining lactate. In this analysis, the excess consumption of recovery is exactly equal to the oxygen missed during exercise. Hill and Meyerhof deduced that the lactic acid which appeared in the blood was an index of the 02 missed during exercise (i.e., of tissue anoxia) and that the removal of this lactate was directly responsible for the postexercise excess consumption. The idea of an “oxygen debt” for tissues which then required repayment was based on the following experiments. Meyerhof‘ demonstrated that the excess RQ of-recovery in isolated exercised frog muscle was unity; thus only carbohydrate is burned. During stimulation to fatigue glycogen disappears in the same amount that lactic acid appears, while during recovery the removal of lactic acid is associated with the resynthesis of glycogen. Only three-fourths of the lactic acid removed in recovery is

Effects of a phosphonic acid analog of adenosine triphosphate on actomyosin systems

Abstract Adenyl-methylenediphosphonate, a new analog of adenosine triphosphate (ATP), has been studied in actomyosin systems. This analog is structurally identical with ATP except for the replacement of the terminal Pue5f8Oue5f8P linkage by Pue5f8CH 2 ue5f8P. It did not replace ATP in causing contraction of glycerinated muscle or a drop in viscosity in actomyosin solutions, and it was not hydrolyzed by a homogenate of glycerinated muscle. A partial inhibition of myofibrillar adenosinetriphosphatase (ATPase) by the analog was observed in the absence of added MgCl 2 . This inhibition was not relieved by increasing the ATP concentration; however, it was abolished by the addition of MgCl 2 . It was concluded that adenyl-methylenediphosphonate does not interact with the actomyosin sites which react with ATP. It was also concluded that the nature of myofibrillar ATPase is altered by the addition of magnesium ions, and a possible relation between this alteration and the activation of contraction by magnesium ions is suggested.

Nucleotide changes in rat liver slices during incubation.

Abstract Concentrations of reduced and oxidized pyridine nucleotide, ATP, and ADP were measured in rat liver slices before and after a 1-hr. aerobic incubation in a Warburg apparatus. Total reduced pyridine nucleotide and ATP were significantly decreased in the incubated slices. There were no alterations in total oxidized pyridine nucleotide and ADP.

Accumulation of polyglucosides in anaerobic rat liver

Abstract When rat liver slices or homogenates are subjected to anoxia, glycogen disappears. The major portion of the glycogen disappearing during anaerobiosis cannot be accounted for as an increase in glucose or lactate. Ninety per cent of the missing carbohydrate was recovered as a series of oligoglucosides containing from 2–5 glucose residues per molecule. These accumulate with time under anoxia, and appear to be a product of glycogen breakdown. Under anaerobiosis, oligoglucoside accumulation was 65 per cent greater than in the presence of air for both rat liver slices and homogenates.

The preparation and characteristics of a purified muscle adenosinetriphosphatase.

Abstract A cholesterol-free soluble ATPase from muscle particles has been prepared by digitonin treatment followed by (NH 4 ) 2 SO 4 precipitation. This preparation exhibited a high specific activity (350 μmoles P i /5 min./mg. N) and was fairly stable. When the enzyme was incubated with ATP in the presence of magnesium ions, an initial burst of activity was observed comparable to that seen in actomyosin preparations. The ATP to Mg ratio was different from that observed in the Kielley-Meyerhof preparation. In other ways (pH, temperature, and substrate dependence), the enzyme behaved in a manner comparable to that isolated by Kielley and Meyerhof.