2 10 HANDBOOK OF PHYSIOLOGY ■^^ CIRCULATION I 



phorylase a formation by activating phosphorylase b 

 kinase (230). In the liver this results in glucose output 

 via glucose-6-phosphatase, but in cardiac muscle 

 the only result is increased glycolysis (200). A study 

 of the phosphorylases present in dog heart (201) has 

 confirmed the general outlines of the enzymatic inter- 

 conversions outlined above (99). It has also been 

 shown by immunochemical studies that the phos- 

 phorylases in different tissues and species of animal 

 are closely related but not identical. 



Acute anoxia in heart muscle is a potent stimulant 

 to glycogenolysis. Under these conditions the absence 

 of epinephrine does not alter the rate of glycogen 

 breakdown (28). The amount of cardiac work which 

 can be sustained through glycolysis under these con- 

 ditions is relatively small. At resting metabolic rate 

 it may be shown that with an initial glycogen con- 

 centration of 0.6 per cent the energy requirements of 

 the heart can be sustained through glycolysis alone 

 for only 4.2 min. In quiescent heart muscle under 

 conditions of complete anaerobiosis the rate of glyco- 

 genolysis is considerably slower (43). Hypothermia 

 reduces the glycogen content of heart muscle through 

 some obscure mechanism (112) even though total 

 respiration is greatly reduced. 



The fact that glycogen is synthesized and degraded 

 by independent pathways in muscle brings the storage 

 of glycogen under a variety of controls. Significant 

 among these controls are genetic factors which may 

 give rise to enzyme deficiencies and result ultimately 

 in glycogen storage disease. Stetten & Stetten (227) 

 have recently reviewed six types of glycogenoses of 

 which at least two are applicable to the heart. One 

 type of cardiac glycogenosis is due to a deficiency of 

 the debranching enzyme, i.e., amylo-i ,6-glucosidase 

 (47); another more common type (Pompe's disease) 

 has no known explanation, since the enzymes neces- 

 sary for synthesis and degradation of glycogen seem 

 to be present in normal concentration (56). 



PYRUVATE OXIDATION. Pyruvate derived from glycol- 

 ysis or obtained directly from the coronary blood is 

 converted to acetyl-CoA in heart sarcosomes by an 

 enzyme pyruvic dehydrogenase first characterized 

 by Schweet et al. (213) from pig heart and pigeon 

 breast muscle. This enzyme complex of molecular 

 weight 4 X 10^ requires five cofactors: thiamine 

 pyrophosphate, a-lipoic acid, DPN+, coenzyme A, 

 and Mg++ ions, and catalyzes the multistage reaction 

 sequence in figure 13. 



The 2-carbon fragment formed after decarboxyla- 

 tion of pyruvate forms transitory compounds with 



LIP(S). 



(ALD-TPP) 



^TPP. 

 CH3-CO-COOH Mg** 



DPNH 



DPN 



CoA-SH 



AC'-SCoA 



FIG. 13. The pyruvic dehydrogenase system. This enzyme 

 system is composed of four enzymes, indicated by letter, which 

 are as follows: (a) pyruvate decarboxylase; (b) hydroxy- 

 ethylthiaminepyrophosphate-lipoic acid transacetyl reductase, 



(c) dihydroacetyllipoic acid-coenzyme .\ transacctylase; 



(d) dihydrolipoic acid dehydrogenase. 



three coenzymes of the pyruvic-dehydrogenase com- 

 plex before entry into the Krebs tricarboxylic acid 

 cycle. The first is hydroxyethylthiaminepyrophos- 

 phate (32, 127) or "active acetaldehyde," the second 

 is acetyl-lipoic acid (90), and the third is acetyl- 

 coenzyme A (144) or "active acetate," representing 

 the oxidation states of the 2-carbon fragment during 

 the oxidation of pyruvate to acetate. 



Acetyl-CoA can undergo a variety of fates in 

 metabolism including hydrolysis to acetic acid, con- 

 densation with oxaloacetic acid to initiate the tri- 

 carboxylic acid cycle, or condensation with other 

 molecules of acetyl-CoA or acetyl acceptors to form 

 fatty acids, cholesterol, and other acetyl derivatives. 

 The first and last pathways are very weak in sarco- 

 somes so that in cardiac muscle almost all of the 

 acetyl-CoA formed is converted to citrate by the con- 

 densing enzyme, first crystallized from heart muscle 

 by Ochoa et al. (172). Cardiac muscle is the richest 

 source of this enzyme in the animal body. Acetate 

 can be directly activated to acetyl-coenzyme A by 

 an enzyme in heart muscle (13, 97) which catalyzes 

 the following reaction : 



acetate -|- ATP -|- Co.\-.SH ^ acetyl-Co.A -|- .\M1' -)- PP 1 7) 



This reaction involves the intermediate formation 

 of an acyl-adenylate (17) and has an equilibrium 

 constant close to i.o. In heart muscle the reaction 

 is forced to the right by the presence of large amounts 

 of citrate condensing enzyme and a high level of ATP. 

 The final common pathway for the oxidation of 

 acetyl groups derived from many sources is the Krebs 

 citric acid cycle. This cycle, first advanced by Krebs 

 & Johnson (128), is shown in figure 14. The purpose 



