4 1. lODOACETATE AND lODOACETAMIDE 



and contractures, what is? Lundsgaard found that phosphagen (mainly 

 creatine phosphate) is only partially broken down during activity in normal 

 muscles (61 mg% to 46 mg%) but that in iodoacetate-treated muscles it 

 is broken down completely (57 mg% to mg%). When the phosphagen 

 reaches a low level, contracture ensues. He postulated that the breakdown 

 of phosphagen is perhaps the source of energy for muscle contraction 

 and that lactate is possibly used to resynthesize phosphagen. It must be 

 realized that at this time the sequence of glycolytic reactions had not yet 

 been established and the intermediates between hexose diphosphate and 

 lactate were unknown. It is interesting that Lundsgaard observed in iodo- 

 acetate-poisoned muscle that the phosphate from phosphagen split during 

 activity does not appear as inorganic phosphate but as hexose phosphates, 

 which markedly increase in the muscles, indirectly indicating a block in the 

 breakdown of hexose phosphates. The incidental observation of Pohl (1888) 

 that muscles in bromoacetate contracture show no increase in acidity could 

 now be explained and the concepts of the role of lactate in muscle con- 

 traction were markedly altered.* 



Numerous investigations, stimulated by these observations, were carried 

 out during the next 3 or 4 years, during which time with the help of the 

 inhibitors fluoride and iodoacetate, perhaps the most important single tools, 

 the glycolytic pathway was worked out and the site of action of iodoacetate 

 localized. The major portion of this work was done in the Institute for 

 Physiology at the Kaiser- Wilhelm Institute in Heidelberg under the direc- 

 tion of Meyerhof, Lohmann, Lipmann, and others. This subsequent devel- 

 opment will now be outlined very briefly. Lundsgaard (1930 b) reasoned 

 that iodoacetate has no inhibiting action on the formation of hexose phos- 

 phates from glycogen or on the breakdown of phosphagen in muscle, and 

 thus must act on the enzymic splitting of glucose {"auf die anoxyhiontische 

 enzymatische Spaltung der Monohexosen eine spezifisch aufhebende Wirkung 

 ausiiht"). In order to study this he turned to glucose fermentation in yeast 

 and found that 0.54-1.1 mikf iodoacetate inhibits the utilization of glu- 

 cose almost completely. No inhibition of invertase, amylase, or catalase by 

 iodoacetate at much higher concentrations was found, so that Lundsgaard 

 concluded that iodoacetate inhibits "zymase" (the name then given to the 

 enzyme complex responsible for the breakdown of glucose). Inhibition of 

 fermentation in cell-free extracts of yeast was well demonstrated by deter- 

 minations of the CO2 production. Another important observation was that 

 iodoacetate requires some time to achieve its maximal inhibition; even 0.4 

 mM inhibits completely after 2 hr incubation. 



* It should be pointed out that Lundsgaard was unaware of the earHer work of 

 Schwartz and Oschmann on muscle contracture when he reported his first studies. 

 These earlier investigations, however, were not concerned with the relationship be- 

 tween lactate and contraction, but only with the development of rigor. 



