500 5. QUINONES 



There are thus two possible actions, an increase in the sensitivity to acetyl- 

 choline and an interference with its synthesis, so that the final effect would 

 depend on the balance of these two actions, and in addition to any direct 

 actions on the muscle. Certainly at high quinone concentrations, where 

 acetylcholine synthesis must be strongly inhibited, the neuromuscular 

 failure could be attributed to this mechanism, as Torda and Wolff (1946 b) 

 pointed out after examining ;p-benzohydroquinone at 9 mM. Further 

 evidence comes from the studies on the naphthoquinones. Choline acetylase 

 is quite potently inhibited by menadione (see Table 5-2) but cholinesterase 

 is not affected up to 1 mM (Torda and Wolff, 1944 b). Menadione does not 

 alter the response of frog muscle to acetylcholine, and at high concentra- 

 tions (around 2.5 mM) causes contracture. Menadione at 0.01 mM increases 

 the latency and threshold of nerve-muscle preparations, and reduces the 

 muscle action potential magnitude, while later there is a slowing of nerve 

 conduction and a fall in the nerve action potential (Torda and Wolff, 

 1949). When menadione is injected into mice and rats there is also a failure 

 in neuromuscular transmission but little if any effect on the direct stimula- 

 tion of muscle. It was believed that a depression of the synthesis of acetyl- 

 choline is the primary mechanism involved. Zefirov and Poletaev (1959) 

 also postulated that interference with acetylcholine synthesis could explain 

 their results with menadione at 0.57 mM. They observed a progressive 

 neuromuscular block and a decrease in muscle contractility, accompanied 

 by a moderate contracture, the muscle action potential duration becoming 

 prolonged. Nerve action potentials are altered only following tetanization. 

 Van der Kloot (1958) found that menadione-8-sulfonate above 0.1 mM 

 causes a loss of muscle K+ and a gain of Na+, and thought this might be 

 related to an inhibition of choline acetylase, but there is little evidence that 

 this enzyme system is involved in Na+ extrusion, and it is more likely that 

 some inhibition of oxidative processes or an uncoupling action is respon- 

 sible. 



Heart 



The heart in the whole animal seems to be relatively insensitive to the 

 quinones and thus little attention has been given to the actions on isolated 

 cardiac preparations. Schweitzer (1931) found, however, that the isolated 

 frog heart is fairly susceptible to p-benzoquinone, a concentration of 

 0.0009 mM generally causing some effect, although concentrations of 

 0.009 0.09 mM are required to produce consistent and characteristic 

 responses; higher concentrations so damage the heart that the results 

 are difficult to interpret. He found the primary action to be on the pace- 

 maker cells, the rate of the heart being depressed before action on the con- 

 tractility is observed. This action is not mediated through vagal mechan- 

 isms since atropine does not prevent it. The contractility is eventually 

 depressed, but may pass through a stage of mild stimulation, and the con- 



