300 TRANSACTIONS OP SECTION I. 



test is, however, limited by the fact that the muscles of frogs kept in confine- 

 ment for some time do not respond to guanidin as was shown by Langley. 



The conclusion we draw from our experiments is that the parathyreoids 

 in some way as yet unknown regulate the metabolism of guanidin in the body 

 and that in doing so thiey may play a part in regulating the tone of the skeletal 

 muscles. 



It is by the continued activity of the efferent neurons of the cord that this 

 tone is maintained, and it is upon these that guanidin acts. Possibly, when the 

 amount of guanidin is small, this action is facilitated by the increased excita- 

 bility of the nerve endings, and, when the amount is further increased, the 

 effect of its overaction upon the cord may be masked by the onset of the curare- 

 like action on the terminations. 



This is not the place to discuss the question of the nerve channels by which 

 impulses concerned in the maintenance of tone reach the muscle. 



iv. Detoxication of Guanidin. 



As I have already indicated, guanidin remains active after methylation, 

 but when it, or its methyl compound, is linked to acetic acid, as in creatin, 

 it becomes inert. Burns has also found that linked to glucose it loses much of 

 its toxicity, and the Camis states that solutions of guanidin become inert when 

 rubbed up with muscle. 



I have all along felt that the significance of creatin must be looked for in 

 its guanidin moiety. Creatin itself is inert, although Maxwell ^* has recorded 

 an exciting action in the cortex cerebri. 



In spite of Pekelharing's results I do not think that there is evidence that 

 the creatin content of muscles is associated directly with the maintenance of 

 muscle tone. Certainly when the nerve to a muscle is cut, the tone is at once 

 lost, and yet, until the marked structural changes of advanced degeneration 

 appear, Cathcart, Henderson, and Noel Paton ^^ find that the creatin content 

 does not markedly decrease. 



While freely admitting the validity of much of the evidence that an increase 

 in tone may be accompanied by an increase of the creatin content of the muscles 

 and an increased excretion of creatinin, there seems to me to be no indication of 

 how the increase in creatin modifies the tone. The administration of creatin 

 subcutaneously does not do so. And hence the only possible explanation must 

 be that the increased tone is associated with an increased amount of guanidin 

 in the blood and that the increase in the creatin is secondary to this — the 

 result of an attempt to remove any excess of guanidin. The evidence in favour 

 of this will be presently considered. 



As regards the relationship of creatin to guanidin, two possibilities have to 

 be considered, either (1) that ci-eatin is the source of free guanidin, or 

 (2) that creatin is formed to fix an excess of guanidin and to detoxicate it. It 

 may then be excreted as creatin or creatinin, or the creatin may be used in the 

 resynthesis of such molecules as arginin or histidin. 



1. The view that creatin is a source of methyl- Efuanidin is favoured by the 

 case with which it is oxidised outside the body by HgO to methyl-guanidin. 

 But, on the other hand, there is no evidence that this occurs in the body. Even 

 in large doses creatin is non-toxic and I have found that when injected into 

 parathyreoidectomised animals it does not accelerate the onset of symptoms, 

 while the injection of even very small doses of guanidin does so. If creatin 

 were a source of guanidin it should act in the same way. 



2. The second view that creatin fixes and detoxicates. guanidin is supported 

 by the following evidence : 



1. Miss Henderson ^^ finds that after parathyreoidectomy there is an increase 

 of the creatin content of the muscle and a decrease, not onlv of the free 

 guanidin, but also of the total guanidin along with the increase of free guanidin 

 in the blnnd recorded by Burns and Sharpe. The decrease in the free guanidin 

 corresponds closely with the increase in the creatin guanidin and suggests 

 that a nrocess of linking is occuiTing. But on the other hand the more marked 

 fall which occurs in the total guanidin of muscle in proportion to the total 

 nitrogen seems to show that there is either (1) an increased elimination of 



