ANALOGS OF NICOTINAMIDE 499 



will depend primarily on the exchange activity of the NADases present, 

 and perhaps secondarily on the ability to oxidize the 3-acetylpyridine to 

 nicotinate. 



Some of the effects of 3-acetylpyridine on tissue functions and whole 

 animals were mentioned at the beginning of this section, and some of the 

 more recently studied actions will now be discussed. The LDjq for the in- 

 traperitoneal route is 300-350 mg/kg in mice and 80 mg/kg in rats (Cogge- 

 shall and MacLean, 1958). Hicks (1955) found that the administration of 

 3-acetylpyridine to rats and mice at doses around the LD50 produces ne- 

 crosis of adrenal medulla, of certain neurons in the supraoptic nucleus of 

 the hypothalamus, and of the pyramidal layer of the hippocampus. No 

 effects on the cerebral cortex were observed, contrary to the action of most 

 metabolic inhibitors. These effects are not seen in nicotinate deficiency, 

 but the picture may represent a more accelerated and acute deficiency; 

 it is possible that the regions affected are more dependent on the pyridine 

 nucleotides, but differential penetration might also be a factor. Coggeshall 

 and MacLean (1958) found that single LD50 doses to rats lead to weakness 

 of the extremities, inspiratory rhonchi, urinary incontinence, and other 

 symptoms, but gross pathological examination of the organs showed no- 

 thing remarkably abnormal. Surviving mice show motor incoordination and 

 a slight to complete loss of neurons in the hippocampal areas CA3 and CA4; 

 some damage to other hippocampal areas and the dentate gyrus may occur, 

 but no changes in other brain areas were detected. It was concluded that 

 the hippocampus must be metabolically different from the rest of the brain. 



Rats given 100 mg/kg of 3-acetylpyridine develop ataxia, hyperkinesis, 

 and convulsions and it was found that 5-10% of the total brain pyridine 

 dinucleotides is 3-AcPyr-NAD (Brunnemann et al., 1962). The maximal 

 levels of the abnormal analogs occur at 6-8 hr and various regions of the 

 brain differ in the fraction incorporated, the highest levels being found in 

 the hippocampus (Herken and Neuhoff, 1963; Willing et al., i964). The ad- 

 ministration of 4-acetylpyridine does not lead to incorporation or to toxic 

 symptoms. This Berlin group of workers favors the concept that the cen- 

 tral neurological effects of 3-acetylp>Tidine are due primarily to interference 

 in electron transport as a result of the inhibitions produced by the 3- AcPyr- 

 NAD(P) formed in the brain. 



Hollander and I have studied the effects of the acetylpyridines on the 

 isolated rat atrium and, although the work is not yet complete, the basic 

 actions are clear.* 3-Acetylpyridine at 1 mM increases the contractile ten- 

 sion of the atria 10% and simultaneously the resting and action potential 

 magnitudes are increased 4-5%. The action potential duration and con- 



* We have found that most commercial samples of the acetylpyridines are quite 

 impure and redistillation under reduced pressure is necessary to obtain reliable pre- 

 parations. 



