SOME EFFECTS ON TISSUES OTHER THAN THE PANCREAS 417 



longed treatment with insulin are normally susceptible to the cytotoxic 

 action of alloxan. We know too little about all these processes to be able 

 to speculate intelligently as to the mechanisms involved. 



SOME EFFECTS ON TISSUES OTHER THAN THE PANCREAS 



The responses of nerve and muscle to alloxan have been studied very 

 little, but it is certain that no obvious changes occur following diabeto- 

 genic doses. Labes and Freisburger (1930) observed convulsions and pa- 

 ralysis in frogs given large doses (300-1250 mg/kg) and felt that the pa- 

 ralysis is central since the muscle are directly excitable. However, an 

 effect on acetylcholine synthesis at the neuromuscular junction is also 

 likely, since Torda and WolflF (1946 b) found a depression of the contrac- 

 tion of the frog gastrocnemius stimulated through its nerve, but no de- 

 pression of the response of the muscle to acetylcholine, and an inhibition 

 of acetylcholine formation by a brain preparation was demonstrated. Labes 

 and Freisburger (1930) noted that the muscles become stiff and one wonders 

 if this is a Lundsgaard effect. Cardiac standstill occurs both in vivo and 

 in vitro, but the doses and concentrations required are high and it seems 

 that the heart is quite resistant to alloxan. We have mentioned that al- 

 loxan often stimulates smooth muscle and that vasoconstriction, with 

 a rise in the blood pressure, is seen, although released epinephrine may be 

 partially responsible (Macqueen, 1952). High concentrations of alloxan 

 may cause vasodilatation, hyperemia, and congestion, with developing 

 edema, and this is a common response to all SH reagents. Intravenous in- 

 jections of alloxan in dogs increase the pulmonary arterial pressure due to 

 an increased resistance in the pulmonary vascular bed (Gruhzit et at., 

 1951). It was postulated that although the pulmonary edema is not caused 

 by the rise in pressure, they may both be the result of capillary damage 

 in the lungs. This has been thoroughly investigated by Aviado and Schmidt 

 (1957), who showed the pulmonary hypertension to be accompanied by 

 a marked vasoconstriction, followed by constriction of the pulmonary 

 veins and lung congestion, this being the cause of the edema. 



Since the early work of Dunn et al. (1943 b) it has been observed that 

 renal changes can occur at doses above the diabetogenic level, the animals 

 dying in a uremic syndrome (Goldner and Gomori, 1943). The renal le- 

 sions were said to be much like those produced by the mercurials, but 

 there seems to be rather marked effects on the glomeruli (Diaz et al., 

 1948; Test et al, 1951; Ramfjord, 1952). Indeed, the primary effect may 

 be glomerular. The nephrotoxicity would probably be much more evident 

 if alloxan were not so unstable. 



Administration of alloxan causes hemolysis, hemoglobinemia, hemoglo- 

 binuria (Kennedy and Lukens, 1944; Gyorgy and Rose, 1949), and a 



