Role of Histamine in Producing the Eosinophilia of Magnesium Deficiency.

Publisher Website
Google Scholar
Abstract
Results and conclusions The acute phase of the magnesium deficient syndrome is characterized by a dermal hyperemia(6) in rats and dermal mast cells degranulate in this phase(3). The blood eosinophilia which occurs in the acute phase of magnesium deficiency (Table I, Group 8) is highly significant (P = < .01) and may be caused by the endogenous release of mast cell secretory products. However, administration of commercial histamine, (Table I, Groups 1, 2, 3) in a variety of doses, routes and time intervals (some not reported here) failed to duplicate the eosinophilia produced by magnesium deficiency. Administration of 48/80 in gradually increasing doses for 3 days produced a significant (P = < .01) eosinophilia (Table I, Group 11) of comparable magnitude to that produced by dietary magnesium deficiency. One large dose of 48/80 (Table I, Group 10) proved fatal to 50% of the animals. Since 48/80 is supposed to be a fairly specific mast cell degranulating agent (7), one would assume that a mast cell product or products were responsible for the blood eosinophilia. Administration of heparin in combination with histamine also failed to significantly elevate the number of circulating eosinophils (Table I, Groups 4, 5). Curiously, the large dose of heparin administered with histamine (Table I, Group 4) killed 50% of the rats. Massive subcutaneous edema was observed and tail vein blood appeared watery and pale pink. This reaction was less apparent when the smaller dose of heparin was administered. Serotonin administered with histamine was without effect on circulating eosinophils. An antihistamine, pyribenzamine, when administered daily to rats while on the magnesium deficient regimen (Table I, Group 9) prevented the eosinophilia which should have occurred at this time (P = < .01 when compared with Group 8). The above observations suggest that the endogenous release of histamine is probably responsible for the rise in circulating eosinophils during the development of a magnesium deficient state. Magnesium deficiency may also interfere with a histamine-inactivating system thus allowing the accumulation of released histamine. The failure of commercial histamine to produce an eosinophilia suggests that histamine may be rapidly inactivated under normal conditions in the rat. The natural resistance of rats and mice to the effects of histamine is well documented(8) but not understood. It has been suggested that these animals may have a more rapid rate of inactivation of histamine by any one of several proposed mechanisms such as binding by a gamma globulin(9) or acetylation or inactivation by histaminase(10). Histamine produces an eosinophilia in sensitive animals such as the guinea pig(11). The experiments reported here suggested that the magnesium deficient rats and rats receiving 48/80 possessed classical symptoms (including eosinophilia) of acute endogenous excess of histamine. Since parenteral administration of histamine in large doses did not cause these effects, it would seem that magnesium deficiency and possibly also 48/80 interfere with the inactivation of histamine as well as cause the release of histamine from mast cells. The pituitary-adrenal system has been widely studied for its influence in controlling the level of circulating eosinophils(12). Although the magnesium deficient regimen seemed stressful, it has been reported that indicators of adrenal function such as adrenal and thymic weights were not altered(2). Both hydrocortisone and adrenocorticotropic hormone (ACTH) when administered to eosinophilic rats (Table II) during the acute phase of magnesium deficiency resulted in a lowering of circulating eosinophils within a 4-hour test period. This suggests that adrenal function is normal in the magnesium deficient rat. Adrenalin administered to magnesium deficient rats was uniformly lethal in doses higher than 70 γ. At the 70 γ level adrenalin produced only a 21% fall in blood eosinophils in normal rats (Table II) but increased eosinophils by 52% in magnesium deficient rats (P = <.01). Splenomegaly occurs in magnesium deficient rats(2) and the possibility that adrenalin caused splenic contraction thus forcing entrapped eosinophils into the circulation was ruled out by repeating the above experiment in splenectomized rats. Adrenalin caused a 91% increase in circulating eosinophils in magnesium deficient, splenectomized rats but an 18% fall in control splenectomized rats (P = <.01). These experiments suggest that the pituitary glands of magnesium deficient rats were unable to respond to sudden stress with an increased output of ACTH, although some ACTH must have been produced in order to maintain a normal adrenal weight. Although the pituitary may be unable to respond to sudden stress with increased ACTH output in magnesium deficient rats, the main cause of the eosinophilia accompanying magnesium deficiency is probably the endogenous release of histamine possibly combined with the inadequate functioning of the histamine inactivating system. Summary. Magnesium deficiency produced a massive blood eosinophilia which could be prevented by administration of pyribenzamine and duplicated by 48/80 administration. Commercial histamine, heparin or serotonin did not produce an eosinophilia of this magnitude. Pituitary function was subnormal in magnesium deficient rats while adrenal function was unimpaired. It was concluded that the eosinophilia of magnesium deficiency is primarily due to the endogenous release of histamine and possibly also to an interference with the histamine inactivating system.