The behavior of adrenocortical transplants in the rat under the influence of ingested sodium and potassium salts
Plachte, Frank Lothar
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An analysis of the factors facilitating or impeding the incorporation and regeneration of adrenal transplants led to the investigation of the possible influence of ingested sodium and potassium salts on adrenal grafts. The important relationship of adrenocortical function to the normal balance of these electrolytes in the organism made this study all the more desirable since as yet no one apparently has studied their possible effect on the incorporation and character of transplanted adrenal tissue. One hundred and eighty-two albino rats of an inbred strain, reared and maintained under uniform conditions, underwent at 90 days of age a complete bilateral adrenalectomy via the dorsolumbar route under ether anesthesia and with aseptic technique. The excised glands were halved and immediately transplanted to dorsal subcutaneous pockets adjacent to blood vessels. The subcutaneous site was chosen for transplantation because of its accessibility and in order to establish a comparison with intramuscular adrenal transplants previously done in this laboratory. The operated animals were distributed in four experimental groups which received the same solid standard laboratory diet. 25 males and 26 females, comprising group I, received tap water and served as control animals. 26 males and 26 females, comprising group II, received 1% NaCl solution in place of drinking water. 14 males and 13 females, comprising group III, received 1$% KCl solution. The experiment with this group was discontinued because of the high mortality among the animals exposed to this toxic concentration of potassium. 27 males and 25 females, comprising group IV, received 0.5% KCl solution. If the animals did not succumb to cortical insufficiency or die of another cause, they were observed for approximately three months following operation. After this period they were either sacrificed or subjected to an exploratory operation with subsequent removal of established transplants. A series of 24 rats with all indications of incorporated grafts underwent this second operation. The operative procedures, the postoperative course of all the animals including their weight changes and fluid intake, and the gross and histological autopsy findings were recorded. Mortality rate in the experimental groups or failure of incorporation of grafts: Group I (H2O): male=25.0%, female=52.0% Group II (1% NaCl): male=12.0%, female=23.1% Group III (1% KCl): male=78.6%, female=61.6% Group IV (0.5% KCl): male=46.2%, female=56.0% The mortality figures for group II show that the administration of NaCl does not bring about an indefinite survival of animals deprived of their cortical tissue. The relatively small number of succumbing animals does not permit a definite statement for or against a specific sex difference in the resistance to cortical insufficiency. However, the longer survival period of females of group I and the fact that eight of the nine rats that reached the stage of chronic insufficiency (group I and II) were females may indicate a more favorable situation for the female sex as to degree and duration of cortical insufficiency. This reasoning is not necessarily contradicted by the observation that the mortality rate of all female groups except for those in group III was higher than that of the corresponding male animals, because one has to take into account the considerable differences in weight and size of the male and female animals at the age of operation. The survival time of rats dying of acute and subacute insufficiency averaged 13.78 days with only slight variations in the different experimental groups. It appears that the failure of the transplant to establish itself leads to death, unless life is prolonged by NaCl, in a period of time similar to that for untreated bilaterally adrenalectomized rats. The group variations do not appear to be sufficiently consistent and significant to warrant any other conclusion. Potassium per se does not seem to shorten the survival period in these animals to any great extent. The values for group IV are actually above the average survival time for all groups. Since the survival periods are little different from those of untreated adrenalectomized rats, it can be concluded that the hormone content of the transplanted tissues is of no significance for the prolongation of life. The postoperative loss of weight in the animals dying of cortical insufficiency averaged 18.2% of the preoperative level. This figure does not differ significantly from that of untreated adrenalectomized rats. No definite sex difference in the loss of weight could be found. No definite correlation between postoperative loss of weight and length of survival or initial preoperative weight level could be made. The NaCl treatment or the existence of accessory cortical tissue brought about a weight gain in some animals but did not prevent the eventual exhaustion of the hormone reserves. The loss of weight in animals dying of chronic insufficiency was usually less than that in the acute cases. Several animals maintained their preoperative weight level and some even made slight gains. The incidence of successful transplants appears to be low when compared with data given by several other investigators. This disparity in the percentage of takes appears to be due to different criteria for a take, to different sites of implantation, and to the author's counting of doubtful cases as negative. The highest number of incorporated transplants was encountered in the KaCl groups. It is suggested that the the life-prolonging influence of sodium promotes survival until adjustments in and around the grafted tissues, such as vascularization and nutrition, which facilitate regeneration can be made. This effect of sodium is not different from the palliative action of this ion in cortical insufficiency. The relatively small number of incorporated transplants in the KCl groups suggests that the toxic potassium, by putting a considerable strain on all functional systems of the organism, interferes with attempts of incorporation and regeneration or kills the animal before cortical restoration is sufficiently extensive to maintain life. The few animals withstanding the intoxication developed excellent takes. It appears that after overcoming the initial obstacles cortical regeneration can proceed irrespective of the ion offered. With the exception of group III, a greater number of male than female animals incorporated transplants. Seventy-three rats of all experimental groups showed a temporary weight loss after operation. No correlation could be found between this loss of weight and the preoperative weight level or the degree of regeneration. A greater number of male animals exhibited this loss of weight than did females. The male rats of groups I, II, and IV that survived with takes averaged a gain in weight of 0.81 Gm a day over approximately three months. The values for the individual groups vary but little. The corresponding value for the females of groups I, II, and IV was 0.38 Gm a day. These figures represent a rate of weight gain which is normal for the strain employed. The average number of regenerated transplants in all experimental groups was 2.4 per animal. The deviation in the individual groups was not significant with the possible exception of the females of group IV. It appears that all animals with successful grafts regenerate on the average the same number of takes, irrespective of the electrolyte offered. This again suggests that the electrolytes administered affect the processes of incorporation only indirectly by improving or aggravating the early period of cortical insufficiency following operation. In the female a slightly greater number of cortical bodies were regenerated than in the male groups. This might perhaps be interpreted as a sex difference in the chances for cortical regeneration. In 14 animals accessory masses of cortical tissue were found together with viable takes. From what is known about the adreno-pituitary relationship and its influence on the existence of accessory bodies it can be said that, were the grafts fully adequate, they would not tolerate the additional accessory cortical tissue. In view of the fact that takes and accessory bodies were encountered together in 14 instances it seems that, in these and perhaps in many other transplanted rats, the functionally subnormal grafts do not engage the entire corticotropin output of the anterior pituitary. Thus, the excess of this stimulant is available for the development of microscopic accessory cortical bodies. It can be concluded that the incorporated transplants did not attain the functional capacity of the normal cortical organ, a fact obscured by the normal growth and behavior of the animals. The electrolyte treatment did not influence this functional impairment to any significant extent. The measurement of the fluid intake of the animals of all experimental groups confirmed data published by other workers on the salt and fluid requirements and appetite of normal and insufficient rats. The histological investigation of the transplanted material revealed a three layer arrangement of cortical cells similar to that of the normal gland. This structure apparently was achieved irrespective of the electrolyte treatment. This finding is in contrast to the statements of several investigators who were unable to observe a normal cellular arrangement in transplanted cortices. It suggests that the regenerative processes follow the same pattern as do the processes in the life cycle of the normal cortical cell. Observations throughout this study suggest that primitive cortical cells, such as are present before the development of accessory bodies, or regressed cortical cells, such as are present in non-viable rests of transplants, may under certain conditions retain a potential regenerative capacity which allows them to develop when stimulated by corticotropin. These cells are called "dormant" and may constitute a cortical reserve system which, if called upon, produce a state of the organism which though not entirely equal to the normal may maintain the life of the animal. Adrenal function and insufficiency, particularly with respect to electrolyte and water balance and renal function; cortical atrophy, hypertrophy, regeneration, and their relationship to the anterior pituitary; and the present status of adrenal transplantation (experimental and therapeutic) were critically reviewed and analysed.
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