Certain synthetic steroids have a greater pathogenic potency than the natural secretory products of the adrenal cortex. Desoxycorticosterone acetate, 2-methyl-9a-chlorocortisol, and other powerful sodium-retaining steroids produce widespread hypertensive disease, represented by cardiac hypertrophy, glomerular and tubular lesions in the kidney and structural changes in the arteries of many viscera, especially if given to rats receiving a high intake of sodium chloride after removal of one kidney (Fig. 1). Some rats develop lesions in the arteries of the mesentery, intestine, and pancreas which bear a superficial resemblance to polyarteritis nodosa. In agreement with Masson, McCormack et al. (1958) we consider that under these conditions this is a species-specific response to hypertension in the rat rather than the experimental equivalent of the human disease. It is now believed that the effect of unilateral nephrectomy is to accelerate the toxic effects of a sodium chloride load (Page el al., 1958) but these steroids will cause hypertension and some pathological changes when given for several weeks to normal rats on a commercial diet without added salt. However, if the intake of sodium chloride is restricted to the smallest amount necessary to meet the nutritional requirements of the animal, the blood pressure is not increased and structural changes do not occur.

Fig. I. Kidney from a rat treated with desoxycorticosterone acetate 5 mg. daily for 40 days. The glomerulus is enlarged, necrotic and bloodless and the adjacent arterioles show hypertensive arteriolonecrosis. Blood pressure 195 mm. Hg. Haematoxylin And Eosinx 290.

Selye (1958) has described the production of myocardial necrosis in experimental animals treated with an excess of other sodium salts (Na2HP04, Na2S04, or Na?C104) and an overdose of a sodium-retaining steroid. Myocardial lesions occur in 100 per cent of such animals stressed by neuromuscular exertion, but there are no reports of stressors causing similar myocardial damage under natural conditions. Wilgram and Ingle (1959) studied the effect of neuromuscular exertion on discarded breeder female rats and found no increase in the incidence and severity of the renal-cardiovascular lesions which seem to occur spontaneously in these aging animals.

Large doses of methylandrostenediol (MAD) cause severe hypertension with cardiovascular-renal damage in the salt-loaded unilaterally nephrectomized rat (Crane et al., 1958). Such animals develop oedema when given a 4 per cent sodium chloride diet by stomach tube, thereby indicating the sodium-retaining effects of this steroid. The histological appearances in the kidney were very similar to those following the administration of desoxycorticosterone acetate. The glomeruli show a deposition of hyaline material or fibrinoid within the tuft in association with hypertensive proliferative sclerosis or fibrinoid necrosis of the afferent arteriole, and many tufts are swollen by the presence of large 'foam' cells, within which lipids and cholesterol can be demonstrated (Fig. 2). Adrenalectomy protects the unilaterally nephrectomized salt-loaded rat against the damaging effects of MAD (Salgado & Selye, 1954) and this could mean that MAD acts through the agency of the adrenal cortex. When, however, adrenalectomized rats are maintained on small constant doses of adrenal cortex extract, the administration of MAD causes hypertension and cardio-renal injury quite as severe as that produced in the presence of the adrenal glands. We conclude, therefore, that the hypertensive effects of this steroid can occur in the absence of the adrenal glands, but that the presence of adrenal cortical hormones is necessary to support or permit the response to MAD (Crane et al., 1958).

Fig. 2. Kidney from an adrenalectomized rat treated with methylandrostenediol 10 mg. and adrenal cortical extract 2 ml. daily for 36 days. There is hypertensive fibrinoid necrosis of a small renal arteriole. Blood pressure 178 mm. Hg. H. & E. x 290.

Injurious effects of other hormones. It was claimed by Wexler and Miller (1958) that small doses of ACTH cause an increase in incidence and severity of the renal-cardiovascular lesions which occur spontaneously in discarded breeder female rats from the Sprague-Dawley farms. Wilgram and Ingle (1959) have given small, moderate, and large doses of ACTH to similar rats with negative results. In other experiments we have found that the administration of very large doses (16 units or more of long-acting ACTH per rat per day) to unilaterally nephroctemized, salt-loaded male rats does result in lesions of the kidney and heart which are rather different from those caused by over-dosage with steroids. These animals become host to disseminated infections which can be partially but not completely suppressed by treatment with antibiotics. The lesions are those of active pyelonephritis with extensive cast formation, suppuration and necrosis; the possibility that the rise in blood pressure in some of the animals overdosed with ACTH may be secondary to renal damage caused by infection cannot be excluded.

Selye (1951) has shown that the administration of hypophyseal growth hormone to unilaterally nephrectomized rats given saline to drink is followed by an increase in the incidence and severity of renal-myocardial lesions. His data show that there is an accompanying rise of more than 100 per cent in the volume of saline which these animals drink. It may well be that this is the primary cause of the pathological changes. We have given growth hormone to unilaterally nephrectomized rats eating a 4 per cent sodium chloride diet and drinking tap water (Crane et al., 1958). The rats given growth hormone showed on the average a 20 per cent increase in the amount of high salt diet eaten ad libitum. The average blood pressure was slightly higher than normal, but the increase in pathological changes was little greater in the group given amounts of growth hormone which accelerated gain in weight and caused polydipsia. Further study of the pathogenic effects of growth hormone will be required to make known the mechanisms whereby it can cause disease.

Stressors

When unilaterally nephrectomized salt-loaded rats are exposed to cold for a period of several weeks, they develop nephrosclerosis and hypertensive vascular disease and some develop cerebral haemorrhages. It has been claimed (Selye, 1956) that this syndrome develops as a consequence of the activation of the adrenal cortex during stress. In our experiments these dramatic changes are associated with a voluntary increase in consumption of the high salt diet-from approximately 15 g. of dry diet per rat per day at room temperature to 30 g. in those animals exposed to cold (Fig. 3). When the intake of the diet is restricted to that normally eaten at room temperature and the cold-exposed animal is allowed to drink sugar water to meet its increased need for heat energy, there is only a small increase in the damage to the renal and cardiovascular systems. When rats having one kidney removed are given by tube amounts of the high salt diet comparable to those freely eaten by cold-exposed rats, the severity of the lesions developing in animals at room temperature is almost as great as that occurring in the cold. Furthermore, when adrenalectomized unilaterally nephrectomized rats are allowed to eat the high sodium chloride diet ad libitum in the cold, while being supported with small doses of adrenal cortex extract, the consequent changes in heart and kidney are comparable to those in rats with their adrenal glands intact.

Fig. 3. Kidney from a rat exposed to cold (3°c.) and given 4 per cent sodium chloride diet. The glomerulus is enlarged, partly necrotic and fills the subcapsular space; the arteriole shows hypertensive fibrinoid necrosis. H. & e.x210.

These results lend strong support to the view that the hypertensive syndrome which develops during exposure to cold is caused by sodium chloride toxicity and is not the result of an increase in adrenal cortical secretion since the administration of small constant doses of adrenal cortical extract permits the development of the syndrome in the adrenalectomized animal. No other naturally occurring stressor has been found to cause nephrosclerosis and hypertensive vascular damage in the intact rat. There is only a small rise in the average blood pressure and some increase in inflammatory changes in kidneys and hearts in groups of unilaterally nephrectomized, salt-loaded rats subjected to a laparotomy, thermal shock or limb ligation shock once each week for 8 weeks (Crane & Ingle, 1958) . Under these circumstances there is no voluntary increase in the consumption of sodium chloride diet. No form of stress has been found to reproduce the 'diseases' caused by corticosteroid overdosage in either the intact or the unilaterally nephrectomized rat on a normal diet.