Dose–Effect Relationship in Desoxycorticosterone Hypertension : Reduced Sensitivity in Adrenalectomized Rats and Its Possible Significance to the Etiology of Adrenal-Regeneration Hypertension

Abstract

Experiments were conducted to determine the smallest dose of DOCA which would cause saline polydipsia and induce hypertensive disease in unilaterally nephrectomized rats. This was found to be about 25 μg/day with the dosages used. This dose, and one five times as great, were then used to compare the sensitivity of adrenalectomized rats with that of animals having intact adrenals. Completely adrenalectomized animals were less responsive to the blood pressure effect at either dosage, whereas animals with regenerating or accessory adrenal glands were even more so. Adrenalectomized animals given either dosage of hormone had a lower serum protein concentration, red cell count, hematocrit, hemoglobin concentration, and red cell volume than did controls, but these parameters were within normal limits in animals found at necropsy to have residual or regenerating adrenal tissue. The hematologic characteristics appear to be useful criteria for distinguishing, during the course of experimentation, completely adrenalectomized rats from those having residual adrenal function. Clearly adrenal insufficiency diminishes the ability of DOCA to induce high blood pressure, and therefore it appears unlikely that adrenal-regeneration hypertension in the rat can be ascribed to heightened sensitivity to mineralocorticoid activity during the state of adrenal insufficiency.

Hypertension with Mineralocorticoid Administration to the Long-Evans Rat

“…In contrast, administration of DOCA at a dose of 125 pg (0.34 pmol)/day in oil to the Sprague-Dawley rat predictably produces hypertension (Hall & Ayachi, 1971). The Long-Evans rat does not exhibit saline polydipsia during mineralocorticoid administration, which is characteristic of other rat strains (Hall & Ayachi, 1971), but does develop hypokalaemia (Hall et al, 1972) and a fall in renal renin concentration (Park,197 1).…”

“…In contrast, administration of DOCA at a dose of 125 pg (0.34 pmol)/day in oil to the Sprague-Dawley rat predictably produces hypertension (Hall & Ayachi, 1971). The Long-Evans rat does not exhibit saline polydipsia during mineralocorticoid administration, which is characteristic of other rat strains (Hall & Ayachi, 1971), but does develop hypokalaemia (Hall et al, 1972) and a fall in renal renin concentration (Park,197 1). A hypothalamic receptor for DOCA, which has been postulated to initiate the saline polydipsia, has been reported to be deficient in the Long-Evans rat, suggesting that this deficiency provides resistance to DOCA hypertension (Lassman & Mulrow, 1974).…”

19-Nor-Deoxycorticosterone: A Potent Mineralcocorticoid Isolated from the Urine of Rats with Regenerating Adrenals*

“…Some investigators (7-9) have found elevated serum concentrations of deoxycorticosterone (DOC; 21-hydroxy-4-pregnene-3,20-dione) and attribute the hypertension to this finding. However, others (4) have contended that DOC excess does not satisfactorily explain ARH, since administration of DOC uniformly produces overt hypokalemia (10) and striking saline polydipsia (11), two features which are not characteristic of ARH (4). Excessive production of other known mineralocorticoids has not been found.…”