No abstract

Earlier studies suggest that cortisol and related glucocorticoids correct the impaired water diuresis of primary and secondary adrenal insufficiency by a direct effect upon the diluting segment of the nephron (1-4); however, no one has conclusively demonstrated that a sustained positive water balance in the adrenal-insufficient patient completely inhibits the secretion of antidiuretic hormone (ADH). Although osmotic inhibition of the release of ADH may be normal in adrenal insufficiency, the human or animal in this state may have a distorted "volume" stimulus that prevents complete inhibition. Recent studies have demonstrated that contraction or redistribution of both vascular and extracellular volumes can cause the continued secretion of ADH in the water-loaded subject (5, 6). Blood loss, quiet standing, venous congestion of the lower extremities, and positive pressure breathing are all events that may produce this contraction or redistribution.Since the adrenal-insufficient patient is hypotensive. has poor vascular reactivity, and exhibits a redistribution of body fluids (7-9), it seems reasonable to assume that a distorted volume stimulus for release of ADH might contribute to his impaired water diuresis. If this were true, it might be possible to improve the water diuresis by an appropriate expansion of either the extracellular or vascular compartment before or during a water load. This was attempted in the present study.

An impaired diuretic response to water is a characteristic abnormality of patient or animal with adrenal or pituitary insufficiency (1-6). This defect can only be corrected by administration of hydrocortisone-like steroids ( 3 -6 ) , probably by direct effect on kidney rather than by extra-renal mechanisms (4,7,(9)(10)(11)(12) . Hydrocortisone increases glomerular filtration, renal blood flow and enhances tubular reabsorption of sodium in the adrenal and pituitary insufficient subject (7-12). However, our previous studies indicate that marked improvement in water diuresis caused by compound F cannot be explained solely by its effects on renal hemodynamics or solute excretion( 7). It seemed therefore of interest to note the effect of MedroP (6 methyl prednisolone) on impaired diuresis of adrenal and pituitary insufficiency. This potent adrenal cortical analogue does not enhance sodium reabsorption or alter renal hemodynamics in normal subjects (13). Materials and methods.Six experiments were performed in 6 male patients: 4 with anterior pituitary insufficiency (secondary adrenal insufficiency) and 2 with primary adrenal insufficiency. Hydrocortisone replacement therapy was withdrawn from all patients for at least 1 week prior to experiments. Subjects with primary adrenal insufficiency were maintained on 100 pg of 9-alpha fluoro-hydrocortisone daily. Experiments were performed in the morning post-prandially, with subjects recumbent. An initial urine specimen was obtained for osmolality, after which an oral water load of 1000 cc was given; this positive water balance was maintained for duration of experiment by infusion of 2.5% glucose in water at a rate equal to urine flow. Collection periods were 20 to 30 minutes, and urine samples collected by spontaneous voiding or by in-*Supported by grants from the Upjohn Co. and Arie Crown Fund. dwelling catheters. When urine volume was below 2 cc/minute, air "wash outs" were also utilized. Samples of venous blood were obtained at midpoint of each period through an indwelling needle. Control collections were begun about 45 minutes after priming dose of inulin and para amino-hippurate and constant sustaining infusion had been started. After at least 3 control periods of maximally sustained urinary flow had been obtained (approximately 2% hours after initiating the water load), 5-20 mg of MedrolB were administered into infusion tubing for 30 minutes. Urinary collections were continued for additional 3 to 5 hours. Experiments ranged from 5 5 to 8 hours in duration. Analysis of serum and urine for sodium, potassium, chloride, indin, PAH, creatinine, and freezing point depression (osmolality : milliosmols/kg of H20) were made utilizing methods previously reported ( 14,15). Characteristics of water diuresis were evaluated in each case by maximal urinary flow, minimal urinary osmolality and magniltude of free water clearance CHzO. t Since the experiments were too rigorous to permit control water loading studies without drug administration on each subject, urine volumes were measured...