Nama Beck

“Essential” hypernatremia due to ineffective osmotic and intact volume regulation of vasopressin secretion

A physiological explanation for sustained hyperosmolality was sought in a patient with histiocytosis. During 23 days of observation with only sodium intake regulated at 100 mEq daily, elevation (mean 310 mOsm/kg of water) and fluctuation (range 298-323) of the fasting plasma osmolality were recorded. The presence of endogenous vasopressin was indicated by the patients ability to concentrate the urine to as high as 710 mOsm/kg of water with a creatinine clearance of 84 cc/min, and by dilution of the urine in response to alcohol. The failure of increasing fluid intake to as high as 6.2 liters daily to lower the plasma osmolality indicated that deficient fluid intake was not solely responsible for the elevated plasma osmolality. Hypertonic saline infusion during water diuresis resulted in the excretion of an increased volume of dilute urine. The water diuresis continued despite a rise in plasma osmolality from 287 to 339. An isotonic saline infusion initiated during hydropenia resulted in a water diuresis which continued despite a rise in the plasma osmolality from 303 to 320. Stable water diuresis induced during recumbency by either oral ingestion of water or intravenous infusion of normal saline was terminated by orthostasis and resumed with the return to the recumbent position. Antecedent alcohol ingestion blocked the antidiuresis of orthostasis. The data are interpreted as indicating impairment of the osmoreceptor mechanism as the primary cause of the hyperosmolar syndrome. They also indicate that vasopressin secretion was regulated primarily by changes in effective blood volume. Chlorpropamide was found to be an effective treatment for the syndrome.

Direct inhibitory effect of hypercalcemia on renal actions of parathyroid hormone.

The effects of calcium on the renal actions of parathyroid hormone (PTH) were studied in vivo and in vitro. In parathyroidectomized rats, variable levels of blood calcium concentration were induced by intravenous infusion of calcium. The renal responses to the injected PTH, i.e. phosphate and cyclic AMP excretion, were compared in these animals. After PTH injection, the increases of both phosphate and cyclic AMP excretion were less in the calcium-infused animals than in the control group without calcium infusion. There was an inverse correlation between the renal responses to PTH and plasma calcium concentration of 4.2-13.5 mg/100 ml. But calcium had no effect on phosphate excretion induced by infusion of dibutyryl cyclic AMP. In the in vitro experiments, the increase of cyclic AMP concentration in response to PTH was less in renal cortical slices taken from the calcium-infused animals than in ones from the control group without calcium infusion. Calcium also inhibited the activation of renal cortical adenylate cyclase in response to PTH, but calcium had no effect on phosphodiesterase. The data indicate that calcium directly inhibits renal actions of PTH both in vivo and in vitro. Such inhibitory mechanism is probably at or before the step of PTH-dependent cyclic AMP generation in the kidney.

Standard oral water load to determine the site of action of diuretics in man With data on metolazone, a new diuretic

Two male volunteers were given metolazone, a new diuretic, intravenously during a stable protracted water diuresis. The drug caused a mean decrease in CH2O of 2.8 c.c. per minute, a mean increase in sodium excretion of 419.5 μEq. per minute and no Significant change in urine flow rate or clearance of either inulin or PAH. The data suggested that metolazone affects the diluting segment of the nephron reducing the ability to clear free water. Five volunteers were given a standard water load with and without metolazone 10 mg. orally. The data revealed that total free water cleared in the 4 hours following the administration of water decreased (387.6 C.c. S.E. ± 73.9, P < 0.02), while osmols cleared increased (546.6 C.c., S.E. ± 106.7, P < 0.01) and sodium excretion increased (60.6 mEq., S.E. ± 10.5, P < 0.01). Urine volumes and potassium excretion were unchanged. Similar studies with oral water loads given to 4 volunteers who were also given 50 mg. of hydrochlorothiazide, which acts on the diluting segment of the nephron, produced changes such as those seen with metolazone. The data suggest, therefore, that metolazone, like hydrochlorothiazide, acts on the diluting segment of the nephron and that the standard oral water load is an accurate and convenient means of determining the site of action of diuretics.

Complications of Diuretic Therapy: Severe Alkalosis and Syndrome Resembling Inappropriate Secretion of Antidiuretic Hormone

Abstract Two patients with benign illnesses who developed life-threatening complications from therapy with ethacrynic acid (Case 1) and furosemide (Case 2) are described. Case 1 presented in a semi-comatose state with severe alkalosis (pH 7.70) on a daily dose of 50 to 100 mg. of ethacrynic acid. Case II presented with marked hyponatremia (sodium, 112 mEq./L.) associated with a normal BUN (10 mg.%), a concentrated urine (600 mOsm/Kg. H 2 O) and high urinary sodium concentration (60 mEq./L.). This combination initially suggested the syndrome of inappropriate secretion of antidiuretic hormone. However, the latter diagnosis was excluded by the correction of the hyponatremia with saline infusion and the history of furosemide ingestion. Case 2 had developed recurrent severe hyponatremia during a two year period while on furosemide therapy. Hyponatremia (130 mEq./L.) recurred during a controlled therapeutic trial with furosemide (20 mg. daily) in the hospital. This hyponatremia resulted in part from water retention which appeared to occur in response to the initial acute volume contraction produced by a single dose of the diuretic in this patient. This initial volume contraction was presumably a stimulus for antidiuretic hormone secretion. The possible mechanisms for the development of severe alkalosis and hyponatremia with these agents are discussed. The need for determination of individual responsiveness to these agents and for careful monitoring of serum electrolytes subsequently is emphasized.