Bernard B. Davis

Impaired water excretion in myxedema

Abstract The response to acute water ingestion (20 ml/kg body weight) was determined in sixteen patients with myxedema and eighteen control subjects. Comparison of the results in the two groups indicated an abnormality in water excretion in the patients with myxedema. This impaired water diuresis in the patients with myxedema, including those with significant hyponatremia, appeared to be related to decreased volume delivery to the distal diluting segment of the nephron rather than to persistent secretion of antidiuretic hormone. The reevaluation of eleven patients with myxedema after thyroid replacement therapy revealed significant improvement in the response to water ingestion.

Effects of vasopressin and prostaglandin E1 on the adenyl cyclase—cyclic 3′,5′-adenosine monophosphate system of the renal medulla of the rat

Vasopressin increased adenyl cyclase activity in homogenates of both inner and outer renal medulla of the rat. It also increased the concentration of cyclic 3,5-adenosine monophosphate (AMP) in slices of both inner and outer medulla but not in renal cortex. In the inner medulla, a concentration of prostaglandin E(1) (PGE(1)), which was ineffective by itself significantly reduced the stimulation of adenyl cyclase activity and cyclic AMP concentration induced by vasopressin. These results are consistent with the hypothesis that PGE(1) can compete with vasopressin for adenyl cyclase-binding sites. However, the findings in the outer medulla suggest the situation is more complex. Although 10(-8) M PGE(1) had no effect by itself and inhibited the vasopressin-induced elevation of cyclic AMP, larger amounts of PGE(1) increased both adenyl cyclase activity and cyclic AMP levels. The maximum effect on the latter parameter was at least 6 times as great as that of maximum amounts of vasopressin.

Depression of fractional sodium reabsorption by the proximal tubule of the dog without sodium diuresis

The effect of infusions of hyperoncotic solutions on fractional sodium reabsorption by the proximal tubule of the dog was studied by the recollection micropuncture method. Tubule fluid to plasma inulin concentration ratios were measured for identified proximal tubule segments before and after infusion of 25% albumin or dextran solutions. Results were compared with changes in fractional reabsorption during saline diuresis. Plasma volume increased 66% +/- SE 5.8 after infusion of albumin solution and 94% +/- SE 8.2 after infusion of dextran solution. Fractional sodium reabosorption by the proximal tubule was depressed after infusion of both of these hyperoncotic solutions. Nevertheless, changes in sodium excretion after infusion of albumin and dextran were small. In contrast, after infusions of isotonic sodium chloride solution, which increased plasma volume 61% +/- SE 5.8, a decrease in fractional reabsorption of 50.7% +/- SE 7.2 was associated with large changes in sodium excretion.

“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.

Decreased bicarbonate threshold and renal magnesium wasting in a sibship with distal renal tubular acidosis

Abstract Two siblings with impaired distal renal tubular acidification and nephrocalcinosis associated with vasopressin-resistant polyuria are described. They also exhibit decreased renal bicarbonate threshold and defective renal magnesium conservation with a concomitant hypomagnesemia. Evaluation of other family member revealed no such abnormalities. Parathyroid hormone (PTH) has been shown to affect the renal tubular handling of both bicarbonate and magnesium. The role of the hormone in the development of the observed abnormalities of excretion of these substances was evaluated in both siblings. Following initial determinations, which in the older child suggested increased PTH effect, studies were performed on the two siblings to assess levels of PTH secretion both by indirect methods and by direct immunoassay of their sera. The results indicated excessive PTH secretion in the older sibling, but not in the younger. It was concluded that increased PTH secretion was not responsible either for the abnormalities of bicarbonate excretion or for the excessive urinary magnesium losses demonstrated in the two siblings. Further, neither vitamin D resistance nor secondary hyperparathyroidism appears necessary for the development of nephrocalcinosis in such disorders. Finally, responses to therapy indicate that the acidosis in both siblings was corrected, as expected, by alkali administration, but the hypomagnesemia did not correct (due to increased urinary losses) with either oral on parenteral magnesium supplements.

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.

Effects of Catecholamines and their Interaction with Other Hormones on Cyclic 3′,5′-Adenosine Monophosphate of the Kidney

Catecholamines have several physiological effects on the kidney. These include: (a) stimulation of renin synthesis in the cortex: (b) antidiuresis by beta adrenergic agents; and (c) diuresis by alpha adrenergic stimulation. The role of cyclic 3,5-adenosine monophosphate (cyclic AMP) in the renal actions of catecholamines was evaluated by measuring the effects of several adrenergic agents on cyclic AMP concentration in the dog kidney. Beta adrenergic activity increased cyclic AMP concentration in the renal cortex, a finding consistent with the hypothesis that beta-adrenergic stimulation augments renin synthesis by increasing cyclic AMP generation. Beta adrenergic stimulation, like vasopressin, increased cyclic AMP concentration in the renal medulla. This suggests that beta adrenergic stimulation causes antidiuresis by augmenting cyclic AMP generation in the renal medulla. Alpha adrenergic activity inhibited the effect of vasopressin to stimulate cyclic AMP generation. These results support the hypothesis that the diuretic effect of alpha adrenergic stimulation is mediated by inhibition of the effect of vasopressin to increase cyclic AMP generation.

The Mechanism of the Increase in Sodium Excretion Following Dopamine Infusion

Summary The renal mechanism for the increased sodium excretion due to dopamine infusion was investigated. Infusion of 10 μg/kg/min of dopamine into the dog caused a mean increase in sodium excretion of 43 μeq/min. There was no change in glomerular filtration rate. Proximal tubule sodium reabsorption, as measured by tubule fluid to plasma inulin ratios and the transit time of lissamine green through the proximal tubule, was likewise unchanged. It is concluded that dopamine increases sodium excretion by a direct or indirect tubule effect at a site distal to the proximal tubule.

Pathogenic Role of Cyclic AMP in the Impairment of Urinary Concentrating Ability in Acute Hypercalcemia

A possible association between the impairment of urinary concentrating ability and an impairment of the vasopressin-dependent cyclic AMP system in hypercalcemia was investigated in rat kidneys both in vivo and in vitro. The increases of urinary osmolality and negative free water clearance and the increase of urinary cyclic AMP excretion by vasopressin injection were significantly less in the hypercalcemic rats than in the control rats. The increase of cyclic AMP concentration by vasopressin in renal medullary tissue was significantly less in the slices obtained from the hypercalcemc rats than in those obtained from the control rats. The activation of adenylate cyclase by vasopressin was significantly less in the group with an increased concentration of calcium in media than the control group, but phosphodiesterase activity was not affected by calcium concentration in the media. These data suggest that the impaired urinary concentrating ability in hypercalcemic kidneys is due at least in part to the direct inhibitory effect of calcium on the vasopressin-dependent cyclic AMP system at the level of adenylate cyclase in renal medulla.

Neurohypophyseal peptides in hypothyroid rats: Plasma levels and kidney response☆

Abstract A degree of impairment of water excretion may be associated with hypothyroidism. The involvement of vasopressin has been suggested, but its role continues to be debated because of lack of studies where vasopressin was directly assayed. In this study, water excretion was assessed and arginine vasopressin was directly measured in unanesthetized and nonstressed normal and thyroidectomized rats at a basal state and after water loading. Following water load, both groups decreased their plasma osmolality. Plasma vasopressin demonstrated an elevated level in hypothyroid rats compared to control (2.04 and 1.04 μU/ml), respectively, at baseline and (1.32 and 0.68 μU/ml), respectively, after water loading. There was a significant and similar correlation between plasma vasopressin and plasma osmolality in both groups. The regression lines for urine osmolality and plasma vasopressin of the two groups were parallel but with a significantly greater vasopressin level for the hypothyroid rats at any given urine osmolality. This suggested that circulating plasma vasopressin was less active in hypothyroid than control rats; a hypothesis that was tested by measuring the responsiveness of renal medullary adenylate cyclase to vasopressin. Both basal and vasopressin stimulated cyclic AMP levels were less in hypothyroid than control rats. Thus, these studies demonstrate that hypothyroidism in the rat was associated with an elevated plasma vasopressin that did not appear to be fully effective in inducing an antidiuresis. Factors other than vasopressin may be more important in the water imbalance of hypothyroidism.