Effect of metabolic acidosis on renal action of parathyroid hormone.
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Biomedical subjects
Publications and source records attributed to N Beck.
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Lithium inhibits the catecholamine-dependent cyclic adenosine monophosphate (AMP) generation in the kidney but not the hemodynamic effects of beta-adrenergic stimulation. Therefore, the possible role of catecholamine-dependent cyclic AMP in the release of renin was investigated in lithium-treated dogs both in vivo and vitro. Lithium therapy had no measurable effect on the increase in plasma renin activity induced by an injection of isoproterenol (2.6 plus and minus 1.2 (SE) ng/hour in control dogs vs. 3.0 plus and minus 1.2 ng/hour in lithium-treated dogs, P greater than 0.05). However, lithium inhibited the isoproterenol-induced increase in urinary excretion of cyclic AMP in vivo (791 plus and minus 199 pmoles/min in control dogs vs. 123 plus and minus 129 pmoles/min in lithium-treated dogs, P less than 0.05) and the increase in cyclic AMP concentration in renal tissue in vitro (4.50 plus and minus 0.15 pmoles/ng wet tissue in control dogs vs. 0.34 plus and minus 0.26 pmoles/mg in lithium-treated dogs, P less than 0.01). The finding that, in the lithium-treated dogs, isoproternol increased plasma renin activity but not cyclic AMP generation in the kidney suggests that the increase in plasma renin activity observed after an injection of isoproterenol is probably not mediated through the beta-adrenergic stimulus-dependent cyclic AMP system in the kidney.
It has been demonstrated that parathyroid hormone (PTH) inhibits the proximal tubular reabsorption of bicarbonate, and increases the urinary excretion of that ion. There is also a qualitative similarity between the alterations of the proximal tubular reabsorption of phosphate, sodium, and water after PTH administration and after acetazolamide administration. These findings suggest that the renal effect of PTH is possibly mediated through the inhibition of carbonic anhydrase in proximal tubules. Therefore, a possible inhibitory effect of PTH on carbonic anhydrase was evaluated in the homogenate of rat renal cortex by an indicator titration method. Incubation of cortical homogenates with PTH for 10 min at 37degreesC inhibited carbonic anhydrase activity. The inhibitory effect of PTH was ATP-, Mg++-, and K+-dependent and temperature-dependent; inactivation of PTH by heating at 100degreesC abolished the effect of PTH both to activate adenylate cyclase and to inhibit carbonic anhydrase. Calcium 5 mM also partially abolished effects of PTH to activate adenylate cyclase and to inhibit carbonic anhydrase. The inhibitory effect of PTH on carbonic anhydrase was specific to renal cortex. Cyclic AMP, the intracellular messenger substance for PTH, also inhibited carbonic anhydrase in renal cortex. The cyclic AMP-induced inhibition was also Mg++ dependent and temperature dependent, and required preincubation at 37degreesC. But 5'-AMP, a metabolic derivative of cyclic AMP without its biological effect, had no inhibitory effect on carbonic anhydrase. All the above results are consistent with the hypothesis that PTH inhibits proximal tubular reabsorption of bicarbonate and phosphate through the inhibition of carbonic anhydrase, and that inhibitory effect is mediated through the cyclic AMP system.
Patients treated with lithium salt have an inability to concentrate urine, possible due to the inhibition of the antidiuretic effect of vasopressin. Since beta adrenergic stimulation also induces antidiuresis, a possible effect of lithium on the catecholamine-induced antidiuresis was investigated in dog kidneys. The urinary concentrating ability induced by the iv injection of isoproterenol 0.1 mug/kg was markedly inhibited in the lithium-treated animals (plasma lithium 1.13 plus or minus 0.10 mM). The increase of cyclic AMP concentration by 1 muM isoproterenol was also significantly less in the renal medullary slices obtained from the lithium-treated animals than in those obtained from the control animals. These findings suggest that the inability to concentrate urine in the patients treated with lithium salt is probably due to the inhibition of the antidiuretic effect of catecholamine as well as that of vasopressin; and the inhibitory mechanism of lithium on the catecholamine-induced antidiuresis is possibly through the inhibition of the catecholamine-dependent cycle AMP system in renal medulla.
Acidic media have been reported to inhibit the hydro-osmotic effect of vasopressin in toad bladders, probably through inhibition of the cyclic AMP system. However, the mechanism of inhibition of the cyclic AMP system is controversial. Therefore, that inhibitory mechanism was further investigated in rat kidneys. The antidiuretic response to vasopression was significantly inhibited in animals with metabolic acidosis. The inhibition of the antidiuretic response was associated with a smaller than normal increase of urinary excretion of cyclic AMP after the iv injection of vasopressin. In in vitro experiments, both the increase of cyclic AMP concentration in renal medullary slices and the activation of adenylate cyclase in medulla by vasopressin were significantly less in acidic than in control media. These findings suggest that medabolic acidosis inhibits the antidiuretic effect of vasopressin by inhibiting the vasopressin-dependent cyclic AMP system in the kidney. Acidic media also inhibited cyclic AMP-phosphodiesterase. These dual effects of acidosis on adenylate cyclase and cyclic AMP-phosphodiesterase may explain the conflicting findings observed in the experiments on toad bladders.
A vasopressin resistant urinary concentrating defect has been described in patients receiving lithium salt for affective disorders. For the pathogenic mechanism of the concentrating defect it has been postulated that lithium inhibits the vasopressin-dependent cyclic AMP system. However, the results of indirect studies on the lithium effect are equivocal. Therefore, the effect of lithium specifically on the vasopressin-dependent cyclic AMP system was investigated in rat renal medulla. The increase of cyclic AMP concentration by vasopressin was inhibited by lithium. But lithium had no effect on the PTH-dependent cyclic AMP concentration in renal cortical slices. Regardless of magnesium concentrations from 0-10 mM in the incubation media, 10 mM lithium had no moeasurable effect on the vasopressin-dependent adenylate cyclase of rat renal medulla. However, 10 mM lithium augmented the cyclic AMP-phosphodiesterase activity in renal medulla in the high Km system. These results suggest that lithium inhibits the vasopressin-dependent cyclic AMP concentration in renal medulla via the augmentation of its catabolism, rather than via the inhibition of cyclic AMP generation.
The effects of hyperoncotic human serum albumin on the excretion rates of several electrolytes and cyclic-AMP were measured in mongrel dogs and the results were compared with those obtained after the infusion of saline. Hyperoncotic albumin increased the excretion rates of sodium, potassium, bicarbonate, and phosphate. There was a small increase in chloride excretion after albumin, while there was a significant decrease in the rate of excretion of cyclic-AMP. Saline, on the other hand, caused a marked increase in the rate of of excretion of all the measured ions. Like albumin, saline was associated with a decrease in the rate of excretion of cyclic-AMP. The marked increase in bicarbonate and phosphate excretion suggests that the response to albumin which includes decreased isotonic reabsorption in the proximal tubule and increased urinary sodium excretion could result from decreased reabsorption in the proximal tubule accompanied by distal sodium and chloride reabsorption. Saline, on the other hand, caused a greater increase in sodium excretion and, although phosphate and bicarbonate excretion also increased, a much greater effect on the excretion of chloride was observed, suggesting that saline may also decrease sodium and chloride reabsorption in the distal nephron.
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.
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 hypercalcem'c 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.
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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 patient's 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.
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The academic achievement scores of 122 children with epilepsy were examined in relation to demographic and clinical seizure variables. As a group, these children were making less academic progress than expected for their age and IQ level. Academic deficiencies were greatest in arithmetic, followed by spelling, reading, comprehension, and word recognition. Results of the multiple regression analyses indicated a modest combined predictive significance of the demographic and clinical seizure variables for academic performance. In addition, the magnitude of these relationships varied by academic area. Among the individual variables examined the strongest correlates of academic performance were age of the child, age of seizure onset, lifetime total seizure frequency, and presence of multiple seizures (absence and tonic-clonic). These results are discussed in relation to developing an understanding of the factors which underlie academic vulnerability in children with epilepsy.
Two studies were conducted to examine the effects of music on analogued labor pain using volunteer nulliparous subjects who were randomly assigned to treatment groups (n = 10 per group). Assessments of the treatments were made in a 1-hour session involving twenty 80-second exposures to a laboratory pain stimulus patterned to resemble labor contractions. In the first experiment, it was hypothesized that subjects listening to easy-listening music would report lower pain ratings and cardiovascular responses than subjects listening to rock music, self-selected music, or a dissertation (placebo-attention) and subjects in a no-treatment control group. No significant group effects were found; significant time effects were found for heart rate, systolic and diastolic blood pressure. Subjects spontaneously reported using imagery as a pain reduction technique. In the second study a combination of music and imagery was examined by randomly assigning subjects to one of five groups: self-generated imagery with music (SIM), guided imagery with music (GIM), self-generated imagery without music (SI), guided imagery without music (GI), or no-treatment control. Again, no significant group effects were obtained. Significant time effects were obtained for heart rate, systolic and diastolic blood pressure.
One hundred nulliparous college female undergraduates were randomly assigned to a series of 10 treatment groups that comprised a variety of cognitive-behavioral pain-coping strategies designed as part of a labor preparation analogue. The efficacy of these treatments was subsequently assessed during a one-hour session involving twenty 80-sec exposures to a laboratory pain stimulus patterned to resemble labor contractions. Dependent variables included self-reported pain, systolic and diastolic blood pressure, frontalis EMG, and heart rate. One of the cognitive strategies--sensory transformation--was found to have a significant effect on self-reported pain. Analyses conducted on the other five dependent variables failed to show significant treatment effects.