Relation between acute changes in diuresis and renal prostaglandins. I: Induced hypotonic polyuria

We have evaluated the effects of indomethacin (I) and of a rich in linoleic acid phosphatidylcholine (E) on the renal function and on the PGE urinary excretion during steady hypotonic polyuria. 5 normal subjects have been studied in the absence of treatment (TA) and after treatment with I, E, E + I. The renal function has been estimated by clearance (cl.) method during hypotonic polyuria induced by oral water loading and i.v. infusion of 5% dextrose solution. The glomerular filtration rate has been estimated by cl. of endogenous creatinine; moreover have been measured the osmotic clearances (Cosm, CH2O), the sodium and potassium clearances (CNa, CK), the mean arterial pressure (PA) and the urinary prostaglandins of E series (PGE) by RIA method. In I condition is observed: a) a trend to a glomerular filtration rate decrement; b) a significant decline of the urinary flow rate, CH2O, UPGV and a significant increment of the urinary osmolarity; c) a trend to an increment of potassium and a decrement of sodium urinary excretions; d) a significant increase of PA. It is possible that the contrary effects observed during the hypotonic polyuria in E condition depend on the stimulating effects of this material on the PG intrarenal synthesis.     

Synergistic effects of nitric oxide and prostaglandins on renal escape from vasopressin-induced antidiuresis

Recent results from our laboratories indicate that renal escape from AVP-induced antidiuresis is accompanied by marked downregulation of kidney aquaporin-2 (AQP2) and AVP V2 receptors. The present studies evaluated the effect of nitric oxide (NO) and PG synthesis blockade on escape from antidiuresis. dDAVP-infused rats were water loaded (WL) for 5 days. l-NAME, an NO synthesis inhibitor, or diclofenac, a cyclooxygenase inhibitor, was infused subcutaneously beginning 1 day before WL. As early as 2 days after WL, urine volume increased and urine osmolality decreased, indicating the onset of escape. Endogenous NO synthesis, measured as urinary NO2 + NO3 excretion, was significantly increased in the WL group compared with the non-WL controls during all 5 days of WL. l-NAME (20 mg. kg(-1). day(-1)) markedly decreased urine volume on days 4 and 5 of WL, indicating inhibition of the escape phenomenon. Kidney AQP2 protein was significantly increased by this dose of l-NAME as well. A lower dose of l-NAME (10 mg. kg(-1). day(-1)) or diclofenac (2.5 mg. kg(-1). day(-1)) did not significantly affect the escape phenomenon by itself, but the combination of l-NAME and diclofenac showed a marked inhibitory effect on the escape phenomenon, which was also accompanied by a significant increase in kidney AQP2 expression. These results therefore suggest that renal NO and PG both play important roles in escape from AVP-induced antidiuresis by acting synergistically to downregulate kidney AQP2 expression.     

GPC phosphodiesterase and phosphomonoesterase activities of renal cortex and medulla of control, antidiuresis and diuresis rats

Glycerylphosphorylcholine (GPC) concentration was reported to be elevated in renal medulla of experimental animals deprived of water. The activities of GPC phosphodiesterases were similar in homogenates and membrane subfractions of renal cortex prepared from control, diuresis and antidiuresis rats. There were no differences in these preparations' ability to hydrolyze phosphorylcholine. In contrast, there was a nearly 50% reduction of non-specific phosphomonoesterase activity, using p-nitrophenylphosphate as substrate and membrane subfractions prepared from the antidiuresis animals. It is suggested that as a consequence, a pathway for the formation from L-alpha-glycerylphosphate is activated.     

Relation of Na-K-ATPase to acute changes in renal tubular sodium and potassium transport

Renal Na-K-ATPase activity changes adaptively in response to chronic alterations in sodium reabsorption or potassium secretion, but the role of this enzyme in rapid adjustments of renal tubular Na and K transport is not known. To evaluate this question, microsomal Na-K-ATPase specific activity and kinetics were determined in the rat and guinea pig kidney after massive but short-term (3 h) sodium or potassium loading. In other experiments renal sodium handling was evaluated in hydropenic and saline-loaded rats in which enzyme synthesis was prevented by the concurrent administration of actinomycin D or cycloheximide. Saline loading increased net sodium reabsorption in both rats and guinea pigs, but microsomal Na-K-ATPase from the outer medulla (where the reabsorptive increment is greatest) did not change significantly in either species. In vitro [3H]ouabain bidint to guinea pig microsomes and apparent Km for sodium of rat microsomal Na-K-ATPase, both from outer medulla, were also unaltered. Actinomycin D and cycloheximide failed to increase sodium excretion and microsomal Na-K-ATPase remained unchanged. KCL loading resulted in a 10-fold increase in K excretion but again Na-K-ATPase specific activity (in cortex, outer medulla, and papilla), and its apparent Km for potassium were not affected. Taken together these results suggest that rapid adjustments in remal tubular Na or K transport are mediated by mechanisms that do not involve the Na-K-ATPase enzyme system.     

The theory of urine formation in water diuresis with implications for antidiuresis

We investigate a model of the renal medulla in which active NaCl transport is restricted to the thick ascending limb of Henle's loop. The model contains a vas rectum, a loop of Henle, salt, and water. The model generates interstitial osmolality curves consonant with the known functioning of the kidney in water diuresis. Using data from the white rat and the curves generated by the model, one can predict the permeability of the thin limb of Henle's loop to NaCl and the percentage of total renal blood flow entering the inner medulla. In this model interstitial osmolality at the papilla can be about twice plasma osmolality, so that NaCl transport restricted to the outer medulla can contribute significantly to the work required in producing a hypertonic urine. However, the interstitial osmolality monotonically decreases proceeding from the junction of the outer and inner medulla to the papilla, and the maximum interstitial osmolality in the outer medulla is greater than the maximum interstitial osmolality in the inner medulla. Thus we infer that a source of active transport located in the inner medulla is needed to explain the high osmolalities observed in hydropenia. A sketch of an alternative model, a “lineal multiplication mechanism”, for the renal concentrating process is presented in which active transport in the inner medulla is restricted to active salt transport by the collecting duct. The lineal multiplication mechanism makes no use of counter-current multipliers in the inner medulla. The research of this author was supported in part by NIH Grant AM06864-03 and a Career Scientist Award from the Health Research Council of New York City, Contr. No. 1391. The research of this author was supported in part by the Office of Naval Research, U.S. Navy under Contr. N(onr) 595(17). The research of this author was supported in part by Grant NSF GP-2067 from the National Science Foundation and was performed at the University of Maryland.     

Renal prostaglandins in postobstructive diuresis. Comparative study of unilateral and bilateral obstruction in conscious dogs

An experimental model in conscious dogs was developed to investigate the role of prostaglandins (PG) in the obstructed kidney. Renal veins were separately catheterized. Urine flow was shunted to the skin by surgically implanted polyurethane loop ureterostomy so as to allow atraumatic manipulation with maintained continuous flow to the bladder between experiments. One week or more after surgery, renal function parameters as well as renal vein and urinary PGE2 and PGF2 alpha, and renal vein renin were studied during and after unilateral (UUO) and bilateral (BUO) ureteral obstruction. The release of ureteral obstruction produced a constant and marked elevation in urinary PGE2 and PGF2 alpha, two times higher after BUO than after UUO. A close correlation exists between PGE2 and sodium excretion in UUO and BUO. Increasing polyuria was observed only after chronic BUO. In BUO, renal vein renin concentration was augmented after 2 hours but was suppressed after 24 hours of BUO. Renal vein PG concentration was also elevated after chronic UUO and BUO but was in the normal range immediately prior to release of obstruction. The data obtained with the current experimental dog model indicate that the release of ureteral obstruction induces a striking increase in renal PGE2 and PGF2 alpha production which may mediate at least partly the phenomenon of postobstructive diuresis.     

Interactions between parathyroid hormone and prostaglandins on renal cortical cyclic AMP

Effects of parathyroid hormone (PTH) and several prostaglandins (PGs) on cyclic AMP (cAMP) metabolism were studied and compared in isolated renal cortical tubules from male hamsters. Both production and intracellular degradation of cAMP were increased by PTH and each of the PGs tested (PGE2, PGE1, PGI2). Production of cAMP was increased to similar levels by maximal concentrations of PTH and each PG, however, degradation of cAMP was significantly higher in response to PTH than with any of the PGs. This difference in intracellular degradation of cAMP was responsible for the much higher concentrations of cAMP in renal cortical tubules exposed to PGs (PGE1, PGE2, PGI2) than to PTH. Submaximal amounts of each PG produced additive increases in cAMP concentrations in the presence of maximal amounts of PTH. Additivity of the combined responses was lost, however, as the PGs concentrations reached their maxima. The results suggest that renal PGs (PGE2 and PGI2) may modulate the effects of PTH on cAMP concentrations in renal cortical tubules.     

Interactions between parathyroid hormone and prostaglandins on renal cortical cyclic AMP

Effects of parathyroid hormone (PTH) and several prostaglandins (PGs) on cyclic AMP (cAMP) metabolism were studied and compared in isolated renal cortical tubules from male hamsters. Both production and intracellular degradation of cAMP were increased by PTH and each of the PGs tested (PGE₂, PGE₁, PGI₂). Production of cAMP was increased to similar levels by maximal concentrations of PTH and each PG, however, degradation of cAMP was significantly higher in response to PTH than with any of the PGs. This difference in intracellular degradation of cAMP was responsible for the much higher concentrations of cAMP in renal cortical tubules exposed to PGs (PGE₁, PGE₂, PGI₂) than to PTH. Submaximal amounts of each PG produced additive increases in cAMP concentrations in the presence of maximal amounts of PTH. Additivity of the combined responses was lost, however, as the PGs concentrations reached their maximas. The results suggest that renal PGs (PGE₂ and PGI₂) may modulate the effects of PTH on cAMP concentrations in renal cortical tubules.     

Altitude diuresis: endocrine and renal responses to acute hypoxia of acclimatized and non-acclimatized subjects

As a result of our recently published studies we have thought that altitude diuresis resulting from hypoxic stimulation of the arterial chemoreceptors reduces the cardiac volume overload. To test this hypothesis, cardiovascular, endocrine and renal responses to stepwise acute exposure to simulated altitude (6,000 m) were compared in ten acclimatized recumbent mountaineers a mean of 24 days, SD 11, after descending from Himalayan altitudes of at least 4,000 m, with those found in ten non-acclimatized recumbent volunteers. The results showed that natriuresis and diuresis typified the renal responses to altitude exposure of both the acclimatized as well as non-acclimatized subjects, as long as altitude was well tolerated. It was concluded that the renal effects were mediated by atrial natriuretic peptide release and slight suppression of arginine-vasopressin (AVP) secretion, that the increased urine flow at altitude offset the cardiac (volume) overload resulting from hypoxic stimulation of the arterial chemoreceptors, and that enhanced AVP secretion, as found in the non-acclimatized subjects at and above 4,000 m, coincided with subjective and objective distress, i.e. with inadequate altitude adjustment owing to insufficient chemoreflex effects and central hypoxia.     

Relation between Plasma Lignocaine Levels and Induced Haemodynamic Changes

Intravenous lignocaine (1 mg./kg. body weight) was found to produce insignificant haemodynamic changes, and in particular no reduction in myocardial contractility. A rate of 2 mg./minute infused intravenously is suggested for therapeutic purposes.In anaesthetized dogs an infusion of 13·5 mg./minute caused moderate haemodynamic depression and a maximum plasma level of 7 μg./ml. Massive injections of 200 and 400 mg. of lignocaine produced a maximum plasma level of 13·8 and 27·8 μg./ml., respectively, and in the latter failure of myocardial contraction in the presence of a normal E.C.G. ensued (“pump failure”). Lignocaine appears to alter the uptake of calcium by myocardial sarcoplasmic reticulum, and this may explain the negative inotropic effect of large doses.