Michael Shalmi

Alterations of lithium clearance in rats by different modes of lithium administration.

This study examines the effects of acute versus dietary lithium administration on proximal tubular fluid output (Vprox) and sodium clearance in 6 groups of unrestrained, conscious rats. Vprox was estimated on the basis of the renal lithium clearance. The aim was to find the mode of lithium administration which least influences the proximal and distal reabsorption of sodium. The lithium doses used resulted in serum lithium concentrations between 0.2 and 0.3 mmol/l with no difference between the groups. Acute intravenous lithium administration increased lithium clearance by 40% and sodium clearance by 109%. Administration by gastric tube increased lithium clearance by 22% and sodium clearance by 78% in comparison to dietary administration of lithium. Potassium excretion did not change by acute lithium administration. The data presented indicate that prior to measurements of lithium clearance, lithium should be administered in the diet for 2 days, since acute lithium administration, intravenously or by gastric tube, causes great changes in renal tubular reabsorption.

Model explaining the relation between distal nephron Li + reabsorption and urinary Na + excretion in rats

Li+ may be reabsorbed via an amiloride-sensitive mechanism in the collecting ducts of rats administered a low-Na+ diet. This was investigated by measuring the increase in fractional urinary excretion of Li+(FELi) in response to amiloride in conscious rats at two different levels of plasma Li+ concentration and after administration of bendroflumethiazide (BFTZ), angiotensin III (ANG III), and aldosterone (Aldo). The results confirmed that amiloride increased (FELi) in rats on a low-Na+ diet (20 ± 1 to 35 ± 1%, means ± SE), whereas no increase was observed in rats on a normal Na+ diet (37 ± 1 to 38 ± 1%). The lithiuretic effect of amiloride was 1) abolished by preadministration of BFTZ (32 ± 1 to 33 ± 2%) to Na+-deprived rats and 2) increased by ANG III (27 ± 3 to 33 ± 2%) and Aldo (25 ± 2 to 37 ± 2%) in Na+-replete rats. Amiloride-induced changes in FELiwere independent of plasma Li+concentration but inversely related to the fractional excretion of Na+ and the amiloride-sensitive excretion of K+. These results are compatible with the hypothesis that a low tubular Na+ concentration reduces end-tubular Na+ reabsorption and results in hyperpolarization of the apical membrane, thus favoring Li+ uptake into the cells.

Inhibition of tubular lithium reabsorption by amiloride in the conscious sodium-restricted rat

We examined the effects of amiloride administration on the renal lithium clearance (CLi) in three series of conscious, unrestrained rats maintained on either a low (5 mmol/kg) or normal (200 mmol/kg) sodium diet. In series 1, six doses of amiloride (0.5-16 mg/kg) were administered s.c., and the renal electrolyte excretion was assessed over a 3-h clearance period. In series 2, the time profile of changes in renal electrolyte excretion following 4 mg/kg of amiloride s.c. was examined, and in series 3, the effect of amiloride infusion i.v. (1 mg/kg followed by 2 mg/kg per h) on renal function was investigated. In all series CLi was lower in sodium-restricted rats than in controls. Amiloride administered s.c. to sodium-restricted rats did not increase the 3-h CLi to the levels found in control rats. When amiloride was administered s.c. or i.v. and urine collected in 30-minute periods, CLi in rats fed a sodium-deficient diet increased to control levels. We conclude that amiloride-induced losses of sodium and water in CLi studies may lead to an erroneous interpretation of data. However, distal tubular lithium reabsorption may be recognized, if present, by the administration of amiloride i.v. or s.c. during collections of urine in short time intervals.

Effects of Uninephrectomy and High Protein Feeding on Lithium-Induced Chronic Renal Failure in Rats

Rats with lithium-induced nephropathy were subjected to high protein (HP) feeding, uninephrectomy (NX) or a combination of these, in an attempt to induce glomerular hyperfiltration and further progression of renal failure. Newborn female Wistar rats were fed a lithium-containing diet (50 mmol/kg) for 8 weeks and then randomized to normal diet, HP diet (40 vs. 19%), NX or HP+NX for another 8 weeks. Corresponding non-lithium pretreated groups were generated. When comparing all lithium treated versus non-lithium-treated groups, lithium caused a reduction in glomerular filtration rate (GFR) without significant changes in effective renal plasma flow (as determined by a marker secreted into the proximal tubules) or lithium clearance. Consequently, lithium pretreatment caused a fall in filtration fraction and an increase in fractional Li excretion. Lithium also caused proteinuria and systolic hypertension in absence of glomerulosclerosis. HP failed to accentuante progression of renal failure and in fact tended to increase GFR and decrease plasma creatinine levels in lithium pretreated rats. NX caused an additive deterioration in GFR which, however, was ameliorated by HP. NX+HP caused a further rise in blood pressure in Li-pretreated rats. The results indicate that Li-induced nephropathy, even when the GFR is only modestly reduced, is associated with proteinuria and arterial systolic hypertension. In this model of chronic renal failure the decline in GFR is not accompanied by a corresponding fall in effective renal plasma flow, which may be the functional expression of the formation of nonfiltrating atubular glomeruli. The fractional reabsorption of tubular fluid by the proximal tubules is reduced, leaving the distal delivery unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of the renal effects of six sedating agents in rats

This study was designed to compare the renal effects of sedation with alphaxalone-alphadolone, etomidate, propofol, midazolam, fentanyl-fluanisone, and thiopental in rats. The sedative dose was defined as the highest dose that abolished the escape response without affecting the righting reflex. Female Wistar rats were chronically catheterized with a jugular vein catheter, and urine flow rate and renal clearances of inulin (glomerular filtration rate = GFR), sodium, and lithium (used as an index of proximal tubular function) were measured in the conscious, unrestrained state (n = 107 experiments). In a separate series (n = 70 experiments), the effect of sedative doses of each drug on the nociceptive threshold was tested with the tail-flick test. Responses in sedated animals were compared to responses in animals infused with the vehicle. Fentanyl-fluanisone and thiopental had hypoalgesic actions in sedating doses. Propofol, fentanyl-fluanisone, and thiopental reduced GFR by 20-30%. Urine flow rate was significantly decreased by propofol (-24%) and thiopental (-48%). Propofol and fentanyl-fluanisone reduced fractional lithium excretion by 9-13%. Only alphaxalone-alphadolone, etomidate, and midazolam produced sedation without affecting renal function in rats. Because midazolam produced the most consistent degree of sedation, we conclude that midazolam is the least confounding sedative agent for renal function studies in conscious rats.

Tetraethylammonium and p-aminohippurate as clearance markers for renal plasma flow in the rat during saline and glucose infusion.

Renal plasma clearances (C) of 14C-tetraethylammonium (TEA) and p-aminohippurate (PAH) as estimates of arterial renal plasma flow (ARPF) were evaluated in anesthetized rats during control conditions and during intravenous glucose infusion. Venous renal blood flow was measured directly by means of a servo-controlled pump, keeping the renal venous pressure constant. Arteriovenous extraction fractions (E = 1 - P(renal venous)/P(renal arterial)) for PAH averaged 88.3 +/- (SE) 0.8% in control rats and 82.0 +/- 0.9% in glucose-infused rats (p less than 0.001); E(TEA) averaged 92.0 +/- 0.6 and 90.1 +/- 0.6%, respectively (p less than 0.05). Under both experimental conditions, (C/E)PAH did not differ significantly from ARPF, while (C/E)TEA underestimated ARPF; the rate of extraction of TEA exceeded the rate of excretion by 15-20%, probably due to accumulation of TEA in renal tissue. It is concluded that, when corrected for E, C(PAH) is in general a more accurate estimate for ARPF than C(TEA). However, under conditions involving changes in plasma glucose levels C(TEA) may provide a better estimate of the effective renal plasma flow than C(PAH).

Role of the adrenal medulla in control of blood pressure and renal function during frusemide-induced volume depletion.

Objective To examine the role of the adrenal medulla in reflex control of mean arterial pressure (MAP), heart rate and renal function parameters during frusemide-induced volume depletion. Design Frusemide (6 mg/kg per h) was administered intravenously to two groups of chronically instrumented rats with either sham adrenal medullectomy (n = 15) or adrenal medullectomy (n = 11). Results Adrenal medullectomy reduced adrenal adrenaline concentration by 99% and plasma adrenaline concentration by 97%. Plasma corticosterone levels were similar in the two groups, which suggests that adrenal cortical function was not affected by adrenal medullectomy. Although frusemide did not affect arterial pressure in the sham-operated rats, MAP fell by 21 ± 3 mmHg (mean ± SEM) during frusemide diuresis in the rats with adrenal medullectomy. Heart rate was lower in the rats with adrenal medullectomy than in the sham-operated rats throughout the study. There were no major differences in renal haemodynamics or overall renal water and sodium handling between the two groups but, at the time of maximal activation of compensatory sodium reabsorption, fractional sodium excretion in the distal nephron segment was significantly higher in the rats with adrenal medullectomy than in the sham-operated rats. Conclusions Adrenal medullary adrenaline release is essential in the control of MAP during frusemide-induced volume depletion. Circulating adrenaline might contribute, by modifying distal tubular sodium reabsorption, to compensatory sodium reabsorption during frusemide-induced volume depletion. Circulating adrenaline might contribute, by modifying distaal tubular sodium reabsorption, to compensatory sodium reabsorption during frusemide-induced volume depletion.

Atubular glomeruli, renal function and hypertrophic response in rats with chronic lithium nephropathy

Experimental lithium nephropathy was induced by administering lithium orally to newborn rats for 8 weeks; thereafter the rats were randomized into four groups which were studied after 8 weeks of further treatment. One group was left untreated, one group was given a high (40%) protein diet, one group was unilaterally nephrectomized, and one group was unilaterally nephrectomized and received high protein diet after nephrectomy. Comparable control groups (not lithiumtreated) were also studied. Stereological methods were used to estimate the total volume of different parts of the nephron, interstitial fibrosis, and the distribution of the volume of individual glomeruli. The structural integrity between the glomerulus and the proximal tubule was investigated on serial sections. No sclerotic glomeruli were present. The most extensive degree of hypertrophy with almost a doubling of the total volume of proximal and distal tubule cells was seen in the groups that were both nephrectomized and fed a high protein diet. In both controls and lithium-treated animals, high protein and nephrectomy induced enlargement of the glomerular tufts to volumes from 4 to 5 times the normal size. A pronounced heterogeneity of the glomerular population was found in the lithium-treated groups with 36–54% atubular glomeruli with small volumes, and 34–48% enlarged glomeruli connected to qualitatively normal proximal tubules. Only glomeruli connected to proximal tubules had a potential for hypertrophy. In multiple regression analysis the percentage of glomeruli connected to normal proximal tubules was correlated with the reciprocal of plasma creatinine, but the volume of fibrosis also contributed to the decreased renal function.

Furosemide prodrugs: synthesis, enzymatic hydrolysis and solubility of various furosemide esters

Abstract Various esters of furosemide were prepared and assessed as potential prodrugs with the aim of enhancing the peroral absorption characteristics of the parent drug. The esters studied included a neutral alkyl ester, alkyl esters containing an amino group, glycolamide esters and an O -acyloxymethyl ester. The esters showed widely different susceptibilities to undergo enzymatic hydrolysis in human plasma and rat liver homogenate, the propionyloxymethyl ester being the most reactive compound. The amino-containing esters were most soluble in water whereas all the esters were more lipophilic than furosemide as expressed by octanol-pH 7.4 buffer partition coefficients.

Effect of Adrenalectomy on Distal Nephron Lithium Reabsorption Induced by Potassium Depletion

In potassium-depleted rats lithium is reabsorbed by an amiloride-sensitive transport mechanism in the distal nephron segments, and the urinary fractional excretion of lithium (FE[Li]) is reduced by almost 50% compared to that of potassium-replete rats. We have used renal clearance techniques to study the effects of adrenalectomy (Adx) or sham operation on amiloride-sensitive lithium reabsorption in conscious potassium-deprived (K5) and control (K200) rats. In the sham-operated rats, administration of a low potassium diet led to a significant reduction in FE(Li) from 27.0 to 16.6% (p < 0.01), whereas in the Adx rats the reduction in FE(Li) was smaller (from 27.0 to 22.6) and not statistically significant. Urinary sodium excretion was similar (1,100 nmol/min/100 g body weight) in all groups. During subsequent amiloride infusion in order to block the distal nephron reabsorption of lithium, urinary sodium excretion increased nearly twofold in the sham-operated groups whereas no change was evident in the Adx rats. Similarly, amiloride led to an increase in FE(Li) in the sham-K5 group but failed to increase FE(Li) in the Adx-K5 group. The results suggest that amiloride-sensitive lithium transport seen during potassium depletion is influenced by the presence of the adrenal glands, most likely due to their production of aldosterone.