Klaus Thomsen

Decreases in Renal Functional Reserve and Proximal Tubular Fluid Output in Conscious Oophorectomized Rats: Normalization with Sex Hormone Substitution

Age-dependent glomerulosclerosis with reduced GFR develops earlier among men than among women. Therefore, whether female sex hormones could prevent the age-dependent decrease in GFR was investigated. The kidney function in oophorectomized rats treated with placebo (OOX group), estrogen (OOX+E(2) group), or estrogen plus progesterone (OOX+E(2)+P group) for 5 mo and in sham-operated rats (sham group) was examined. The rats were 13 mo of age at the time of the investigation. They were conscious and chronically instrumented. The results demonstrated that estrogen, alone or in combination with progesterone, was without effect on the baseline GFR and effective renal plasma flow but prevented severe decreases in the renal functional reserve and fractional proximal tubular fluid output (lithium clearance technique, fractional lithium excretion), which were observed in the OOX group. The renal functional reserve (estimated by stimulation with glycine) was -223 +/- 151, 483 +/- 129, 675 +/- 76, and 208 +/- 140 micro l/min in the OOX, OOX+E(2), OOX+E(2)+P, and sham groups, respectively. Fractional lithium excretion was 12.4 +/- 3.1, 26.8 +/- 2.0, 31.8 +/- 2.5, and 23.6 +/- 3.3% in the OOX, OOX+E(2), OOX+E(2)+P, and sham groups, respectively. In conclusion, oophorectomy at the age of 8 mo did not produce a decrease in baseline GFR in female rats within a period of 5 mo. However, oophorectomy led to severe decreases in the renal functional reserve and fractional proximal tubular fluid output. Both effects were prevented with administration of estrogen. Sham-operated rats demonstrated values for renal functional reserve and fractional lithium excretion that were between those observed for the OOX group and the groups treated with sex hormones.

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.

Effects Of Glycine On Glomerular Filtration Rate And Segmental Tubular Handling Of Sodium In Conscious Rats

1.u2002Infusion of the amino acid glycine leads to an increase in effective renal plasma flow (ERPF) and glomerular filtration rate (GFR) by a mechanism that possibly involves stimulation of nitric oxide (NO). Because NO also increases proximal tubular fluid output (Vprox) by inhibition of proximal tubular Na+ reabsorption and modulation of the tubuloglomerular feedback system, we hypothesized that glycine would increase Vprox as measured by lithium clearance (CLi).

Amiloride inhibits proximal tubular reabsorption in conscious euvolemic rats

Based on the results of micropuncture studies, it is generally assumed that amiloride inhibits Na+ (and Li+) reabsorption in the distal nephron, without affecting proximal tubular reabsorption. This is the basis for the use of amiloride to test for distal nephron Li+ reabsorption. We have examined the validity of this assumption by administering amiloride in doses of 0, 0.02, 0.07, 0.2 and 2.0 mg x kg(-1) x h(-1) to conscious, chronically instrumented rats fed a diet with a normal Na+ and K+ content. Na+ and water homeostasis was maintained by servo-controlled replacement in order to avoid any effect of volume depletion on proximal tubular reabsorption. The effects of the two highest doses of amiloride were also examined without Na+ and water replacement. In the servo-controlled rats, the two highest doses of amiloride increased the fractional excretion of both Na+ (FE(Na)) and Li+ (FE(Li)), whereas the two lowest doses affected only FE(Na). In the rats without servo-control, FE(Li) also rose in response to amiloride infusion, but the increase was significantly lower than that observed in the servo-controlled animals. Since distal Li+ reabsorption is absent or negligible in rats fed a diet with a normal Na+ and K+ content, the large increase in FE(Li) following the highest doses of amiloride (15-18% of the filtered load in servo-controlled rats) indicates inhibition of proximal tubular reabsorption. We conclude that amiloride, in doses usually employed to detect distal Li+ reabsorption, inhibits proximal tubular reabsorption in conscious euvolemic rats.

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.

Search for a therapeutic range for serum zuclopenthixol concentrations in schizophrenic patients.

The aim of our study was to find a therapeutic range for the serum concentration of zuclopenthixol (S-Zu) in chronic schizophrenic patients. S-Zu was measured in 17 patients and dosage reduction was suggested by the laboratory if S-Zu exceeded 15 nmol/L. The clinical symptoms and side effects were evaluated blindly using the Brief Psychiatric Rating Scale (BPRS) and the UKU rating scale, respectively. S-Zu and ratings were repeated 6, 12, and 24 weeks after the final dosage adjustments. In 7 of 10 patients with S-Zu >15 nmol/L the dosage was reduced by 20–67%. After dosage reduction the S-Zu was below 15 nmol/L in 10 of the 17 patients. The mean BPRS score and the side effects, evaluated by the UKU scale, were reduced in patients in whom the dosage was reduced. It is suggested that S-Zu in the range 5–15 nmol/L may serve as a preliminary therapeutic range for S-Zu.

Effects of Recovery from Anesthesia and Surgery on Renal Sodium Handling in Conscious Rats

The accumulating evidence that the delivery of fluid from the proximal tubules to the loop of Henle (Vprox) can be measured in conscious rats by the lithium clearance (CLi) technique has renewed interest in developing a method by which also the glomerular filtration rate can be measured in conscious rats in a steady-state condition without influence from anesthesia and surgery. In the present study, Wistar rats of both sexes were put into a restraining cage, catheters were implanted in the jugular vein and the bladder, and renal parameters were determined under various conditions: different types of surgery, absence or presence of infusion with saline or glucose, normal or reversed diurnal rhythm, and examination at various times after surgery. In acutely operated and restrained rats given saline infusion, the proximal tubular fluid output (CLi) as well as the urinary excretion of sodium (UNaV) increased markedly during the first hours after anesthesia and surgery. After 5 h, both variables were significantly higher than in unoperated, unrestrained rats (CLi 364 +/- 40 vs. 151 +/- 38 microliters/min/100 g; UNaV 1,243 +/- 433 vs. 219 +/- 88 nmol/min/100 g; means +/- SD). Reversal of the diurnal rhythm did not change this pattern. Rats infused with 150 mM glucose instead of saline showed similar increases in CLi and UNaV, although the absolute levels were lower than in saline-infused rats. Rats given no infusion at all had subnormal values of CLi and UNaV. Rats operated 1-3 days before experiments and infused with saline showed enhanced although more stable values of CLi and UNaV.(ABSTRACT TRUNCATED AT 250 WORDS)

Interindividual variation in serum zuclopenthixol and perphenazine concentrations in orally treated patients

The interindividual variation of the serum concentrations of orally administered zuclopen thixol perphenazine was investigated to evaluate the possible advantages of therapeutic drug monitoring in the initial treatment of acute psychosis. In 94 patients given 20 mg of zuclopenthixol daily under routine conditions, the mean serum concentration was 24.2 nmol/1 (range, 0–80 nmol/1), and the coefficient of variation (CV) was 52%. In 10% of the patients the values were below 10 nmol/1, whereas 26% had values above 30 nmol/1. In 154 patients treated orally with 16 mg perphenazine daily, the mean serum concentration was 2.0 nmol/1 (range, 0–20 nmol/1), and the CV 150%. It is recommended that the serum concentrations be determined during steady state 1 week after start of the treatment, to disclose insufficiently low or unnecessarily high serum concentrations.

Mechanisms of distal-nephron Li+ reabsorption during dietary K+ restriction in rats.

The mechanism by which dietary K⁺ restriction induces distal–nephron Li⁺ reabsorption was investigated by administration of bendroflumethiazide (BFTZ) or vehicle in conscious Wistar rats. Changes in fractional excretion of Li⁺ following administration of amiloride (ΔFE_Li) were used as an index of distal tubular Li⁺ reabsorption. The results revealed an absence of distal tubular Li⁺ reabsorption in K⁺–replete rats (ΔFE_Li = 3.6±2.4%), in contrast to K⁺ restriction in which ΔFE_Li was 24.0±2.7%. The distal tubular Li⁺ reabsorption in K⁺–depleted rats was significantly reduced by preadministration of BFTZ (ΔFE_Li = 9.2±0.9%). The fractions of Li⁺ and Na⁺ reabsorbed in the amiloride–sensitive segment were different in K⁺–replete rats (9±6 vs. 60±6%), but similar in K⁺–depleted rats (61±5 vs. 73±4%). BFTZ administration to K⁺–depleted rats resulted in a proportional decrease in these fractions, suggesting competition between Na⁺ and Li⁺ for reabsorption in the distal–nephron segment during K⁺ depletion. These results are compatible with the hypothesis that during K⁺ depletion the reabsorption of Li⁺in the distal–nephron segment is competitively inhibited by Na⁺.

Renal responses to acute volume expansion in spontaneously hypertensive rats is related to the baseline sodium excretion

Abstract Essential hypertension is associated with an exaggerated natriuresis in response to intravenous infusion of isotonic saline. We examined proximal tubular fluid output and segmental tubular handling of sodium in conscious spontaneously hypertensive rats (SHR), their normotensive counterparts Wistar-Kyoto rats (WKY), and ordinary Wistar rats using servo-controlled sodium and fluid balance and Li clearance technique. Sodium (Na) excretion rose to 2.72 ± 0.75 (by a factor of 8) and 1.73 ± 0.68 μmol/min (by a factor of 6.3) (p < 0.05) in SHR and WKY, respectively, thus confirming the presence of exaggerated natriuresis in SHR. FELi rose to 34 ± 4 and 29 ± 2 (p < 0.05) and CNa/CLi rose to 3.0 ± 0.8 and 2.0 ± 0.6 (p < 0.05) in SHR and WKY, respectively, demonstrating that Na reabsorption in both the proximal and the distal nephron was involved. Additional experiments showed that giving the rats saline instead of water to drink for four days prior to the clearance measurement led to a remarkable increase in the natriuretic response to volume expansion. There was a close correlation between the peak increase in FENa and the logarithmic values of the baseline FENa values. In conclusion, the study confirms the presence of an exaggerated natriuresis in response to volume expansion in conscious SHR rats compared to WKY rats, and that the renal response to acute volume expansion is related to the baseline sodium excretion.