Prevalence of people at risk of developing type 2 diabetes mellitus and the involvement of community pharmacies in a national screening campaign: a pioneer action in Brazil.

BACKGROUND: Brazil is one of top 10 countries with the highest number of people with diabetes mellitus (DM), affecting 16.8 million peoples. It is estimated that 7.7 million people (20-79 years) in the country have not yet been diagnosed, representing an under-diagnosis rate of 46.0%. Herein we aimed to screen people for high blood glucose or risk for developing type 2 DM (T2DM) through community pharmacies in Brazil. METHODS: A cross-sectional study was carried out in November 2018, involving 977 pharmacists from 345 municipalities in Brazil. The study evaluated people between 20 and 79 years old without a previous diagnosis of DM. Glycemia was considered high when its value was ≥ 100 mg/dL fasting and ≥ 140 mg/dL in a casual feeding state. The FINDRISC (Finnish Diabetes Risk Score) was used to estimate the risk for developing T2DM. The prevalence of high blood glucose was estimated and the associated factors were obtained using Poisson's multivariate analysis with robust variance. RESULTS: During the national screening campaign, 17,580 people were tested with the majority of the consultations (78.2%) being carried out in private pharmacies. The population was composed mainly of women (59.5%) and people aged between 20 and 45 years (47.9%). The frequency of participants with high blood glucose was 18.4% (95% CI 17.9-19.0). Considering the FINDRISC, 22.7% of people had a high or very high risk for T2DM. The risk factors associated with high blood glucose were: Body Mass Index > 25 kg/m2, abdominal circumference > 94 cm for men and > 80 cm for women; education level below 15 years of study, no daily intake of vegetables and fruits; previous diagnosis of arterial hypertension; history of high blood glucose and family history of DM. CONCLUSIONS: This is the largest screening study that evaluated the frequency of high blood glucose and its associated factors in a population without a previous diagnosis ever performed in community pharmacies in Brazil. These results may help to improve public health policies and reinforce the role of pharmacists in screening and education actions aimed at this undiagnosed population in a continent-size country such as Brazil.

Selective blockade of oxytocin and vasopressin V(1a) receptors in anaesthetised rats: evidence that activation of oxytocin receptors rather than V(1a) receptors increases sodium excretion.

BACKGROUND: Although it is known that moderate-to-high doses of the neurohypophysial hormones oxytocin and vasopressin are natriuretic, doubts remain over the identity of the receptors responsible. To address this issue, we have used highly selective antagonists of oxytocin and vasopressin receptors in animals with elevated endogenous circulating levels of the 2 hormones. METHODS: Rats were anaesthetised and prepared surgically for clearance studies, thereby raising plasma oxytocin and vasopressin concentrations. Sodium excretion, glomerular filtration rate and lithium clearance (an index of end-proximal fluid delivery) were measured: first during a control period, then after administration of the selective oxytocin receptor antagonist desGly-NH(2),d(CH(2))(5)[D-Trp(2),Thr(4),Dap(5)]OVT, the selective vasopressin V(1a) receptor antagonist d(CH(2))(5)[Tyr(Me)(2),Dab(5)]AVP, or vehicle alone. RESULTS: Absolute and fractional sodium excretion fell in rats given the oxytocin antagonist (by 32 and 27%, respectively, compared with corresponding values in vehicle-infused rats), but not in those given the V(1a) antagonist or vehicle. Antinatriuresis was associated with a small reduction in the ratio of sodium clearance to lithium clearance (an index of the fraction of distally delivered sodium that escapes reabsorption in the distal nephron). CONCLUSIONS: These results corroborate previous studies showing that activation of oxytocin receptors increases sodium excretion and imply that the natriuretic effect of elevated plasma vasopressin concentrations results from stimulation of oxytocin receptors.

Natriuretic effect of caffeine: assessment of segmental sodium reabsorption in humans.

In order to assess the intrarenal mechanisms responsible for the natriuretic action of caffeine, the renal clearances of (51)Cr-EDTA [used as a measure of glomerular filtration rate (GFR)] and lithium (used as an index of end-proximal fluid delivery) were measured in eight healthy males before (control period) and immediately after (experimental period) a 400 mg oral dose of caffeine (given over 90 min) or placebo. In caffeine-treated subjects, the fractional excretion of sodium rose from 1.00+/-0.25% in the control period to 1.47+/-0.18% in the experimental period, while corresponding values on the placebo day were 1.04+/-0.16% and 0.70+/-0.07% respectively. GFR was unchanged following either caffeine or placebo. When compared with the placebo day, caffeine caused increases in lithium clearance (experimental period values: caffeine, 37+/-1 ml/min; placebo, 28+/-2 ml/min; P <0.001), the fractional excretion of lithium (caffeine, 34+/-1%; placebo, 26+/-2%; P <0.001) and the sodium/lithium clearance ratio (used as an index of the fraction of sodium delivered to the distal nephron that escapes reabsorption therein: caffeine, 4.4+/-0.3%; placebo, 2.8+/-0.2%; P <0.001). These results suggest that reduced fractional sodium reabsorption in both the proximal tubule and the distal nephron contributes to the acute natriuretic effect of caffeine. The data also confirm the importance of controlling caffeine intake when investigating renal function using lithium clearance.

Effects of the potassium channel blocker barium on sodium and potassium transport in the rat loop of Henle in vivo.

In vitro evidence suggests that the 'recycling' of K(+) ions through luminal K(+) channels in the thick ascending limb of the loop of Henle (TALH) is essential for the normal operation of the luminal Na(+)-K(+)-2Cl(-) co-transporter. In the present study these channels were investigated in vivo by perfusing superficial loops of Henle in anaesthetised rats with and without the K(+) channel blocker barium. Using a standard perfusate, intraluminal barium (5 mmol l(-1)) reduced sodium reabsorption (J(Na)) from 1887 +/- 50 to 1319 +/- 53 pmol min(-1) (P < 0.001). When the experiment was repeated using a low-Na(+) perfusate, designed to inhibit reabsorption in the pars recta (the initial segment of the loop of Henle), a similar reduction in J(Na) was observed (from 698 +/- 47 to 149 +/- 23 pmol min(-1), P < 0.001), strongly suggesting that the effect of barium is localised to the TALH. The magnitude of the reduction in J(Na) during blockade of K(+) channels confirms the importance of K(+) recycling in facilitating Na(+) reabsorption in the TALH in vivo. However, the reduction in J(Na) was not associated with a fall in the K(+) concentration of the fluid collected at the early distal tubule. When bumetanide, an inhibitor of the Na(+)-K(+)-2Cl(-) co-transporter, was included in the low-Na(+) perfusate, net K(+) secretion was observed. Addition of barium to this perfusate reduced, but did not abolish, the secretion, suggesting that bumetanide-induced K(+) secretion results partly from paracellular transport. Experimental Physiology (2001) 86.4, 469-474.

Localization of diuretic effects along the loop of Henle: an in vivo microperfusion study in rats.

In order to clarify the effects on sodium reabsorption in the loop of Henle of methazolamide (a carbonic anhydrase inhibitor), chlorothiazide and the loop diuretics frusemide and bumetanide, superficial loops were perfused in vivo in anaesthetized rats and the individual diuretics were included in the perfusate. Differentiation between effects in the pars recta and in the thick ascending limb of Henle (TALH) was achieved by comparing responses to the diuretics when using a standard perfusate, designed to mimic native late proximal tubular fluid, and a low-sodium perfusate, designed to block net sodium reabsorption in the pars recta. With the standard perfusate, methazolamide caused decreases in sodium reabsorption (J(Na)) and water reabsorption (J(V)); with the low-sodium perfusate, a modest effect on J(Na) persisted, suggesting that carbonic anhydrase inhibition reduces sodium reabsorption in both the pars recta and the TALH. The effects of chlorothiazide were very similar to those of methazolamide with both the standard and low-sodium perfusates, suggesting that chlorothiazide also inhibits sodium reabsorption in the pars recta and TALH, perhaps through inhibition of carbonic anhydrase. With the standard perfusate, both frusemide and bumetanide produced the expected large decreases in J(Na), but J(V) was also lowered. With the low-sodium perfusate, the inhibitory effects of the loop diuretics, particularly those of frusemide, were substantially reduced, while net potassium secretion was found. These observations indicate that a significant component of the effect of frusemide (and possibly of bumetanide) on overall sodium reabsorption is located in the pars recta, and that loop diuretics induce potassium secretion in the TALH.

Upregulation of H+-ATPase in the distal nephron during potassium depletion: structural and functional evidence.

In the present study, we have investigated the effects of dietary potassium depletion on the activity and distribution of the H+-ATPase in the distal nephron of the Sprague-Dawley rat. H+-ATPase activity was assessed from the change in transepithelial potential difference (Vte) in response to bafilomycin A1 during perfusion of the late distal tubule in vivo, with solutions containing inhibitors of known ion channels. Bafilomycin A1 caused a negative deflection in Vte in control animals, an effect that was significantly enhanced during potassium depletion (P < 0.01). The distribution of H+-ATPase within the population of intercalated cells was assessed using a specific monoclonal antibody (E11). Hypokalemia was associated with a highly significant redistribution of the staining pattern (P < 0. 001), with an increase in the percentage of cells displaying immunoreactivity in the apical membrane. These results indicate that dietary potassium depletion increases electrogenic H+-ATPase activity in the rat distal tubule; this may be associated with increased insertion of pumps into the apical membrane.

Transepithelial electrochemical gradients in the proximal convoluted tubule during potassium depletion in the rat.

1. In order to examine the electrochemical gradient for potassium reabsorption across the S2 segment of the proximal convoluted tubule, transepithelial potential differences and transepithelial potassium concentrations were measured in anaesthetized potassium-replete and potassium-depleted rats. 2. Potassium-depleted rats were markedly hypokalaemic (plasma potassium, 1.4 +/- 0.1 vs. 4.1 +/- 0.1 mmol l-1 in potassium-replete rats) and had a significantly reduced muscle potassium content. In confirmation of previous reports, glomerular filtration rate was slightly reduced, while fractional reabsorption in the proximal convoluted tubule was enhanced. 3. In potassium-replete animals, the transepithelial potential difference (PD) at the late proximal convoluted tubule was +2.1 +/- 0.3 mV (lumen positive) and the tubular fluid to plasma ultrafiltrate concentration ratio for potassium (TFK/UFK) at the same site was 1. 03 +/- 0.01. In potassium-depleted rats, there was a striking reversal of the transepithelial PD (to -4.0 +/- 0.4 mV), while the TFK/UFK was increased to 1.19 +/- 0.03. 4. The data from both potassium-replete and potassium-depleted animals are consistent with accumulating evidence that potassium reabsorption in the proximal convoluted tubule is passive in nature and depends partly on diffusion down an electrochemical gradient.

Contribution of Na+-H+ exchange to sodium reabsorption in the loop of henle: a microperfusion study in rats.

1. The contribution of apical Na+-H+ exchange to sodium reabsorption in the thick ascending limb of the loop of Henle (TALH) in vivo was examined in anaesthetized rats by perfusing loops of Henle of superficial nephrons with solutions containing the Na+-H+ exchange inhibitor, ethyl isopropyl amiloride (EIPA). 2. Using a standard perfusate, no statistically significant effect of EIPA on net sodium reabsorption (JNa) was detected. However, when sodium reabsorption in the pars recta of the proximal tubule was minimized by using a low-sodium perfusate, EIPA reduced JNa from 828 +/- 41 to 726 +/- 37 pmol min-1 (P < 0.05), indicating that apical Na+-H+ exchange can make a small contribution to net sodium reabsorption in the TALH in vivo. This contribution appears to be dependent on the bicarbonate load, since an increase in the latter led to an enhancement of EIPA-sensitive sodium transport. 3. Addition of the Na+-K+-2Cl- cotransport inhibitor, bumetanide, to the low-sodium perfusate reduced baseline JNa to 86 +/- 27 pmol min-1. In this setting, EIPA reduced JNa further, to -24 +/- 18 pmol min-1 (P < 0.05), an effect similar to that seen in the absence of bumetanide. This finding argues against previous suggestions (based on in vitro evidence) that inhibition of the Na+-K+-2Cl- cotransporter leads to an increase in apical Na+-H+ exchange in the TALH.

Renal effects of glibenclamide: a micropuncture study.

The renal effects of glibenclamide were investigated using free flow micropuncture techniques in anesthetized Sprague-Dawley rats. Intravenous infusion of the drug (3 mg/hr) evoked a natriuresis and diuresis; potassium excretion remained unchanged. Fractional reabsorption in the proximal convoluted tubule in glibenclamide-infused rats did not differ significantly from that in control animals, although the late proximal tubular fluid to plasma concentration ratio for potassium was reduced. Fractional sodium delivery to the early distal tubule was elevated, while the fractional deliveries of water and potassium to this nephron site were unaffected. We conclude that glibenclamide impairs sodium reabsorption in one or more of the nephron segments that comprise the loop of Henle. These results are consistent with the hypothesis that the natriuresis resulting from glibenclamide administration is a consequence of blockade of potassium channels in the apical membrane of the thick ascending limb of Henle's loop. The data suggest that glibenclamide may additionally inhibit a small secretory potassium flux in the proximal tubule.

Renal tubular lithium reabsorption in potassium-depleted rats.

1. In order to identify the tubular sites responsible for the reduced fractional excretion of lithium (FELi) during potassium depletion, free-flow micropuncture was performed in anaesthetized rats that had been fed a low potassium (low-K+) diet or a control diet for 5-6 days. FELi in low-K+ rats was 0.09 +/- 0.02, compared with 0.25 +/- 0.01 in control animals. 2. Fractional water reabsorption in proximal convoluted tubules was enhanced in potassium-depleted rats. However, fractional lithium reabsorption was not. Consequently, the tubular fluid-to-plasma lithium concentration ratio at the late proximal convoluted tubule was raised in the low-K+ animals (1.50 +/- 0.03 vs. 1.18 +/- 0.02; P < 0.001). 3. Fractional lithium delivery to the early distal tubule in low-K+ rats (0.31 +/- 0.01) was similar to that in control animals (0.30 +/- 0.02). However, whereas in control rats there was no significant difference between early and late distal tubular deliveries of lithium, late distal fractional lithium delivery in the low-K+ group was reduced markedly (to 0.10 +/- 0.01). 4. Treatment of potassium-depleted rats with amiloride had no effect on lithium reabsorption in the proximal convoluted tubule or loop of Henle. However, fractional lithium delivery to the end of the distal tubule was increased slightly (to 0.15 +/- 0.02; P < 0.05) and FELi was increased substantially (to 0.22 +/- 0.01; P < 0.001). 5. It is concluded that two factors contribute to the reduced FELi seen in potassium-depleted rats: lithium reabsorption in the superficial distal tubules and amiloride-sensitive lithium reabsorption in the collecting ducts. The data also suggest heterogeneity with respect to lithium handling between superficial and deep nephrons during potassium depletion.

Role of volume status in vasopressin-induced natriuresis: studies in Brattleboro rats.

The influence of volume status on the effect of physiological doses of vasopressin on sodium excretion was assessed in anaesthetized Brattleboro rats. Following a 1 h control period, animals were divided into four groups. Group 1 (control) rats were kept in water balance throughout (by adjustment of the rate of i.v. glucose infusion) and received no vasopressin. In group 2 rats, vasopressin (20 microU/min) was infused i.v. for 2 h, then withdrawn during the following 2 h; the vasopressin-induced antidiuresis and subsequent return to water diuresis were matched by appropriate changes in the i.v. infusion, thus maintaining water balance. In this group, vasopressin had no effect on sodium excretion. Group 3 rats received the same dose of vasopressin, but the infusion rate of the glucose solution was not reduced; consequently these rats became water-loaded. In this group, sodium excretion increased significantly during vasopressin infusion, and rapidly returned to baseline values when the vasopressin was discontinued. Group 4 rats were treated in the same way as group 3 animals except that the vasopressin infusion was maintained (but without additional water loading) for a further 2 h; this did not prevent the fall in sodium excretion during the final 2 h of the experiment. We conclude that the natriuretic effect of physiological levels of vasopressin reported elsewhere may be dependent on an accompanying acute volume expansion during infusion of the hormone.

Mechanism of the impaired natriuretic response to frusemide during sodium depletion: a micropuncture study in rats.

1. The nephron sites involved in the blunted natriuretic response to frusemide during sodium depletion were investigated using micropuncture techniques in anaesthetized rats. 2. Glomerular filtration rate was lower, and fractional sodium reabsorption in the proximal convoluted tubule higher, in sodium-depleted than in sodium-replete rats. Consequently, sodium delivery to the loop of Henle was reduced (by approximately 35%) in the sodium-depleted animals. Intravenous frusemide (2.5 mg h-1 kg-1; urinary water and electrolyte losses replaced) had no effect on glomerular filtration rate or proximal tubular sodium reabsorption in either group. 3. The inhibitory effect of intravenous frusemide on fractional sodium reabsorption in the nephron segments constituting the loop of Henle (measured by free-flow micropuncture) was attenuated during sodium depletion. However, when loops of Henle were microperfused at identical rates with artificial late proximal tubular fluid, no difference in the responses of sodium-depleted and sodium-replete rats to intraluminal frusemide (10(-5) mol/l) could be detected. 4. In sodium-replete animals, the increased load of sodium delivered from the loop of Henle during frusemide administration resulted in a lowering of fractional sodium reabsorption in the distal tubule. In contrast, in sodium-depleted rats given frusemide, fractional distal sodium reabsorption tended to increase, so that values in the two groups of frusemide-treated animals were markedly different (0.30 +/- 0.04 versus 0.51 +/- 0.03). 5. It is concluded that the blunted natriuretic response to frusemide during sodium depletion results from at least three factors: a reduced sodium delivery to the loop of Henle; a reduced inhibitory effect of frusemide on fractional sodium reabsorption in the loop of Henle, which may be a consequence of the reduced sodium load; and enhanced fractional reabsorption of sodium in the distal tubule, which partially buffers the diuretic-induced increase in sodium delivery from the loop.

Effect of vasopressin on renal lithium reabsorption: a micropuncture and microperfusion study.

Micropuncture techniques were used to investigate the nephron site(s) responsible for the vasopressin-induced reductions in lithium clearance and fractional lithium excretion (FELi) in anesthetized Brattleboro rats lacking endogenous vasopressin. In rats treated intravenously with the vasopressin analogue 1-desamino-8-D-arginine vasopressin (DDAVP; 40 pg/min), FELi was significantly lower than in untreated animals (0.23 +/- 0.01 vs. 0.28 +/- 0.02, P < 0.05). Free-flow micropuncture showed that fractional lithium delivery (FDLi) to late proximal convolutions was identical in the two groups, whereas at the early distal tubule both FDLi (0.28 +/- 0.02 vs. 0.33 +/- 0.01, P < 0.05) and the tubular fluid-to-plasma lithium concentration ratio (1.18 +/- 0.04 vs. 1.36 +/- 0.06, P < 0.05) were lower in the DDAVP-treated group. No differences between the groups with respect to lithium handling beyond the early distal tubule were observed. In rats subjected to in vivo microperfusion of loops of Henle, intravenous infusion of DDAVP (40 pg/min) increased fractional lithium reabsorption in the loop from 0.56 +/- 0.03 to 0.66 +/- 0.04 (P < 0.05) and from 0.39 +/- 0.02 to 0.45 +/- 0.02 (P < 0.05) at perfusion rates of 10 and 15 nl/min, respectively. We conclude that DDAVP stimulates lithium reabsorption in the loop of Henle and suggest that this results from an increased transepithelial potential difference in the thick ascending limb.

The natriuretic effect of lithium in man: is the proximal tubule involved?

The possible role of the proximal tubule in the natriuresis which follows the administration of small doses of lithium, as used in lithium clearance studies, was investigated in 12 healthy males on a fixed sodium intake. Subjects were given placebo tablets, or 100 mg or 600 mg of lithium carbonate; renal function was assessed 3-6 h later. The 600-mg dose of lithium carbonate caused a 50-60% increase in sodium excretion, whereas the 100-mg dose was without effect. Creatinine clearance, used as an index of glomerular filtration rate, was unaffected by either dose. Three indices of end-proximal fluid delivery were used simultaneously: urine flow rate during suppression of vasopressin secretion (Vmax), phosphate clearance and lithium clearance (the latter only on the days on which lithium was administered). No effect of either dose of lithium on Vmax or phosphate clearance was evident; nor was there a difference between values for lithium clearance following the two doses. We conclude that administration of the standard 600-mg test dose of lithium carbonate does not affect proximal tubular function.

A micropuncture study of the renal response to haemorrhage in rats: assessment of the role of vasopressin.

The acute effects of haemorrhage (15 ml (kg body wt)-1) on renal function at whole-kidney and single-nephron levels were studied in Inactin-anaesthetized rats. In order to assess the role of vasopressin in mediating the haemodynamic effects, responses in untreated Long-Evans rats were compared with those in Brattleboro rats (which lack circulating vasopressin) and in Long-Evans rats treated with a V1 receptor antagonist. In time-control animals, there were no significant changes in mean arterial pressure (MAP), excretion rates, glomerular filtration rate (GFR), superficial-nephron GFR (SNGFR) or fluid reabsorption in the superficial proximal tubules during the course of the experiment. Following haemorrhage, the immediate reduction in MAP was followed in each group by partial recovery for 30 min; thereafter, MAP was stable. In untreated Long-Evans rats, haemorrhage was followed by a 26% reduction in GFR (P < 0.001, measured 60-150 min post-haemorrhage) and a larger reduction (45%, P < 0.001) in SNGFR, so that the SNGFR/GFR ratio fell significantly ((27.9 +/- 1.9) x 10(-6), control period; (20.2 +/- 2.2) x 10(-6) post-haemorrhage, P < 0.01). Slightly greater reductions in GFR and SNGFR were seen in Brattleboro rats and V1 antagonist-treated Long-Evans rats, which corresponded to slightly greater haemorrhage-induced reductions in blood pressure in these groups; the falls in the SNGFR/GFR ratio were similar to that in untreated Long-Evans rats. In all three groups of bled rats, fractional reabsorption by the proximal convoluted tubule increased slightly 30-60 min after haemorrhage, but during the subsequent period (60-150 min) returned to values indistinguishable from those during the control period. The results suggest that the renal haemodynamic changes that follow moderate haemorrhage include a preferential reduction in the GFR of superficial nephrons. Vasopressin appears to play no role in this response. Increases in fractional reabsorption in the proximal tubules are seen only during the immediate post-haemorrhage period.

A micropuncture study of renal tubular lithium reabsorption in sodium-depleted rats.

1. The marked reduction in fractional lithium excretion (FELi) which accompanies chronic sodium depletion was investigated using free-flow micropuncture in anaesthetized rats which had been maintained in a sodium-depleted state for 8-10 days. 2. Compared with previous values in sodium-replete rats, sodium depletion was associated with small reductions in total and superficial nephron glomerular filtration rate and enhanced fractional reabsorption of water, sodium and lithium in the proximal convoluted tubule. 3. In untreated (sodium-depleted) rats, fractional deliveries of lithium (FDLi) to the late proximal convoluted tubule, early distal tubule and late distal tubule were 0.41 +/- 0.02, 0.20 +/- 0.01 and 0.18 +/- 0.02 (means +/- S.E.M.), respectively. Fractional lithium excretion (0.08 +/- 0.01) was significantly lower than late distal FDLi (P < 0.001). 4. Treatment with amiloride did not affect segmental lithium handling up to the late distal tubule. Frusemide had no effect on lithium reabsorption in the proximal convoluted tubule, but early distal FDLi (0.30 +/- 0.01) was raised compared with the untreated group (P < 0.001). Both diuretics eliminated the difference between late distal FDLi and FELi, respective values being 0.17 +/- 0.02 and 0.15 +/- 0.01 (amiloride-treated rats) and 0.31 +/- 0.02 and 0.34 +/- 0.02 (frusemide-treated rats). 5. These data indicate that part of the reduction in FELi in chronic sodium depletion is due to enhanced fractional fluid (and lithium) reabsorption in the proximal convoluted tubule. In addition, however, they provide direct evidence for amiloride-sensitive lithium reabsorption in the collecting ducts.(ABSTRACT TRUNCATED AT 250 WORDS)

A method for filtering respiratory oscillations.

We present a method based on dynamical systems theory which can be used to filter time series in a way which is superior to classical Fourier decomposition. This method is applied to three data-sets, taken from respiratory measurements of two children in quiet and REM sleep. Our purpose is to filter the several different oscillatory mechanisms which operate, in order to provide clearer signals on which further analysis and diagnosis can be based.

Lithium reabsorption in perfused loops of Henle: effects of perfusion rate and bumetanide.

The contribution of the loop segments to lithium reabsorption in sodium-replete, anesthetized Sprague-Dawley rats was examined by perfusing superficial loops of Henle between late proximal convolutions and early distal tubules. Preliminary experiments in which lithium was initially present only inside or outside the perfused loop confirmed substantial permeability of one or more of the loop segments to lithium. In subsequent experiments, in which lithium was infused intravenously and included in the perfusate so that the perfusate-to-plasma lithium concentration ratio was close to that found in late proximal tubules during lithium clearance studies, lithium reabsorption was inversely related to the perfusion rate: values for fractional lithium reabsorption (FRLi) at perfusion rates of 10, 20, and 30 nl/min were 58 +/- 3, 17 +/- 2, and 2 +/- 2%, respectively. Bumetanide (10(-6) M) markedly inhibited FRLi but also reduced water reabsorption, suggesting an effect on the pars recta at this dose; 10(-7) M bumetanide, which was without effect on water reabsorption, had only a small effect on FRLi at a perfusion rate of 10 nl/min but reduced FRLi by approximately 70% at 20 nl/min. We argue that the remarkable flow dependency of lithium reabsorption, together with its bumetanide sensitivity, provides evidence for significant voltage-driven lithium reabsorption in the thick ascending limb of Henle.

Simulation of lithium transport along the thin segments of Henle's loop.

Although the renal clearance of lithium is widely used as an index of sodium and water delivery to the end of the proximal tubule, micropuncture studies of superficial nephrons suggest that lithium may be reabsorbed additionally in the loop of Henle. In order to examine the possibility of lithium transport in the thin loop segments of deep nephrons, we conducted a computer simulation study using a modification of the mathematical model reported previously. The data for the model were obtained from measurements of osmolality and electrolyte concentrations in systemic plasma and renal papillary interstitial fluid of control and furosemide-treated rats. Papillary interstitium/plasma Li+ concentration ratios were 3.23 and 1.48 in the control and the furosemide group, respectively. Assuming that solute concentration in the renal medulla increases as an exponential function, and applying phenomenological coefficients obtained from hamsters, the transport profiles of Li+ along the thin loop segments were calculated to be very similar to those of Na+. In the control group, about 82% of delivered Li+ was reabsorbed along the entire thin loop segments, with all segments contributing equally. This value may represent the highest possible capacity of the thin loop segments. In the furosemide group, Li+ reabsorption in the thin loop was reduced to 31% of delivered Li+. From these analyses, we conclude that an appreciable amount of lithium may be reabsorbed in the thin loop segments of long-looped nephrons by passive mechanisms. Furosemide inhibits Li+ reabsorption by dissipating the osmotic concentration gradient in the renal medulla.(ABSTRACT TRUNCATED AT 250 WORDS)