Effect of lithium on renal transport and utilization of alpha-ketoglutarate in the rat

Experiments were carried out in the intact functioning rat kidney to study the effect of lithium on both the renal transport of alpha-ketoglutarate (alpha-KG) along the nephron by micropuncture techniques and the renal uptake and peritubular transport of alpha-KG by measuring the renal blood flow, the urinary flow and the rate of renal alpha-KG delivery, filtration, reabsorption or secretion and excretion. At endogenous plasma alpha-KG concentration, 2.3 mM plasma lithium caused an increase in the fractional excretion of alpha-KG, whereas 4.6 mM plasma lithium led to a net secretion of alpha-KG. The micropuncture data indicate that this secretion occurred between the late proximal and the distal tubule, i.e., in the pars recta and/or in the loop of Henle. When plasma alpha-KG concentration was elevated, the two doses of lithium used inhibited the reabsorption of alpha-KG both in the proximal tubule and in the pars recta and/or the loop of Henle. Renal arteriovenous measurements reveal that, at low plasma alpha-KG concentrations, lithium caused a significant decrease in both the renal uptake of alpha-KG and the peritubular transport of this organic anion. These results suggest that the alpha-KG secreted in the pars recta and/or the loop of Henle was synthesized within the renal cells of the latter segments and not transported from the blood to the tubular lumen. At higher plasma alpha-KG concentrations, both the peritubular transport and the renal reabsorption were reduced by lithium.     

Effects of organic anion,organic cation,and dipeptide transport inhibitors on cefdinir in the isolated perfused rat kidney

Cefdinir (Omnicef; Abbott Laboratories) is a cephalosporin antibiotic primarily eliminated by the kidney. Nonlinear renal elimination of cefdinir has been previously reported. Cefdinir renal transport mechanisms were studied in the erythrocyte-free isolated perfused rat kidney. Studies were performed with drug-free perfusate and perfusate containing cefdinir alone to establish the baseline physiology and investigate cefdinir renal elimination characteristics. To investigate cefdinir renal transport mechanisms, inhibition studies were conducted by coperfusing cefdinir with inhibitors of the renal organic anion (probenecid), organic cation (tetraethylammonium), or dipeptide (glycylsarcosine) transport system. Cefdinir concentrations in biological samples were determined using reversed-phase high-performance liquid chromatography. Differences between treatments and controls were evaluated using analysis of variance and Dunnett's test. The excretion ratio (ER; the renal clearance corrected for the fraction unbound and glomerular filtration rate) for cefdinir was 5.94, a value indicating net renal tubular secretion. Anionic, cationic, and dipeptide transport inhibitors all significantly affected the cefdinir ER. With probenecid, the ER was reduced to 0.59, clearly demonstrating a significant reabsorptive component to cefdinir renal disposition. This finding was confirmed by glycylsarcosine studies, in which the ER was elevated to 7.95, indicating that reabsorption was mediated, at least in part, by the dipeptide transporter system. The effects of the organic cation tetraethylammonium, in which the ER was elevated to 7.53, were likely secondary in nature. The anionic secretory pathway was found to be the predominant mechanism for cefdinir renal excretion.     

Stereoselective renal tubular secretion of carbenicillin.

The stereoselective disposition of carbenicillin epimers was studied in healthy human volunteers. There was a difference between the two epimers in the extent of plasma protein binding in vitro, with the unbound fraction of the R epimer being greater than that of the S epimer. Renal clearance (CLR) of each epimer was greater than the glomerular filtration rate, suggesting renal tubular secretion of both epimers. Although the CLR was greater for the R epimer, renal tubular secretion was greater for the S epimer. When probenecid was coadministered, the CLR of each epimer was significantly reduced and was approximately equal to the glomerular filtration rate. The difference in CLR between the two epimers was simply due to differences in plasma protein binding. The observations in the present study suggest that both carbenicillin epimers are secreted by an organic anion transport system in the renal proximal tubule in humans and that the two epimers may be distinguished in the secretion process, resulting in the differences in the secretion rates.     

Involvement of rat and human organic anion transporter 3 in the renal tubular secretion of topotecan [(S)-9-dimethylaminomethyl-10-hydroxy-camptothecin hydrochloride

Topotecan [(S)-9-dimethylaminomethyl-10-hydroxy-camptothecin hydrochloride] is primarily excreted into urine in humans, with approximately 49% of the dose recovered as total topotecan (topotecan lactone plus topotecan hydroxyl acid form). The renal elimination of topotecan involves tubular secretion in addition to glomerular filtration, but little is known about the molecular mechanism of the renal tubular secretion. In the present study, we investigated the transport characteristics of topotecan hydroxyl acid across the renal basolateral membrane using rat kidney slices and rat or human transporter-expressing Xenopus laevis oocytes. Pravastatin and probenecid significantly inhibited the uptake of topotecan hydroxyl acid by rat kidney slices with K(i) values of 10.6 and 8.1 microM, respectively, and p-aminohippurate was weakly inhibitory at high concentrations, whereas excess tetraethylammonium had no effect. The uptake of topotecan hydroxyl acid by oocytes injected with complementary RNA of either rat or human organic anion transporter 3 (rOAT3 or hOAT3) was greater than that of water-injected oocytes. Kinetic analysis showed that the K(m) values for rOAT3 and hOAT3 were 21.9 and 56.5 microM, respectively. Neither rOAT1 nor hOAT1 stimulated topotecan hydroxyl acid transport. These results suggest that the urinary excretion of topotecan hydroxyl acid is accounted for by transport via OAT3, as well as glomerular filtration, in both rats and humans; therefore, drug-drug interactions involving OAT3 may cause a change in clearance of topotecan.     

Effects of different doses of chlorpromazine on renal function in the dog.

This study was carried out to examine the effects of low 'alpha-blocking' and higher 'membrane-stabilizing' doses of chlorpromazine (CPZ) on renal function. CPZ was given at slow infusion rate either intravenously or into the left renal artery at three levels (0.5-1.0, 3-8, and 10-15 mg/kg) to 10 anesthetized dogs. An increase in plasma hemoglobin sometimes occurred within few minutes after infusion of more than 10 mg/kg CPZ, probably due to a hemolytic effect of such high doses. Systemic infusion of 0.5-1 mg/kg CPZ caused an increase in urine volume, sodium excretion, and renal plasma flow, and a decrease in filtration fraction and free water clearance was demonstrated in all dogs. At higher CPZ doses renal plasma flow increased further, whereas urine volume and electrolyte excretion were of the same order at all dose levels. A 21% decrease in tubular maximum para-aminohippurate transport (Tm(PAH)) was observed at the highest CPZ doses. After unilateral renal intra-arterial CPZ infusion the percentage change in urine volume, urinary sodium excretion, and Tm(PAH) were of the same order on the infused side as on the contralateral side. Even though the results at all dose levels can be explained by an 'alpha-blocking' effect of CPZ, possible membrane-stabilizine effects of CPZ cannot be excluded.     

Oral carbidopa has no effect on the renal response to angiotensin II in normal man.

1. The effect of inhibition of intrarenal dopamine synthesis by carbidopa on the renal response to angiotensin II infusion was studied in six healthy salt-loaded volunteers. 2. Subjects received an infusion of angiotensin II at two doses (0.5 and 1.0 ng min-1 kg-1) on two occasions. Before one study they took a single dose of carbidopa (100 mg) by mouth. 3. The plasma concentrations of angiotensin II produced by the infusion were similar on both study days. Angiotensin II infusion reduced urinary dopamine excretion on the control day. Urinary dopamine excretion was undetectable at all times after carbidopa, but carbidopa did not change the basal excretion rate of sodium. Despite inhibition of renal dopamine synthesis, the reductions in both absolute and fractional sodium excretion during the angiotensin II infusion were not different from those seen in the control study. 4. The reductions in glomerular filtration rate and effective renal plasma flow which occurred during angiotensin II infusion were not modified by pretreatment with carbidopa. 5. The renal response to angiotensin II is not modulated either wholly or in part by endogenous intrarenal dopamine levels. The fall in urinary dopamine excretion which occurs during angiotensin II infusion is consistent with a modulatory role for tubular reabsorptive capacity in the regulation of proximal tubular dopamine synthesis.     

Renal handling of fleroxacin in rabbits, dogs, and humans.

The renal handling of fleroxacin was studied by renal clearance and stop-flow techniques in rabbits and dogs and by analyzing the pharmacokinetics with and without probenecid in humans. In rabbits the excretion ratios (fleroxacin intrinsic renal clearance/glomerular filtration rate) were greater than unity (2.01) without probenecid and were decreased to a value below unity (0.680) with probenecid. In dogs, on the other hand, the excretion ratios were less than unity (0.608 and 0.456) both without and with probenecid, and so were not affected by probenecid. This fact suggested that fleroxacin was excreted into urine by both glomerular filtration and renal tubular secretion in rabbits, but only by glomerular filtration in dogs, accompanied by partial renal tubular reabsorption in both species; these mechanisms were also supported by stop-flow experiments. In humans probenecid treatment induced increases in the elimination half-life and area under the serum concentration-time curve and decreases in apparent serum clearance, renal clearance, and urinary recovery of fleroxacin. The excretion ratio without probenecid was 1.13, which was significantly decreased to 0.750 with probenecid. These results indicated that both renal tubular secretion and reabsorption contributed to renal excretion of fleroxacin in humans. The contribution of tubular secretion was species dependent and was extensive in rabbits, minimal in dogs, and moderate in humans. Renal tubular reabsorption was commonly found in every species. The long elimination half-life of fleroxacin in humans might be explained by its small total serum clearance and small renal clearance, which are attributed to less tubular secretion and more tubular reabsorption.     

Renal tubular action of prostaglandin E2 on water and electrolyte excretion in the nonanesthetized chicken

The tubular effects of prostaglandin (PG) E2 on electrolyte and water excretion were investigated in vitro in the nonanesthetized chicken by the Sperber technique. This technique allowed the administration of PGE2 directly into the peritubular space of one kidney by way of the venous portal circulation. When compared to the contralateral, noninfused kidney, PGE2 in the infused kidney (0.6-4.5 X 10(-10) mol/kg X min) induced a dose-dependent increase in urinary flow rate, a mild natriuresis and kaliuresis, with a concomitant decrease in urinary osmolality and an increase in free-water clearance. These effects occurred without changes in renal plasma flow or glomerular filtration rate. PGA2 (1.7-7.8 X 10(-10) mol/kg X min), another vasodepressor PG, did not modify electrolyte excretion. The tubular handling of PGE2 was observed by following the administration of [3H]PGE2. [3H] PGE2 was metabolized extensively during its renal tubular excretion. The 3H label was secreted actively into the urine by the organic anion transport system which was inhibited by novobiocin. Inhibition of the organic anion transport system did not modify the renal tubular effects of PGE2 on electrolyte and water excretion. These results indicate that PGE2 exerts a tubular inhibitory effect on sodium and water excretion, this action being located on the peritubular side.     

Interaction and transport of thiazide diuretics, loop diuretics, and acetazolamide via rat renal organic anion transporter rOAT1

The renal tubular secretion of thiazides and loop diuretics via the organic anion transport system in renal tubules is required for them to reach their principal sites of action. Similarly, acetazolamide, a diuretic clinically administered for glaucoma, is excreted from the kidney by glomerular filtration and tubular secretion. In this study, we investigated the interaction and transport of these diuretics via the rat renal organic anion transporter rOAT1 by using Xenopus laevis oocyte expression system. p-[(14)C]Aminohippurate (PAH) uptake by rOAT1-expressing oocytes was inhibited in the presence of a thiazide (chlorothiazide, cyclothiazide, hydrochlorothiazide), a loop diuretic (bumetanide, ethacrynic acid, furosemide), or a carbonic anhydrase inhibitor (acetazolamide, ethoxzolamide, methazolamide). Dixon plot analysis demonstrated that the inhibition constant (K(i)) value was 1.1 mM for acetazolamide, 150 microM for hydrochlorothiazide, 9.5 microM for furosemide, and 5. 5 microM for bumetanide. Kinetic analysis revealed that acetazolamide inhibited rOAT1 competitively and that inhibition style of furosemide was a mixture of competitive and noncompetitive. [(14)C]PAH efflux was significantly enhanced when the rOAT1-expressing oocytes were incubated in the presence of unlabeled PAH, alpha-ketoglutarate, acetazolamide, chlorothiazide, or hydrochlorothiazide. rOAT1 stimulated acetazolamide uptake, which was inhibited by probenecid. Although the loop diuretics had little trans-stimulation effect on [(14)C]PAH efflux via rOAT1, the rOAT1-mediated furosemide uptake was observed. These findings suggest that rOAT1 contributes, at least in part, to the renal tubular secretion of acetazolamide, thiazides, and loop diuretics.     

Mechanism of renal excretion of carumonam in rats, rabbits, dogs, and monkeys.

The mechanism of the renal excretion of carumonam (CRMN) was investigated in rats, rabbits, dogs, and monkeys. Stop-flow analysis in dogs demonstrated that CRMN is exclusively excreted by glomerular filtration. There was no specific CRMN peak corresponding to the peak of p-aminohippuric acid (PAH) secretion or to the trough of Na+-K+ reabsorption in the stop-flow pattern. Although the PAH peak disappeared when probenecid was administered, the CRMN stop-flow pattern showed no change. In rabbits, however, the CRMN concentration peak corresponding with the PAH peak was detected in the stop-flow pattern; the CRMN peak disappeared when probenecid was administered. The pharmacokinetic parameters in plasma, such as the area under the concentration-time curve, the half-life, and the clearance rate, were affected by probenecid in rats, rabbits, and monkeys, but not in dogs. The results suggest that the renal excretion of CRMN in dogs takes place exclusively through glomerular filtration. In rats, rabbits, and monkeys, however, CRMN is excreted through both glomerular filtration and renal tubular secretion.     

Effect of sympathetic blocking agents on the antinatriuresis of reflex renal nerve stimulation.

To evaluate the effects of reflex renal sympathetic nerve stimulation on renal tubular sodium handling, clearance studies were performed in anesthetized dogs. With renal perfusion pressure held constant, baroreceptor reflex renal sympathetic nerve stimulation was produced by controlled arterial hemorrhage or carotid sinus perfusion. Significant decreases in urinary sodium excretion occurred in the presence of minor insignificant alterations in renal blood flow and no changes in glomerular filtration rate. Renal alpha adrenergic receptor blockade (phenoxybenzamine) or adrenergic blockade (guanethidine) completely reversed the fall in urinary sodium excretion; this could not be attributed to alterations in glomerular filtration rate or renal blood flow. These studies support the interpretation that adrenergic innervation of the renal tubules is involved in the regulation of renal tubular sodium reabsorption.     

Lithium clearance in dogs: effects of water loading, amiloride and lithium dosage.

1. The influences of lithium dosage, urine flow rate and acute administration of amiloride on the renal handling of lithium in normal conscious dogs were investigated. 2. Lithium was administered in the diet at daily doses of 100 mg or 2 mg of lithium carbonate for the 2 days preceding the investigation. Urine flow rate was altered by water loading with and without arginine vasopressin infusion (5 pg min-1 kg-1). Amiloride was administered as an intravenous bolus (130 micrograms/kg) followed by a continuous infusion (1.22 micrograms h-1 kg-1). 3. Glomerular filtration rate (exogenous creatinine clearance) did not change within series and was not different between series; it averaged 3.27 ml min-1 kg-1. Control levels of fractional lithium excretion (12.4 +/- 1.2%, mean +/- SEM) were not influenced by hydration, hydration plus arginine vasopressin administration or the lithium dosage. However, in hydrated dogs having a plasma lithium concentration of 130-140 mumol/l, amiloride administration was associated with a 5% increase in fractional lithium excretion (P less than or equal to 0.01). 4. It is concluded that distal tubular lithium reabsorption may take place in sodium-replete conscious dogs undergoing water diuresis. The low fractional lithium excretion even during amiloride infusion (14.1-16.8%) may well be due to a high fractional reabsorption of lithium in the proximal tubules; however, a significant reabsorption of lithium distal to the proximal straight tubules by amiloride-insensitive pathways cannot be excluded.     

Mechanism of renal excretion of AM-715, a new quinolonecarboxylic acid derivative, in rabbits, dogs, and humans.

The mechanisms of the renal excretion of AM-715, a synthetic antimicrobial agent, were studied in rabbits, dogs, and humans. In both rabbits and humans, AM-715 clearance was greater than creatinine clearance and was profoundly decreased by the administration of probenecid. Thus, in these subjects, AM 715 was cleared by both tubular secretion and glomerular filtration. In dogs, however, the excretion ratio (close to unity), biological half-life, and stop-flow pattern of AM-715 were not affected by probenecid, indicating that the renal excretion of AM-715 took place mostly through glomerular filtration. These results suggest that renal excretion of AM-715 differs with animal species.     

Effect of lithium on the renal actions of alpha-human atrial natriuretic peptide in normal man

1. alpha-Human atrial natriuretic peptide (7.5 pmol min-1 kg-1) was infused intravenously into eight healthy men after pretreatment with lithium carbonate (750 mg) or placebo. 2. Baseline sodium excretion was significantly increased after lithium, but the natriuresis during infusion of alpha-human atrial natriuretic peptide was attenuated. 3. Similar decreases in plasma renin activity with infusion of alpha-human atrial natriuretic peptide occurred on both days. 4. Administration of lithium may be associated with pharmacological effects and further work is required to validate the use of lithium clearance as a marker of proximal renal tubular sodium handling.     

Atrial natriuretic peptide increases albuminuria in type I diabetic patients: evidence for blockade of tubular protein reabsorption

BACKGROUND: It has been suggested that atrial natriuretic peptide (ANP) contributes to the glomerular hyperfiltration of diabetes mellitus. Infusion of ANP increases the urinary excretion of albumin in patients with type I diabetes mellitus (IDDM). Although the increased albuminuria is attributed to a rise in glomerular pressure, alterations in tubular protein handling might be involved. PATIENTS AND METHODS: We have studied the effects of ANP in nine microalbuminuric IDDM patients. After obtaining baseline parameters, ANP was infused over a 1-h period (bolus 0.05 microgram kg-1, infusion rate 0.01 microgram kg-1 min-1). Renal haemodynamics, sodium and water clearance and tubular protein handling were studied. RESULTS: The glomerular filtration rate (GFR) increased from 116.4 +/- 8.9 to 128.3 +/- 8.8 mL min-1 1.73 m-2, whereas the effective renal plasma flow (ERPF) decreased from 534.3 +/- 44.3 to 484.9 +/- 33.3 mL min-1 1.73 m-2 (P < 0.05). As a result, the filtration fraction was significantly higher during infusion of ANP. ANP attenuated proximal tubular sodium reabsorption. Urinary albumin excretion rose from 87.57 +/- 21.03 to 291.40 +/- 67.86 micrograms min-1 (P < 0.01). Changes in the urinary excretion of beta 2-microglobulin and free kappa light chains were more marked, the excretion of beta 2-microglobulin increasing from 0.28 +/- 0.21 to 51.87 +/- 10.51 micrograms min-1 (P < 0.01), and of free kappa-light chains from 4.73 +/- 1.74 to 46.14 +/- 6.19 micrograms min-1 (P < 0.01). CONCLUSIONS: The observed rise in albuminuria during infusion of ANP does not simply reflect a change in glomerular pressure, but might at least partly result from an attenuation of tubular protein reabsorption.     

The influence of extracellular volume expansion on renal phosphate reabsorption in the dog

Extracellular volume expansion (ECVE) was produced, by normal saline infusion, in five normal and six thyroparathyroidectomized anesthetized dogs while glomerular filtration rate was reduced by the inflation of an intra-aortic balloon located above the renal arteries. The effect of ECVE on the maximum renal tubular reabsorptive capacity of phosphate (phosphate Tm) was also evaluated in five additional dogs. During ECVE, phosphate excretion increased both in normal and thyroparathyroidectomized dogs, and a direct and significant correlation was found between the fractional excretion of phosphate and sodium. Despite a substantial decrease in filtered phosphate which is produced by the acute reduction in glomerular filtration rate, phosphate excretion, during ECVE, exceeded control values. ECVE was associated with a reduction in phosphate Tm. The results demonstrate that ECVE increases phosphate excretion independent of changes in glomerular filtration rate and parathyroid gland activity. The data indicate that ECVE produced by saline infusion decreases the renal tubular reabsorption of phosphate.     

Mechanism of active renal tubular efflux of tenofovir

Tenofovir (TFV) undergoes renal elimination by a combination of glomerular filtration and active tubular secretion. While transporter-mediated uptake of TFV from the blood into proximal-tubule cells has been well characterized, comparatively little is known about the efflux system responsible for transporting TFV into the lumen during active tubular secretion. Therefore, members of the ATP-binding cassette family of efflux pumps expressed at the apical side of proximal-tubule cells were studied for the ability to transport TFV. Studies in multiple independent in vitro systems show TFV not to be a substrate for P glycoprotein (Pgp) or multidrug resistance protein type 2 (MRP2). In contrast to Pgp and MRP2, TFV was observed to be a substrate for MRP4. TFV accumulated to fivefold lower levels in MRP4-overexpressing cells, and its accumulation could be increased by an MRP inhibitor. Furthermore, MRP4-overexpressing cells were found to be 2.0- to 2.5-fold less susceptible to cytotoxicity caused by TFV. ATP-dependent uptake of TFV was observed in membrane vesicles containing MRP4 but not in vesicles lacking the transporter. On the basis of these and previous results, the molecular transport pathway for the active tubular secretion of TFV through renal proximal-tubule cells involves uptake from the blood mediated by human organic anion transporters 1 and 3 and efflux into urine by MRP4. A detailed understanding of the molecular mechanism of TFV active tubular secretion will facilitate the assessment of potential renal drug-drug interactions with coadministered agents.     

Active lucifer yellow secretion in renal proximal tubule: evidence for organic anion transport system crossover

Recent studies show that organic anion secretion in renal proximal tubule is mediated by distinct sodium-dependent and sodium-independent transport systems. Here we investigated the possibility that organic anions entering the cells on one system can exit into the lumen on a transporter associated with the other system. In isolated rat kidneys perfused with 10 microM lucifer yellow (LY, a fluorescent organic anion) plus 100 micrograms/ml inulin, the LY-to-inulin clearance ratio averaged 1.6 +/- 0.2, indicating net tubular secretion. Probenecid significantly reduced both LY clearance and LY accumulation in kidney tissue. In intact killifish proximal tubules, confocal microscopy was used to measure steady-state LY uptake into cells and secretion into the tubular lumen. Probenecid, p-aminohippurate, and ouabain nearly abolished both uptake and secretion. To this point, the data indicated that LY was handled by the sodium-dependent and ouabain-sensitive organic anion transport system. However, leukotriene C4, an inhibitor of the luminal step for the sodium-independent and ouabain-insensitive organic anion system, reduced luminal secretion of LY by 50%. Leukotriene C4 did not affect cellular accumulation of LY or the transport of fluorescein on the sodium-dependent system. A similar inhibition pattern was found for another fluorescent organic anion, a mercapturic acid derivative of monochlorobimane. Thus, both organic anions entered the cells on the basolateral transporter for the classical, sodium-dependent system, but about half of the transport into the lumen was handled by the luminal carrier for the sodium-independent system, which is most likely the multidrug resistance-associated protein. This is the first demonstration that xenobiotics can enter renal proximal tubule cells on the carrier associated with one organic anion transport system and exit into the tubular lumen on multiple carriers, one of which is associated with a second system.     

Molecular assessment of the potential for renal drug interactions between tenofovir and HIV protease inhibitors

BACKGROUND: Active renal secretion of tenofovir (TFV) across proximal tubules occurs via uptake by human organic anion transporters 1 and 3 (hOAT1 and hOAT3) coupled with efflux by multidrug resistance protein 4 (MRP4). Co-administration of some HIV protease inhibitors (PIs) with tenofovir disoproxil fumarate (TDF), an oral prodrug of TFV, has been shown to increase systemic levels of TFV, leading to a hypothesis that PIs may affect tubular secretion of TFV and potentially alter the renal safety of TDF. METHODS: The effect of PIs on the transport of TFV by hOAT1, hOAT3 and MRP4 was assessed using in vitro cell-based transport models. RESULTS: At concentrations equal to their therapeutic peak plasma levels (Cmax) all PIs showed <20% inhibition of TFV transport by hOAT1. hOAT3 was more sensitive to Pls with ritonavir (RTV) and lopinavir being the most potent inhibitors of TFV transport (62% and 37% inhibition, respectively, at their Cmax). In the absence of human serum, RTV at concentrations exceeding its therapeutic Cmax also exhibited a minor effect on the cellular efflux of TFV by MRP4 (<30% inhibition at 20 microM). However, no effects of PIs on hOAT1, hOAT3 or MRP4 were detected in the presence of human serum with the exception of RTV that inhibited hOAT3 by approximately 35% at its Cmax. In addition, PIs did not affect the cytotoxicity of TFV or TDF in MRP4- or MRP2-overexpressing cells. CONCLUSION: These data indicate a low potential of PIs to interfere with the active tubular secretion of TFV and to alter the clinical renal safety profile of TDF.     

Role of renal arterial pressure in the regulation of extracellular volume in conscious dogs.

1. This study in conscious dogs examined the quantitative effects of a reduction in the renal arterial pressure on the renal homeostatic responses to an acute extracellular fluid volume expansion. 2. Seven female beagle dogs were chronically instrumented with two aortic catheters, one central venous catheter and a suprarenal aortic cuff, and were kept under standardized conditions on a constant high dietary sodium intake (14.5 mmol of Na+ day-1 kg-1 body weight). 3. After a 60 min control period, 0.9% (w/v) NaCl was infused at a rate of 1 ml min-1 kg-1 body weight for 60 min (infusion period). Two different protocols were applied during the infusion period: renal arterial pressure was maintained at 102 +/- 1 mmHg by means of a servo-feedback control circuit (RAP-sc, 14 experiments) or was left free (RAP-f, 14 experiments). 4. During the infusion period, in the RAP-sc protocol as well as in the RAP-f protocol, the mean arterial pressure increased by 10 mmHg, the heart rate increased by 20 beats/min, the central venous pressure increased by 4 cmH2O and the glomerular filtration rate (control 5.1 +/- 0.3 ml min-1 kg-1 body weight, mean +/- SEM) increased by 1 ml min-1 kg-1. 5. Plasma renin activity [control 0.85 +/- 0.15 (RAP-f) and 1.08 +/- 0.23 (RAP-sc) pmol of angiotensin I h-1 ml-1] decreased similarly in both protocols.(ABSTRACT TRUNCATED AT 250 WORDS)