Effects of intravenous bumetanide administration on renal haemodynamics and proximal and distal tubular sodium reabsorption in conscious rats

The renal effects of 0.02-62.5 mg/kg bumetanide given as intravenous bolus injections were studied in water diuretic conscious rats. Clearances of 14C-tetraethylammonium, 3H-inulin and lithium were used as markers for renal plasma flow (RPF), glomerular filtion rate (GFR) and proximal tubular output, respectively. Bumetanide caused biphasic, transient and dose-independent changes in the renal haemodynamics without significant alterations of the filtration fraction. At dose-levels above 0.02 mg/kg bumetanide increased urine flow, absolute and fractional Na excretion as well as the indices for fractional output of Na from the proximal tubules (CLi/CIn) and the distal nephron segments (CNa/CLi). The changes in CLi/CIn became maximal at doses above 0.5 mg/kg, whereas CNa/CLi was increased with the dose up to 12.5 mg/kg. Paradoxically, doses above 12.5 mg/kg were less natriuretic due to a decrease of CNa/CLi. It is concluded that in rats bumetanide is an effective although short-acting diuretic when administered intravenously. When comparing peak responses bumetanide is equipotent to furosemide but has a lower maximal efficacy. Judged from the changes in fractional lithium excretion, the natriuretic effect of bumetanide is effected by inhibition of Na reabsorption in the proximal tubule in addition to the well-known effect on the distal nephron segment.     

Lack of effect of non-steroid antiinflammatory drugs on lithium clearance and on delivery of tubular fluid to the loop of Henle in rats

This paper examines a possible interaction between non-steroid antiinflammatory drugs (NSAI drugs) and renal lithium clearance in conscious, unoperated rats with diabetes insipidus (Brattleboro strain) and ordinary Wistar rats. The drugs were given with the food for 5 days before clearance determinations in the following daily doses per kg body weight: acetylsalicyclic acid 115 mg/kg, phenylbutazone 20 mg/kg, indomethacin 5 mg/kg, and penicillamine 65 mg/kg. None of the drugs affected the lithium clearance. Also urine flow, sodium clearance, potassium clearance, and prostaglandin E2 excretion remained unaffected by the treatments. The results suggest that a continued lowering of lithium clearance cannot be produced, at least not by administration of the drugs with the food. Since lithium clearance is a quantitative measure of the delivery of tubular fluid from the proximal tubules to the loop of Henle, the results also suggest that chronic administration of NSAI drugs does not influence delivery from the proximal tubules in rats. The lowering of lithium clearance observed by others after administration of the drugs by injection or by gastric tube may have been transient, lasting only for a short period after each administration.     

Effects of furosemide on renal haemodynamics and proximal tubular sodium reabsorption in conscious rats.

1. The effects of furosemide given as constant i.v. infusion (7.5 mg kg-1 h-1) or bolus injections (0.5, 7.5 and 120 mg kg-1) on renal haemodynamics and proximal tubular Na reabsorption were studied in conscious water diuretic rats. The clearance of Li (CLi) was used as marker for Na delivery from the proximal tubules, and clearance of [14C]-tetraethylammonium (CTEA) and [3H]-inulin (CIn) as markers for renal plasma flow (RPF) and glomerular filtration rate (GFR), respectively. 2. Furosemide caused a transient increase of RPF and GFR followed by a secondary decrease below baseline levels; the latter could in part be counteracted by volume replacement. The filtration fraction (FF = GFR/RPF) was not significantly changed by furosemide. Fractional proximal Na excretion (CLi/CIn) was significantly increased by all doses of furosemide independent of changes in RPF, GFR and FF. 3. The peak diuretic/natriuretic effect of furosemide was markedly potentiated by volume replacement, probably due to prevention of antinatriuretic mechanisms triggered by volume depletion. 4. It is concluded that following i.v. furosemide administration there is a biphasic change in renal haemodynamics in conscious, restrained rats, and that the inhibition of proximal Na reabsorption, as manifested by changes in fractional Li excretion, is not likely to be due to changes in total renal haemodynamics.     

Involvement of the renal kallikrein-kinin system in furosemide-induced natriuresis in rats

This study examined whether the renal kallikrein-kinin system (KKS) is involved with furosemide-induced natriuresis in rats. Intravenous administration of furosemide (10 mg/kg) to anesthetized rats infused with physiological saline (saline) increased renal KK excretion as well as urine volume and urinary excretions of sodium, chloride and potassium. The change in the increase of renal KK excretion by furosemide at a dose of 1.0 mg/kg relative to the control was larger than that of urine volume. Pretreatment with a B2-receptor antagonist, 8-[3-[N-[(E)-3-(6-acetamidopyridin-3-yl)acryloylglycyl]-N-methylamino]-2,6-dichlorobenzyloxy]-2-methylquinoline (FR173657, 100 mg/kg), significantly inhibited the furosemide-induced natriuresis by 58.6%. The effect of FR173657 on the furosemide-induced natriuresis was also examined in hypotonic saline-loading rats. Similar to the saline-loading rats, urinary excretion of sodium collected during the first 8 h in metabolic cages significantly reduced by 22.4% when FR173657 (100 mg/kg) was given concurrently with furosemide (100 mg/kg) and hypotonic saline (5% of body wt.). These results indicate that furosemide increased renal KK excretion through a mechanism different from a washout mechanism and induced natriuresis partly through an augmentation of the renal KKS following the increase in renal KK excretion in both the saline- and hypotonic saline-loading rats.     

The diuretic action of 8-cyclopentyl-1,3-dipropylxanthine, a selective A1 adenosine receptor antagonist.

1. The diuretic effect of the selective A1 adenosine receptor antagonist, 8-cyclopentyl-1,3-dipropylxanthine (CPX), was investigated in anaesthetized rats. 2. CPX (0.1 mg kg-1, i.v.) produced significant increases in urine flow, and the excretion rate and fractional excretion of both sodium and chloride. By contrast, CPX administration did not result in any significant change in the excretion of potassium. 3. The diuretic effect of CPX was accompanied by a transient increase in inulin clearance although p-amino-hippurate clearance was unaffected, indicating the CPX induced a temporary elevation of glomerular filtration rate but no change in renal blood flow. 4. The fractional excretion of lithium (a marker of delivery of fluid out of the proximal tubule) was also significantly increased by CPX. However, other measures of tubular function derived from lithium clearance indicated that there were no changes in the handling of sodium or water in the distal regions of the nephron. 5. CPX did not significantly alter the relationship between either free water reabsorption or free water clearance and the distal delivery of sodium, which suggests that CPX does not affect the renal concentration/dilution mechanism. 6. The results of this study show that the diuresis and increased excretion of sodium and chloride induced by CPX (0.1 mg kg-1) in the rat, occurs with only transient elevation in glomerular filtration rate and no change in renal blood flow. The primary reason for the diuresis appears to be inhibition of sodium reabsorption in the proximal tubule.(ABSTRACT TRUNCATED AT 250 WORDS)     

Renal effects of alpha-adrenoceptor blockade during furosemide diuresis in conscious rats.

Clearance experiments were performed in conscious rats in order to investigate whether intravenous infusion of the non-selective alpha-adrenoceptor antagonist phentolamine could block compensatory sodium reabsorption during furosemide-induced volume contraction. By measuring inulin clearance, urinary excretion rates of sodium and water, and lithium clearance, the effects on proximal and distal nephron segments were dissociated. The renal effect of intravenous infusion of 0.3 mg/kg/hr phentolamine (n = 6) was compared with time control animals (n = 9). Furosemide was administered as constant intravenous infusion (7.5 mg/kg/hr) with simultaneous phentolamine infusion at four dose levels: 0 (n = 9), 0.3 (n = 6), 1.0 (n = 7) and 3.0 mg/kg/hr (n = 6). Phentolamine infusion reduced norepinephrine-induced increase in blood pressure at all three dose levels (n = 5). Phentolamine infusion induced transient antidiuresis and a prolonged antinatriuretic response. Compared with rats given furosemide only, phentolamine attenuated dose-dependently the diuretic and natriuretic peak response to furosemide. This effect was associated with dose-dependent reductions in mean arterial pressure. The reduced natriuretic response was due to a reduced fractional sodium excretion in the distal nephron segment (at all doses of phentolamine) and a reduction of the glomerular filtration rate (1.0 and 3.0 mg/kg/hr phentolamine). The fractional lithium excretion (FELi) increased to 65 +/- 3% at 0.3 mg/kg/hr phentolamine during the natriuretic peak response of furosemide, while it only increased to 52 +/- 3% during furosemide alone. At steady-state conditions (120-180 min. after start of furosemide infusion) after infusion with furosemide plus 0.3 mg/kg/hr phentolamine the animals were still volume-depleted, but the compensatory tubular Na reabsorption in the proximal tubules was inhibited (FELi = 48 +/- 2% versus 39 +/- 1% in rats given furosemide alone). During furosemide infusion plasma epinephrine increased 700% and plasma norepinephrine increased 50%. These results are compatible with increased systemic sympathetic nervous activity and a contributory role of proximal tubular alpha-adrenoceptors in mediating compensatory sodium reabsorption during acute furosemide-induced volume contraction.     

Influence of captopril on renal hemodynamics and segmental tubular reabsorption of sodium in humans

Acute angiotensin-converting enzyme inhibitors (ACEIs) have been found to induce natriuresis in humans as well as in experimental animals. However, the tubular sites involved have not been precisely evaluated in humans. Using both free-water and lithium clearance, the latter as a marker of proximal tubular reabsorption, we measured segmental tubular movement of sodium before and after acute captopril administration in eight healthy normotensive volunteers on normal sodium diet. Captopril decreased slightly but significantly glomerular filtration rate (GFR), filtration fraction, and mean arterial pressure (MAP), whereas renal plasma flow (RPF) was unchanged. Captopril acutely increased excretion rate and fractional excretion of sodium. When assessed by lithium clearance, both absolute and fractional proximal reabsorption of sodium and fractional distal reabsorption of sodium were found to be decreased by captopril. When assessed by free-water clearance, both fractional proximal and distal reabsorption of sodium were found to be decreased by captopril but only the decrease in fractional proximal reabsorption was significant. These results indicate that captopril-induced natriuretic effect is due to decreased sodium reabsorption in both proximal and distal sites of the nephron. Shifts in segmental tubular sodium reabsorption obtained from either free-water or lithium clearance are directionally similar but quantitatively different. Results obtained from lithium clearance indicate that the rate of fluid delivery to the diluting segment is at least twice as great as that estimated from free-water calculations. Lithium clearance techniques therefore appear to be more sensitive in detecting subtle changes in segmental tubular reabsorption.(ABSTRACT TRUNCATED AT 250 WORDS)     

Renal Effects of α-Adrenoceptor Blockade During Furosemide Diuresis in Conscious Rats

Abstract: Clearance experiments were performed in conscious rats in order to investigate whether intravenous infusion of the non-selective α-adrenoceptor antagonist phentolamine could block compensatory sodium reabsorption during furosemide-induced volume contraction. By measuring inulin clearance, urinary excretion rates of sodium and water, and lithium clearance, the effects on proximal and distal nephron segments were dissociated. The renal effect of intravenous infusion of 0.3 mg/kg/hr phentolamine (n=6) was compared with time control animals (n=9). Furosemide was administered as constant intravenous infusion (7.5 mg/kg/hr) with simultaneous phentolamine infusion at four dose levels: 0 (n=9), 0.3 (n=6), 1.0 (n=7) and 3.0 mg/kg/hr (n=6). Phentolamine infusion reduced noepinephrine-induced increase in blood pressure at all three dose levels (n=5). Phentolamine infusion induced transient antidiuresis and a prolonged antinatriuretic response. Compared with rats given furosemide only, phentolamine attenuated dose-dependently the diuretic and natriuretic peak response to furosemide. This effect was associated with dose-dependent reductions in mean arterial pressure. The reduced natriuretic response was due to a reduced fractional sodium excretion in the distal nephron segment (at all doses of phentolamine) and a reduction of the glomerular filtration rate (1.0 and 3.0 mg/kg/hr phentolamine). The fractional lithium excretion (FE_Li) increased to 65±3% at 0.3 mg/kg/hr phentolamine during the natriuretic peak response of furosemide, while it only increased to 52±3% during furosemide alone. At steady-state conditions (120–180 min. after start of furosemide infusion) after infusion with furosemide plus 0.3 mg/kg/hr phentolamine the animals were still volume-depleted, but the compensatory tubular Na reabsorption in the proximal tubules was inhibited (FE_Li=48±2% versus 39±1%> in rats given furosemide alone). During furosemide infusion plasma epinephrine increased 700% and plasma norepinephrine increased 50%. These results are compatible with increased systemic sympathetic nervous activity and a contributory role of proximal tubular α-adrenoceptors in mediating compensatory sodium reabsorption during acute furosemide-induced volume contraction.     

Stereoselective saluretic effect and localization of renal tubular secretion of enantiomers of S-8666, a novel uricosuric antihypertensive diuretic

S-8666, a newly developed antihypertensive uricosuric diuretic, possesses an asymmetric carbon and exists as a racemic mixture. The enantioselectivity of S-8666 in natriuresis and the renal excretory mechanisms of the S-8666 enantiomers were examined. Dose-dependent natriuresis of the S-(?)-enantiomer was observed in male Sprague-Dawley rats (3–100 mg/kg, p.o.), female Slc:ddy mice (3–300 mg/kg, p.o.) and male NIBS Japan white rabbits (1–10 mg/kg, i.v.). The R-(+)-enantiomer produced no significant change in sodium excretion within dose ranges of 100–200 mg/kg p.o. for rats, 3–300 mg/kg p.o. for mice, and 10 mg/kg i.v. for rabits. The (?)-enantiomer and racemic S-8666 showed a high-ceiling property like that of furosemide and unlike that of trichlormethiazide. Plasma protein binding of S-8666 was over 95% in rabbits and 73% in beagle dogs. In rabbits, both enantiomers of S-8666 were secreted equally from the proximal tubule; however, only the (?)-enantiomer of S-8666 showed diuresis in a stop-flow pattern. In beagle dogs, secretion of racemic S-8666 occurred from the proximal tubule and could be inhibited by probenecid. The renal excretion of S-8666 was largely the result of tubular excretion in rabbits whereas in beagle dogs, some glomerular filtration was also involved in urinary excretion. In conclusion, S-8666 shows enantioselectivity in natriuresis. Both enantiomers of S-8666 are excreted mostly by the organic acid transport system in the proximal tubule, but only the (?)-enantiomer of S-8666 induces natriuresis from the luminal side of the tubule.     

Effects of glycine on glomerular filtration rate and segmental tubular handling of sodium in conscious rats

1. Infusion 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). 2. In the first series of experiments, the effect of glycine infusion (4 mg/min) was examined in conscious, unstressed, chronically catheterized rats. In an additional series of experiments, the effect of glycine was examined under similar conditions in rats pretreated with a NO synthase (NOS) inhibitor (NG-nitro-L-arginine methyl ester (L-NAME), 2.5 microg/min). 3. Glycine significantly increased ERPF (from 3268 to 4018 microL/min per 100 g bodyweight (BW)), GFR (from 874 to 1009 microL/min per 100 g BW), CLi (from 275 to 461 microL/min per 100 g BW) and Na+ clearance (CNa; from 2.9 to 14.0 microL/min per 100 g BW). Fractional excretion of lithium (FELi; from 32 to 46%) and CNa/CLi (from 0.99 to 2.99%) also rose, indicating inhibition of proximal and distal nephron Na+ reabsorption, respectively. In the rats pretreated with L-NAME, similar haemodynamic and tubular responses to glycine infusion were seen, suggesting that the effects were not mediated by NO. 4. We conclude, that glycine increases ERPF and GFR and it also inhibits proximal and distal nephron Na+ reabsorption leading to an increase in CLi and CNa. There was no indication that any of these effects were mediated by NO.     

Effect of N-acetylcysteine on gentamicin-mediated nephropathy in rats

Studies were performed on the mechanisms of the protective effects of free-radical scavengers against gentamicin-mediated nephropathy. Administration of gentamicin, 100 mg/kg s.c., for 5 days to rats induced marked renal failure, characterised by a significantly decreased creatinine clearance and increased blood creatinine levels, fractional excretion of sodium Na(+), lithium Li(+), urine gamma glutamyl transferase and daily urine volume. A significant increase in kidney myeloperoxidase activity and lipid peroxidation was observed in gentamicin-treated rats. Immunohistochemical localisation demonstrated nitrotyrosine formation and poly(ADP-ribose)synthase activation in the proximal tubule from gentamicin-treated rats. Renal histology examination confirmed the tubular necrosis. N-acetylcysteine (10 mg/kg i.p. for 5 days) caused normalisation of the above biochemical parameters. In addition, N-acetylcysteine treatment significantly prevents the gentamicin-induced tubular necrosis. These results suggest that (1) N-acetylcysteine has protective effects on gentamicin-mediated nephropathy, and (2) the mechanisms of the protective effects can be, at least in part, related to interference with peroxynitrite-related pathways.     

Effects of the calcium channel blocker AE0047 on renal function in conscious spontaneously hypertensive rats: Focus on renal proximal tubules

The hypotension induced by peripheral vasodilators is occasionally accompanied by diminished urine formation induced via various anti-diuretic mechanisms. The question of whether an antihypertensive agent has diuretic action is therefore relevant to its usefulness. In the present study, conducted in conscious, spontaneously hypertensive rats (SHR), the lithium clearance technique was used to investigate the effect of intravenously administered AE0047 on renal function; the effect of orally administered AE0047 on uric acid excretion was also investigated. Intravenous injection of AE0047 (10 and 30 μg/kg) produced potent hypotension, accompanied by diuresis and natriuresis. The diuretic action was accompanied by an elevation of FE_Na and FE_Li levels, with minimal change in GFR. Oral administration of AE0047 (1 and 3 mg/kg) led to a dose-related increase in urine volume and in urinary excretion of sodium and uric acid (U_UAV). Simultaneous administration of pyrazinamide, an inhibitor of uric acid secretion in proximal tubules, mitigated the increase in U_UAV. These findings indicate that systemically administered AE0047 produces diuresis and natriuresis, in part via an inhibition of sodium and water reabsorption in the proximal tubules. The action of AE0047 at renal proximal tubular sites thus offers benefit in hypertension therapy. Drug Dev. Res. 41:91–98, 1997. © 1997 Wiley-Liss, Inc.     

Acute effects of candesartan on rat renal haemodynamics and proximal tubular reabsorption

1. The effects of the specific angiotensin II receptor type I (AT1) antagonist candesartan on renal proximal tubular sodium transport were studied using lithium clearance. The effects of candesartan on mean arterial blood pressure (MABP), renal plasma flow (RPF), glomerular filtration rate (GFR) and sodium and potassium excretion were also investigated. 2. Male Wistar rats were anaesthetized with Inactin (thiobutabarbital sodium; Sigma, St Louis, MO, USA). Clearance markers (8% polyfructosan, 1% para-aminohippuric acid and 4 mmol/l lithium chloride) were given into a jugular vein at the rate of 1.6 mL/h per 100 g bodyweight. Candesartan was given as bolus injection (0.01, 0.1, 0.2, 0.5 and 1.0 mg/kg) followed by 60 min continuous infusion at a rate of 0.5, 5, 10, 25 and 50 microg/min per kg, respectively. 3. The non-depressor dose of candesartan (0.01 mg/kg) did not alter RPF or GFR, whereas diuresis, natriuresis and kaliuresis were observed. The higher doses of candesartan reduced MABP, RPF and GFR, although diuresis, natriuresis and kaliuresis were still observed. 4. Renal tubular sodium and water reabsorption were inhibited after intravenous administration of candesartan independently of an alteration in arterial pressure. Lithium clearance data indicate that the site of inhibition was in the proximal nephron segment.     

Effects of the selective neutral endopeptidase inhibitor, retrothiorphan, on renal function and blood pressure in conscious normotensive Wistar and hypertensive DOCA-salt rats.

Atrial natriuretic peptide (ANP) is degraded by neutral endopeptidase (NEP) mainly in the proximal tubule of the kidneys. We studied the effects of retrothiorphan, a potent and highly specific NEP inhibitor on renal function and blood pressure (BP). A 25-mg/kg bolus injection (group bolus), or bolus injection plus infusion 25 mg/kg + 25 mg/kg/h (group infusion), was given to conscious normotensive Wistar and hypertensive DOCA-salt rats. Bolus and infusion produced increases in diuresis (110 +/- 15 vs. 103 +/- 15 vs. 42 +/- 9 microliters/min) and natriuresis (10.6 +/- 3.0 vs. 7.0 +/- 1.0 vs. 5.4 +/- 1.0 mumol/min) in normotensive rats, with a maximum change at 30 min. Change in kaliuresis was not significant. These renal effects were associated with nonsignificant increases in urinary cyclic GMP and ANP. Arterial pressure and heart rate (HR) were not affected. Bolus or infusion of retrothiorphan also induced increases in diuresis (92 +/- 16 vs. 124 +/- 13 vs. 38 +/- 6 microliters/min) and natriuresis (10.3 +/- 2.0 vs. 12.5 +/- 1.0 vs. 5.0 +/- 1.0 mumol/min) in DOCA-salt hypertensive rats, with a maximum change at 30 min. The changes in diuresis and natriuresis induced by retrothiorphan were correlated with a significant increase in urinary cyclic GMP excretion (r = 0.89, p < 0.001 and r = 0.91, p < 0.001). Urinary ANP did not change in controls but significantly increased in the treated rats; urinary immunoreactive bradykinin (BK) also tended to increase. Plasma ANP and hematocrit did not change after retrothiorphan, but plasma cyclic GMP increased significantly after infusion. Only infusion caused a decrease in arterial pressure in DOCA-salt rats (-20 mm Hg at 120 min). Renal clearance studies in DOCA-salt rats showed that retrothiorphan has a transient effect on renal hemodynamics, with increases in glomerular filtration and renal blood flow (RBF) and a decrease in renal vascular resistance (RVR). Its renal action was also tubular, with an increase in fractional sodium excretion. We also compared the effects of retrothiorphan in normotensive Brown-Norway kininogen-deficient rats (BN-Kat) and DOCA-salt hypertensive kininogen-deficient rats. The NEP inhibitor induced increases in diuresis and natriuresis in both groups, with increased urinary cyclic GMP. Urinary immunoreactive BK did not change significantly in normotensive or DOCA-salt hypertensive kininogen-deficient rats.(ABSTRACT TRUNCATED AT 400 WORDS)     

Eukaliuric diuresis and natriuresis in response to the KATP channel blocker U37883A: micropuncture studies on the tubular site of action.

1. Systemic application of U37883A, a blocker of ATP sensitive potassium (KATP) channels, elicits diuresis and natriuresis without significantly altering urinary potassium excretion. 2. To elucidate tubular sites of action upstream to the distal nephron, micropuncture experiments were performed in nephrons with superficial glomeruli of anaesthetized Munich-Wistar-Fr?mter rats during systemic application of U37883A (1, 5 or 15 mg kg-1 i.v.). 3. The observed eukaliuric diuresis and natriuresis in response to U37883A at 15 mg kg-1 was accompanied by an increase in early distal tubular flow rate (VED) from 10 - 18 nl min(-1) reflecting a reduction in fractional reabsorption of fluid up to this site (FR-fluid) of 13%. The latter proposed an effect on water-permeable segments such as the proximal tubule which could fully account for the observed reduction in fractional reabsorption of Na+ up to the early distal tubule (FR-Na+) of 8% and the increase in early distal tubular Na+ concentration ([Na+]ED) from 35 - 51 mM whereas [K+]ED was left unaltered. 4. In comparison, furosemide (3 mg kg-1 i.v.), which acts in the water-impermeable thick ascending limb, elicited diuresis, natriuresis and kaliuresis which were associated with a fall in FR-Na+ of 10% with no change in FR-fluid, and a rise in [Na+]ED from 42 - 117 mM and [K+]ED from 1.2 - 5.7 mM with no change in VED. 5. Direct late proximal tubular fluid collections confirmed a significant inhibition of fluid reabsorption in proximal convoluted tubule in response to systemic application of U37883A. 6. These findings suggest that the diuretic and natriuretic effect upstream to the distal tubule in response to systemic application of U37883A involves actions on water-permeable segments such as the proximal convoluted tubule.     

Effects of icatibant on the ramipril-induced decrease in renal lithium clearance in the rat

The interaction between an inhibitor of angiotensin I converting enzyme (ramipril) and renal lithium handling was analysed in conscious, normotensive Wistar rats in the absence or the presence of a specific bradykinin B2 receptor antagonist, icatibant. The rats were treated for 5 days with ramipril (1 mg/kg/day p.o.) or its vehicle, alone or together with icatibant (0.1 mg/kg/day, s.c. infusion). Lithium chloride (8.3 mg/kg i.p.) was given as a single dose on day 5. Systolic blood pressure and heart rate were measured by tail plethysmography on day 3 (3, 9 and 15 h after ramipril administration) and renal function on day 4 (0-6 and 6-24 h urine sampling) and day 5 (0-6 h urine sampling). In another group of rats, 24 h sodium excretion was assessed during the first 4 days of ramipril treatment. Ramipril decreased renal lithium clearance (90+/-8 vs. 142+/-10 microl/min/100 g, P<0.001, n=24) and increased the fractional lithium reabsorption (74.3+/-1.9 vs. 66.7+/-1.7%, P<0.05) and plasma lithium concentration (0.108+/-0.006 vs. 0.085+/-0.004 mM, P<0.01). Alteration of renal lithium handling by ramipril was associated with a decrease in systolic blood pressure (-15% 3 h after ramipril administration) and sodium excretion (0-6 h after ramipril). The 24-h sodium excretion, however, tended to increase. Icatibant had no effect per se on renal function but attenuated the ramipril-induced decrease in renal lithium clearance (118+/-16 vs. 90+/-8 microl/min/100 g, n=12 and 24 respectively, P<0.05 one-tailed test) and systolic blood pressure. These results suggest that endogenous bradykinin contributes to the ramipril-associated alteration in renal lithium handling. Bradykinin B2 receptor-mediated vasodilation seems to be involved.     

Nonlinear disposition of lithium in rats and saturation of its tubular reabsorption by the sodium‐phosphate cotransporter as a cause

We previously reported the contribution of sodium‐phosphate cotransporter to the tubular reabsorption of lithium in rats. In the present study, the dose dependency of the renal handling of lithium was examined in rats. When lithium chloride at 1.25 mg/kg, 2.5 mg/kg and 25 mg/kg was intravenously injected as a bolus, the areas under the plasma concentration‐time curve of lithium until 60 minutes were calculated to be 6.23 mEq·min/l, 8.77 mEq·min/l and 64.6 mEq·min/l, respectively. The renal clearance of lithium and its fractional excretion increased with increments in the dose administered. The renal clearance of lithium strongly correlated with the urinary excretion rate of phosphate in the 1.25 mg/kg group (r = 0.840) and 2.5 mg/kg group (r = 0.773), whereas this correlation was weak in the 25 mg/kg group (r = 0.306). The infusion of foscarnet, a typical inhibitor of sodium‐phosphate cotransporter, decreased the fractional reabsorption of lithium in rats administered lithium chloride at 2.5 mg/kg, but did not affect it in rats administered 25 mg/kg. These results demonstrate the nonlinearity of the renal excretion of lithium in rats, with the saturation of lithium reabsorption by the sodium‐phosphate cotransporter potentially being involved.     

RENAL HANDLING OF ENDOGENOUS LITHIUM IN EXPERIMENTAL DIABETES MELLITUS IN THE RAT

1. The usefulness of determining the renal handling of endogenous lithium as a marker of proximal tubular sodium reabsorption was assessed in streptozotocin induced diabetes mellitus in the Sprague-Dawley rat. 2. The clearance and fractional excretion of lithium were determined before and following the development of diabetes mellitus, and compared with measurements of proximal tubular reabsorption made directly using micropuncture techniques. Endogenous lithium was measured in order to avoid the toxic tubular effects of exogenously administered lithium salts. 3. Although a trend existed for a reduction in the fractional excretion of lithium in diabetic animals (1.8 +/- 0.3 vs 2.4 +/- 0.5%; P greater than 0.20), this did not reach statistical significance and did not accurately reflect the change in directly measured tubular Na reabsorption. 4. The decrease in proximal tubular Na reabsorption demonstrated in diabetic animals treated with phlorizin was not significantly reflected in the fractional lithium excretion, although again a corresponding trend was evident (1.9 +/- 0.8 vs 0.6 +/- 0.2%; P greater than 0.10. 5. In summary, the significant alterations in tubular Na handling in diabetes mellitus, previously demonstrated directly using micropuncture techniques, are not reflected in the renal handling of endogenous lithium. This indirect method is inadequate to assess proximal tubular Na transport in experimental diabetes mellitus.     

Natriuresis, kaliuresis and diuresis in the rat following microinjections of carbachol into the septal area.

The effects of intraseptal injection of carbachol on natriuresis, kaliuresis and diuresis has been studied in conscious, unrestrained water-loaded male rats. Urinary sodium and potassium excretion increased following injections into the septal area. The intensity of the natriuresis and kaliuresis was dose-related. An antidiuretic effect was also observed. The Na+/K/ ratio increased with increasing doses of carbachol, indicating that the rise in urinary sodium exceeded that of potassium. Systematic mapping of the septal area yielded about the same results for all sites, excepting a zone located in the anterior-dorsal part of the medial nucleus which appeared more sensitive. The natriuretic effect of intraseptal carbachol in adrenalectomized rats demonstrated the secondary role played by the adrenals. Contrariwise the decrease of the natriuretic effect observed either in hypophysectomized rats or in rats bearing a median eminence lesion receiving intraseptal carbachol showed the important participation of these structures in urinary Na+ excretion. Adrenalectomy or median eminence lesions did not modify the kaliuretic response while hypophysectomy produced a transitory diminution. This fact favours the hypothesis of different mechanisms involved in Na+ and K+ excretion following intraseptal carbachol. These results leave open the question as to mechanism of action but suggest a possible role of the pituitary in mediating the responses. Also, the possibility of a role played by hemodynamic shifts is suggested.     

Involvement of the renal kallikrein-kinin system in K(+)-induced diuresis and natriuresis in anesthetized rats

Intravenous infusion of a high-K(+) solution (67.5 mM KCl, 67.5 mM NaCl) to anesthetized rats increased urine volume by 47.6% after 60 min, compared with infusion of a Na(+) solution (135 mM NaCl). This treatment also increased urinary excretion of Na(+) by 32.2%, in parallel with an increase in excretion of K(+) or Cl(-). Urinary excretion of kallikrein increased within 60 min after the start of K(+) infusion. A bradykinin B(2) receptor antagonist, 8-[3-[N-[(E)-3-(6-acetamidopyridin-3-yl)acryloylglycyl]-N-me thylamino ]-2,6-dichlorobenzyloxy]-2-methylquinoline (FR173657; 1.0 mg/kg, i.v. ), inhibited the K(+)-induced diuresis and natriuresis by 41.0% and 26.7%, respectively. These results indicate that K(+) load induces diuresis and natriuresis through the renal kallikrein-kinin system in rats.