Effects of the rate and composition of fluid replacement on the pharmacokinetics and pharmacodynamics of intravenous furosemide

Effects of differences in the rate and composition of intravenous fluid replacement for urine loss on the pharmacokinetics and pharmacodynamics of furosemide were evaluated using the dog as a model animal. Each of six dogs received 8-hr constant intravenous infusion of 20 mg (15 mg used in one dog) of furosemide with 0% replacement (treatment I), 50% replacement (treatment II), and 100% replacement (treatment III) with lactated Ringer's solution, as well as with 100% replacement with 5% dextrose in water (treatment IV). Most pharmacokinetic parameters, such as plasma clearance, steady-state volume of distribution, mean residence time, and terminal half-life, were essentially the same in all four treatments. Renal clearances and urinary excretion rates of the drug in treatments II-IV were essentially the same, but about 20% higher than those in treatment I. In spite of the similarities in kinetic properties, diuretic and/or natriuretic effects from furosemide were markedly different among the four treatments. For example, mean 10-hr urine outputs were 646, 1046, 3156, and 1976 ml and mean 10-hr sodium excretions were 87.0, 142, 383, and 97.2 mmole for treatments I-IV, respectively. Except for treatment III, diuresis and/or natriuresis were found to be time-dependent, generally decreasing with time until reaching a low plateau during later hours of infusion. The present findings also showed that no fluid replacement and 100% replacement with 5% dextrose solution both produced the same degree of severe acute tolerance in natriuresis, indicating the insignificance of water compensation in tolerance development; in treatment II, where neutral sodium balance was achieved, the development of acute tolerance in diuresis and natriuresis can mainly be attributed to negative water balance under this special condition; at steady state the hourly diuresis and natriuresis could differ up to about ten times between treatments. Some implications for the kinetic/dynamic relationship or modeling, in the clinical use, and in the bioequivalence evaluation of dosage forms are discussed.     

Effects of the rate and composition of fluid replacement on the pharmacokinetics and pharmacodynamics of intravenous azosemide

The effects of differences in the rate and composition of intravenous fluid replacement for urine loss on the pharmacokinetics and pharmacodynamics of azosemide were evaluated using rabbit as the animal model. Each rabbit received a 4 h constant intravenous infusion of 1 mg kg⁻¹ azosemide with 0% replacement (treatment I, n =4), 50% replacement (treatment II, n =5), and 100% replacement (treatment III, n =5) with lactated Ringer's solution, as well as with 100% replacement with 5% dextrose in water (D-5-W, treatment IV, n =5). Renal clearance and urinary excretion rate of the drug in treatment III were considerably higher than those in treatments I, II, and IV. In spite of the similarities in kinetic properties, diuretic and/or natriuretic effects of azosemide were markedly different among the four treatments. For example, the mean 8 h urine output values were 98·2, 178, 733, and 237 mL for treatments I–IV, respectively, and the corresponding values for sodium excretion were 11·1, 19·4, 76·4, and 14·2 mmol, and for chloride 13·4, 23·8, 78·9, and 17·1 mmol. Except for treatment III, diuresis and/or natriuresis were found to be time dependent, generally decreasing with time until reaching a low plateau during the later hours of infusion. The present findings also show that (i) no fluid replacement and 100% replacement with D-5-W both produce the same degree (not significantly different) of severe acute tolerance in natriuresis, indicating the insignificance of water compensation in tolerance development; (ii) in treatment II, where neutral sodium balance was achieved, the development of acute tolerance in diuresis can mainly be attributed to negative water balance under this special condition; and (iii) at steady state the hourly diuresis and natriuresis can differ up to about 6·87- and 5·21-fold between treatments. Some implications for the bioequivalence evaluation of dosage forms of azosemide are discussed. © 1997 John Wiley & Sons, Ltd.     

Input rate as a major determinant of furosemide pharmacodynamics: influence of fluid replacement and hypoalbuminemia.

To investigate how the response to a bolus and an infusion of furosemide is modulated by the rate of fluid replacement and by hypoalbuminemia, rabbits received 5 mg/kg of furosemide as a bolus or infused over 60 min, whereas diuresis was replaced with 13, 121, or 238 ml/h NaCl 0.9%/glucose 5% (50:50). Natriuretic and diuretic efficiencies were greater with the infusion than with the bolus of furosemide. Fluid replacement increased natriuretic and diuretic efficiency of furosemide bolus but only diuretic efficiency of furosemide infusion. Furosemide net fluid depletion reached a plateau when fluid replacement increased beyond 121 ml/h. Repeated plasmapheresis decreased plasma albumin by 30% (P <.05) and increased furosemide unbound fraction (P <.05). Compared with control rabbits, hypoalbuminemia decreased the natriuresis of the bolus (22.7 +/- 1.5-16.6 +/- 1.3 mmol, P <.05) but not that elicited by furosemide infusion (26.2 +/- 1.8 mmol). Given as a bolus, furosemide natriuretic and diuretic response as a function of its urinary rate of excretion exhibited an hyperbolic relationship, and after its infusion a clockwise hysteresis, denoting tolerance. Plasma renin activity was increased by the bolus and the infusion of furosemide, even in the presence of 121 ml/h of fluid replacement. It is concluded that: 1) the increase in natriuretic/diuretic efficiency of the bolus induced by fluid replacement is greater than when furosemide is infused, 2) furosemide net effect does not increase proportionally to fluid replacement, and 3) the infusion of furosemide prevents the hypoalbuminemia-induced decrease in response of furosemide given as a bolus.     

Response to furosemide during dehydration with and without naproxen pretreatment of kidney donors and renal transplant recipients

Summary The response to 40 mg furosemide p.o. in 6 healthy kidney donors and 6 renal transplant recipients with and without naproxen pretreatment has been studied. No volume replacement was given in order to study the development of tolerance. The subjects showed an average dehydration of 1.5 kg · 6 h^–1.While mean creatinine clearance was equal in patients and donors (76 vs 80 ml/min), renal furosemide clearance was significantly lower in the patients (47 vs 81 ml/min; P<0.05). The patients also excreted a smaller fraction of the dose in the urine (5.7 vs 7.8 mg/6 h; P<0.05). As the overall renal sensitivity was similar in the two groups, the natriuretic response was correspondingly smaller in transplant recipients as compared to donors.Within the observation period of 6 h after dosing, acute tolerance developed in the donors and in 4 of the 6 patients, as shown by clockwise hysteresis in the dose (urine furosemide excretion rate)-response (natriuresis) curves. Pretreatment with naproxen reduced renal sensitivity to furosemide (right shift of the dose response curve) in all the donors but in only 2 of the patients.In both groups acute tolerance was less pronounced after naproxen, which may indicate involvement of the prostaglandin system in the development of acute tolerance. The results may also indicate regeneration of sympathetic nerves with functional capacity in at least some renal transplants, or that other mechanisms of salt regulation compensate for loss of sympathetic nerve activity.     

Pharmacokinetics and pharmacodynamics of furosemide in protein-calorie malnutrition

The influence of dietary protein deficiency on pharmacokinetics and pharmacodynamics of furosemide was investigated after iv bolus (1 mg/100 g) and oral (2 mg/100 g) administration of furosemide to male Sprague-Dawley rats fed on a 23% (control) or a 5% (protein-calorie malnutrition: PCM) protein diet ad lib.for 4 weeks. After iv administration, the mean values of CL _R , V _{ss, and the percentages of dose excreted in 8-hr urine as furosemide were increased 81, 31, and 61%, respectively, in PCM rats when compared with those in control rats, however}, CL _NR was 54% decreased in PCM rats. The decreased CL_NR in PCM rats suggested the significantly decreased nonrenal metabolism of furosemide. The urine volume per g kidney after iv administration was not significantly different between the two groups of rats although the amount of furosemide excreted in 8-hr urine per g kidney increased significantly in PCM rats. The diuretic, natriuretic, kaluretic, and chloruretic efficiencies reduced significantly in PCM rats after iv administration. After oral administration, the extent of bioavailability increased considerably from 27.6% in control rats to 47.0% in PCM rats, probably as a result of decreased gastrointestinal and hepatic first-pass metabolism. This was supported by a tissue homogenate study; the amount of furosemide remaining per g tissue after 30-min incubation of 50 g of furosemide with the 9000 × gsupernatant fraction of stomach (42.4 vs. 47.9 g) and liver (41.4 vs. 45.9 g) homogenates increased significantly in PCM rats. No significant differences in CL_R and t_1/2 were found between the control and the PCM rats after oral administration. The 24-hr urine volume and the amount of sodium excreted in 24-hr urine per g kidney increased significantly in PCM rats, and this might be due to a significantly increased amount of furosemide reaching the kidney excreted in urine per g kidney.This work was supported in part by a research grant from the Korea Science and Engineering Foundation, 1990–1992.     

Renal clearance of digoxin in man after sodium loading or furosemide treatment

Summary To evaluate the influence of different types of natriuresis on the renal clearance of digoxin (Cl_dig) and the Cl_dig/Cl_cr ratio, studies were performed in which sodium-depleted patients were placed on a moderately high sodium diet for 6 days. In another group natriuresis was evoked by furosemide. In the first study, in 10 patients, there was a 10-fold increase in Na excretion and a small rise in diuresis (V) and Cl_cr, which was accompanied by an increase in Cl_dig from 57.5±32, and 60.7±27.3 (duplicate measurements) to 103.9±55.4 (p<0.01) and 103.8±46.5 ml min^–1 (p<0.01). Cl_dig/Cl_cr rose from 0.60±0.24 and 0.61±0.16 to 0.91±0.31 and 0.91±0.21, respectively (bothp<0.005). Serum digoxin concentration declined from 1.24±0.35 and 1.19±0.40 to 1.02±0.35 and 0.97±0.32 µg/l (bothp<0.01) during the high sodium diet. In the furosemide — induced natriuresis (6 patients), changes in Na excretion and V were a multiple of those caused by Na loading, but the Cl_dig/Cl_cr ratio was not increased. The results are in accordance with the concept of digoxin backdiffusion in the proximal tubules, which is dependent on proximal Na reabsorption. In the more distal segments of the nephron, where the action of furosemide occurs, there does not appear to be any transtubular movement of digoxin.     

Role of dopamine1-receptors in mediating renal responses to furosemide in the rat.

1. Dopamine (DA) infusion enhanced the diuresis, natriuresis and kaliuresis evoked by furosemide, but this increase was significantly lower in the presence of SCH 23390, a selective DA1-dopaminergic antagonist. 2. Water, Na+ and K+ excretion induced by furosemide were reduced by haloperidol, and SCH 23390, whereas they were not affected by +/- sulpiride, a preferentially DA2-dopaminergic antagonist. 3. The treatments used did not modify the mean blood pressure during the experiments. 4. Our data show that renal responses to furosemide are attenuated by the DA1-dopaminergic antagonist. It is possible that endogenous DA, stimulating DA1 receptors in the rat kidney may be an important factor involved in the Na+, K+ and water excretion evoked by furosemide.     

Comparison of the short-term effects of the loop diuretic piretanide and furosemide in patients with renal insufficiency

Summary The natriuretic effect of the new loop diuretic piretanide was investigated in patients with severe renal insufficiency and was compared with that of furosemide. In the first study 4 hospitalized patients (serum creatinine 407 to 1220 µmol/l) were examined after administration of piretanide (12, 24, 48 and 96 mg to two patients, and 24, 48, 96 and 192 mg to 2 other subjects, given every third day). In the second study 6 hospitalized patients (serum creatinine 194 to 698 µmol/l) were studied after receiving orally 2 different doses of piretanide and 2 different doses of furosemide orally, given every fourth day. The mean natriuretic effect of 48 mg and 96 mg piretanide was 250 and 340% of the control value for the entire group, and 311 to 480% in the subgroup of patients with serum creatinine below 530 µmol/l. For a given dose the natriuresis was inversely correlated with renal function, and at a given serum creatinine level the natriuretic response was dose-dependent. The drug had less effect on water and potassium diuresis than on natriuresis. No significant difference in natriuretic effect was found on comparison with furosemide given in the ratio furosemide: piretanide 3.33:1. The pharmacokinetic data showed a direct correlation between the dose and the mean plasma concentration and also between urinary recovery of the drug and the measured natriuretic response.     

Natriuretic and diuretic effects of cicletanine in conscious,hydrated, normotensive rats

The natriuretic and diuretic actions of cicletanine, a novel agent with vasorelaxant and antihypertensive properties, were examined in conscious, hydrated, normotensive rats. Cicletanine, the (+)- and (?)-enantiomers of cicletanine, hydrochlorothiazide (HCTZ), or vehicle(s) were administered orally or intravenously (1, 3, 10, 30 mg base/kg) to water-loaded (27 ml/kg) rats and 3 hr urine volume, Na⁺ and K⁺ were measured. Racemic cicletanine (3 mg/Kg, p.o.) caused a significant increase in urinary Na⁺(+174%) and K⁺ (+46%) excretion, unaccompanied by diuresis. Diuresis was detected only with larger oral doses of racemic cicletanine (10–30 mg/kg). Oral administration of a 1-mg/kg dose of (+)-cicletanine caused significant natriuresis that was not detected with either racemic or (?)-cicletanine. The (+)-enantiomer (3–30 mg/kg) produced natriuresis and diuresis quantitatively similar to that of racemic cicletanine. By contrast, (?)-cicletanine induced only slight natriuresis, kaliuresis, and diuresis upon administration of the largest dose (30 mg/kg, p.o.). Intravenous administration of the racemate and enantiomers of cicletanine caused natriuretic/diuretic activity that was very similar to that seen with oral administration. The natriuresis caused by a 3-mg/kg dose of racemic cicletanine was unaffected by indomethacin. However, indomethacin attenuated the natriuresis and eliminated the diuresis produced by the 10- and 30-mg/kg doses of cicletanine. Indomethacin had no effect on the kaliuretic actions of cicletanine. Indomethacin blunted the natriuresis and eliminated the diuresis caused by all doses of HCTZ. In conclusion, the natriuretic, kaliuretic, and diuretic effects of racemic cicletanine in the conscious, hydrated, normotensive rat appear to be mediated primarily by the ( + )-enantiomer. A dose-dependent separation exists between the natriuretic and diuretic actions of cicletanine, with only natriuresis noted at smaller doses. The natriuresis caused by racemic cicletanine has both indomethacin-resistant and indomethacin-sensitive components, while cicletanine-induced diuresis appears to be mediated exclusively by prostaglandins.     

Comparison of the effects of muzolimine and furosemide in patients with end-stage renal failure on chronic dialysis

Summary The pharmacodynamic effects of muzolimine and furosemide were compared in a single dose cross-over study in 8 patients on regular dialysis treatment, who had a residual diuresis of more than 300 ml/day. The study periods comprised two dialysis-free intervals of 3 days. On the second dialysis-free day either muzolimine 240 mg or furosemide 240 mg was administered orally. Urine was collected in 12-h periods on the pre-treatment, treatment and post-treatment days, and the excretion of sodium, potassium, urea and creatinine were measured. After administration of muzolimine 240 mg urine volume rose to twice that of the previous day, and sodium excretion increased approximately threefold. In contrast, the effect of furosemide 240 mg was not as pronounced; the diuresis was only 1.6 times that on the previous day and natriuresis was only 2.2 times as large. Excretion of potassium and creatinine was only slightly increased by either substance. The elimination of urea was increased by both substances to the same degree as the corresponding increase in diuresis.     

Diuretic effect of NG-nitro-l-arginine methyl ester in the rat

Abstract— Intravenous infusion of the nitric oxide synthase inhibitor N^G-nitro-l -arginine methyl ester, l -NAME (10 μg kg^?1 min^?1), to anaesthetized rats produced a diuresis and natriuresis. By contrast, infusion of the same dose of N^G-nitro-d -arginine methyl ester had no effect on either urine output or sodium excretion. The effects of l -NAME were first evident 120 min after the start of infusion and by 170 min a fivefold increase in urine volume and sodium excretion was recorded. l -NAME also produced a transient fall in inulin clearance and a persistent decline in renal blood flow. These renal effects of l -NAME were associated with a gradual elevation of mean arterial blood pressure, although this only attained statistical significance, in comparison with saline-infused animals, 170 min after the start of infusion. The findings indicate the diuresis and natriuresis evoked by l -NAME in the rat is a result of a direct tubular action together with a pressure diuresis.     

Diuretic effects of a novel uricosuric antihypertensive S-8666 in rats,mice, monkeys,and dogs: Comparison with furosemide and trichlormethiazide

Oral dose-response relationships of S-8666 to Na excretion were established in male and female Sprague-Dawley rats (3–100 mg/kg), male and female ddy mice (3–300 mg/kg), female cynomolgus monkeys (2–50 mg/kg), and female beagle dogs (3–100 mg/kg). The natriuretic potency of S-8666 was almost comparable to that of furosemide in rats but was lower in mice, monkeys, and dogs. The maximal effects were similar for S-8666 and furosemide, which had higher ceiling values than trichlormethiazide (TCM) in rats, mice, monkeys, and dogs. Thus, S-8666 seems to have a “loop diuretic” property like furosemide. After oral administration of S-8666 to rats (20–100 mg/kg), the onset of natriuresis was rapid, with the peak effect occurring within 1–2 hr. TCM showed a longer lasting pattern of natriuresis than S-8666 and furosemide. With intravenous administration (1–10 mg/kg) to rats, the t_1/2 for natriuresis was 16–20 min for S-8666 and furosemide in rats. S-8666 showed enantioselectivity; its (S)-(–)-form was natriuretic, whereas the (R)-(+)-form was inactive. These results indicate that S-8666 is a diuretic with a high ceiling property that has a lower potency than TCM and a longer lasting effect than furosemide.     

The influence of food intake on the effect of two controlled release formulations of furosemide

Differences in the urinary excretion rate of furosemide may explain discrepancies observed between the bioavailability and the total diuretic effect of different formulations of this drug. Furosemide was given at a dose of 60 mg as two oral controlled release (CR) formulations (FR and LR), with and without breakfast, in a randomized, four-treatment, four-period, crossover design to 28 healthy volunteers. Urinary volume, and contents of furosemide and sodium, were measured in samples taken over 24 h. The extent and rate of absorption of furosemide from FR were decreased after breakfast as compared to fasting: the mean (SD) of total furosemide excreted decreased from 11.38 (3.12) to 7.73 (1.67) mg, p<0.0001, and the median (range) mean residence time increased from 6.3 (4.1–9.3) to 9.5 (5.9–11.8) h, p <0.001. On the other hand, the extent of absorption of LR was increased after breakfast, from 8.04 (3.32) to 9.45 (1.83) mg, p <0.05, without a significant change in MRT. FR had a higher extent and rate of absorption than LR during fasting, but its extent of absorption was lower than that of LR in the postprandial state. Interestingly, the total fraction of furosemide absorbed, as estimated from total furosemide excretion, was not correlated with the total diuresis (r² = 0.079) and the differences in drug response compared among the four periods were much smaller than would be expected from the differences in amount absorbed. This discrepancy may be explained by differences in urinary excretion rate of furosemide and, related to this, differences in efficiency profiles between the four treatments. Therefore, the urinary excretion profile of a formulation of furosemide may be more important for the cumulated drug effect than the amount absorbed.     

Pharmacological properties of the novel highly potent diuretic 7-chloro-2,3-dihydro-1-(2-methylbenzoyl)-4(1H)-quinolinone 4-oxime-O-sulfonic acid potassium salt.

7-Chloro-2,3-dihydro-1-(2-methylbenzoyl)-4(1H)-quinolinone 4-oxime-O-sulfonic acid potassium salt (M17055, CAS 114417-20-8) showed potent diuretic and saluretic effects dose-dependently, in rats (p.o.), mice (p.o.) and dogs (i.v.), at doses of 0.1-100 mg/kg, 0.3-100 mg/kg and 0.01-30 mg/kg, respectively. The efficacy of M17055 for diuresis, natriuresis and chloruresis was much higher than that of hydrochlorothiazide and almost the same as that of furosemide. These results indicate that this compound may be classified as a "high ceiling diuretic". The potencies of M17055 for natriuresis in rats (p.o.), mice (p.o.) and dogs (i.v.) calculated with ED50 values were 38, 34 and 24 times, respectively, more potent than those of furosemide. Urinary excretions of sodium, chloride and potassium increased in parallel with urinary volume with the administration of M17055 or furosemide, whereas an apparent dissociation with urinary calcium and sodium excretion was observed with M17055 alone. In rats, the increase of urinary calcium excretion with M17055 was significantly lower than that with furosemide under comparable conditions of natriuresis. Moreover, in mice, M17055 decreased urinary calcium excretion at doses with low effectiveness. In clearance studies using anesthetized dogs, M17055 suppressed negative free water clearance (CH2O) under saline loaded conditions, and it decreased positive CH2O under water diuretic conditions. These changes in the effects on CH2O induced by M17055 resemble those of loop diuretics. However, M17055 could not shift negative CH2O to positive, while furosemide was able to do so. Moreover, positive CH2O decreased to nearly zero with M17055, while urine remained dilute with furosemide even at 30 mg/kg.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

Potassium-sparing effect of amiloride in a diuretic factorial study in man

1. The effects of amiloride (M, 20 mg/day), chlorothiazide (C, 1000 mg/day), ethacrynic acid (E, 100 mg/day) and frusemide (F, furosemide 80 mg/day), given alone and in combination, were investigated in eight patients in a 2⁴ factorial study. Effects between blocks of four treatments in each sixteen-treatment replicate were confounded with higher interactions to allow for differences between early and late diuresis. 2. All patients exhibited marked diuresis, with significant mean increases in daily urinary sodium excretion (P < 0·05) and urinary volume (P < 0·01) induced by chlorothiazide, frusemide and ethacrynic acid (68, 69 and 38%; and 35, 40 and 34%, respectively). Amiloride appeared to be half to one-third as potent as the other diuretics. 3. Amiloride produced a significant potassium-sparing effect (P < 0·01), reducing urinary potassium excretion by 30%, compared to significant urinary potassium wasting with frusemide (increase of 33%, P < 0·01) and chlorothiazide (increase of 31%, P < 0·05). 4. No adverse reactions occurred, but serum potassium levels twice rose to 6 mmol/l and subsided without additional therapy, and on one occasion fell to 2·5 mmol/l, requiring a potassium supplement for 4 days. 5. It was concluded from these factorial studies that amiloride is a mild diuretic and potent potassium-sparing agent acting independently and additively in combination with chlorothiazide, ethacrynic acid or frusemide. For the three latter diuretics, all two-drug interactions were simply additive also, without evidence of synergism or antagonism between drugs.     

Indomethacin differentiates the renal effects of sphingosine-1-phosphate and sphingosylphosphorylcholine

The sphingomyelin breakdown products sphingosine-1-phosphate (S1P) and sphingosylphosphorylcholine (SPC) constrict intrarenal microvessels in vitro in a pertussis toxin (PTX) sensitive manner, and S1P also reduces renal blood flow in vivo. Nevertheless, both S1P and SPC have been reported to enhance diuresis and natriuresis. This pattern is similar to that of neuropeptide Y, which also reduces renal blood flow and enhances diuresis and natriuresis. The latter effects are inhibited by the cyclooxygenase inhibitor indomethacin, and various S1P and SPC responses have also been linked to the cyclooxygenase pathway. Therefore, we have investigated whether indomethacin can alter the renal effects of S1P and SPC in anaesthetised rats in vivo. In line with earlier experiments S1P bolus injections dose-dependently reduced renal blood flow (by up to 4.8±0.5 ml min⁻¹), and this was not significantly affected by indomethacin treatment (5 mg kg⁻¹ i.p.). Infusion of S1P but not of SPC (30 μg kg⁻¹ min⁻¹ each) for 60 min reduced renal blood flow by up to 0.8±0.2 ml min⁻¹, and this was not markedly altered by indomethacin. Despite the differential renovascular effect, both S1P and SPC enhanced diuresis by up to 215±65 and 201±58 μl 15 min⁻¹ respectively, and natriuresis by up to 25±9 and 29±11 μmol 15 min⁻¹ respectively. While indomethacin abolished the SPC-induced diuresis and natriuresis, it, if anything, slightly enhanced the diuretic and natriuretic effect of S1P. To determine whether tubular SPC effects are receptor-mediated, PTX experiments were performed. SPC-induced enhancements of diuresis and natriuresis were abolished by PTX. We conclude that S1P, SPC and neuropeptide Y exhibit distinct patterns of modulation of renal function and that indomethacin allows such effects to be differentiated.     

Renal effects of the high ceiling diuretic torasemide in rats and dogs

The mode of action of torasemide was investigated by clearance experiments in dogs and rats. In the dog, torasemide (1 mg/kg i.v.) had no significant effect on glomerular filtration rate (GFR) but increased p-aminohippuric acid (PAH) clearance by 16% (p less than 0.01). In the rat both GFR and PAH clearance were significantly decreased, on an average 8-17%, by torasemide infused in the dose range of 1 to 20 mg/kg i.v. After i.v. injection the onset of diuresis was observed within 5 to 10 min and peak effect within 20 to 40 min in the rat and within 40 to 60 min in the dog. Fractional water and sodium excretions of nearly 25% were obtained in the rat with a dose of 8 mg/kg i.v. At equipotent doses, torasemide and furosemide induced similar diuretic and natriuretic effects in function of time in the rat. In the dog the effects lasted much longer with torasemide than with furosemide. This difference can be related to the longer half-life (about 8 h) of torasemide in the dog. In both species significant differences could be noted between torasemide and furosemide with respect to the time course of their effects on the urinary excretion of potassium. From the first experimental hour on, torasemide proved to be significantly less kaliuretic than furosemide as shown by increased Na/K ratios, during the third experimental hour they reached 20.5 vs 9.9 in the dog and 11 vs 7.5 in the rat with torasemide and furosemide, respectively. In hydropenic dogs, free water reabsorption was significantly reduced with torasemide and osmolar clearance significantly increased.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects Of L-Arginine And Furosemide On Blood Pressure And Renal Function In Volume-Expanded Rats

1. The aim of the present study was to investigate the effects of L-arginine (L-Arg) on blood pressure and water and electrolyte excretion in control and extracellular fluid volume-expanded rats (10% bodyweight with 0.9% NaCl) and to determine whether diuretic treatment with furosemide (FUR) can be optimized by the administration of L-Arg in this model. 2. Both groups of animals were anaesthetized, divided into groups and treated with either 7.5 mg/kg FUR, 250 mg/kg L-Arg, 1 mg/kg NG-nitro-L-arginine methyl ester (L-NAME), FUR + L-NAME or FUR + L-Arg. Mean arterial pressure (MAP), diuresis, natriuresis and kaliuresis were determined. 3. Extracellular fluid volume expansion induced no changes in MAP in control and volume-expanded rats (92+/-6 vs 100+/-8 mmHg, respectively). The hypotension induced by FUR in control and volume-expanded rats (69+/-7 and 76+/-5 mmHg, respectively) was significantly (P < 0.01) enhanced by the administration of L-Arg (54+/-3 and 64+/-3 mmHg, respectively). 4. Injection of L-NAME increased MAP and diminished diuresis, natriuresis and kaliuresis in both groups. 5. Furosemide-induced water and electrolyte excretion was blunted by the administration of L-NAME. 6. The combination of L-Arg + FUR increased diuresis induced by FUR alone (control rats: 29.33+/-1.68 vs 12.91+/- 0.41 microL/min per 100 g, respectively; volume-expanded rats: 248.5+/-25.4 vs 112,6+/-8.3 microL/min per 100 g, respectively; P < 0.01). 7. The administration of the combination of L-Arg + FUR promoted a decrease in the sodium/water excretion ratio compared with the administration of FUR alone (control rats: 0.230+/-0.018 vs 0.45+/-0.03, respectively, P < 0.001; volume-expanded rats: 0.091+/-0.010 vs 0.22+/-0.03, respectively, P < 0.01). 8. The potassium/water excretion rate induced by FUR alone and in the presence of L-Arg followed a pattern similar to that seen for natriuresis (control rats: 0.35+/-0.05 vs 0.20+/-0.05 microEq/min per 100 g, respectively; volume-expanded rats: 0.045+/-0.008 vs 0.014+/-0.003 microEq/min per 100 g, respectively; P < 0.01). 9. The decrease in the electrolyte/water excretion ratio observed with FUR + L-Arg in volume-expanded rats was greater than in control animals. 10. The results of the present study show that the administration of FUR with L-Arg contributes to enhanced hypotensive and diuretic effects of FUR, thus diminishing the relative electrolyte excretion in normal conditions and in extracellular fluid volume expansion.     

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.