Diuretic action of the novel loop diuretic torasemide in the presence of angiotensin II or endothelin-1 in anaesthetized dogs.

The effects of torasemide (0.1 and 1 mg kg-1, i.v.) and furosemide (3 mg kg-1) on renal haemodynamics and excretory responses in the presence of angiotensin II and endothelin-1 was examined in anaesthetized dogs. Angiotensin II or endothelin-1 was continuously infused into the renal artery throughout the experiment and a bolus of torasemide or furosemide was injected into the bracheal vein. Continuous intrarenal arterial (i.r.a.) infusion of angiotensin II, at a dose of 5 ng kg-1 min-1, increased renal vascular resistance (RVR) and decreased renal blood flow (RBF) and glomerular filtration rate (GFR), but had no effect on systemic mean arterial pressure (MAP). Urinary excretion of sodium (UNaV) and urine flow (UF) were significantly decreased during angiotensin II infusion. Intravenous injections of torasemide in the presence of angiotensin II caused a dose-dependent increase in UF, UNaV and urinary excretion of potassium (UKV), while a decrease in RVR was accompanied by an increase in RBF. UKV was greater in the furosemide group than in the torasemide group, despite both groups having the same degree of aquaresis and natriuresis. Continuous i.r.a. infusion of endothelin-1, 1.5 ng kg-1 min-1, produced effects similar to those of angiotensin II on renal haemodynamics; however, the onset of action was extremely slow compared with the effects produced by angiotensin II. Endothelin-1 caused a significant decrease in UF, UNaV and UKV only at a later period, despite a relatively early depression of renal haemodynamics. Torasemide and furosemide also produced a sufficient diuretic action in this model.(ABSTRACT TRUNCATED AT 250 WORDS)     

Diuretic and hypotensive actions of torasemide in hypertensive models of rat

The diuretic and the antihypertensive actions of torasemide were examined in renal and genetic hypertensive rats and compared to the effects of furosemide. Oral administration of torasemide (1 and 3 mg/kg) elicited a dose-dependent increase in the excretion of urine and electrolytes and elevated the urinary Na/K ratio in both renal and genetic hypertensive rats. Torasemide and furosemide had a similar maximum diuretic effect in the normotensive Wistar rat and the spontaneously hypertensive rat (SHR). However, the diuretic activity of furosemide was weaker in the renal hypertensive rat (RHR). Torasemide showed approximately 30 times greater diuretic potency than furosemide. Torasemide and furosemide demonstrated hypotensive action in hypertensive rat models, but not in the normotensive Wistar rat. Especially in the RHR, torasemide exhibited a more potent hypotensive action than furosemide. These results show that the diuretic and antihypertensive activities of torasemide are effective in various rat models of hypertension, while the diuretic activity of furosemide is weak in certain hypertensive rat models. © 1992 Wiley-Liss, Inc.     

Renal effects of torasemide in the rat. Clearance and micropuncture studies

The effects of torasemide on renal glomerular and tubular functions were studied in rats using clearance and micropuncture techniques. A dose-response relationship of torasemide in the range of 0.2-20 mg/kg b.w. on the increase of urine volume, urinary sodium and potassium excretion was established. The effect of a dose of 0.2 mg/kg b.w. torasemide was completely abolished by preinjection of 10 mg/kg probenecid, whereas the effects of higher doses remained unchanged. Torasemide had no significant effect on glomerular filtration rate. Proximal fractional reabsorption was not influenced. A remarkable depression of fluid and electrolyte reabsorption, however, occurred in the loop of Henle after torasemide under free flow conditions, as well as in functionally isolated microperfused loops of Henle. No further inhibition of fluid and electrolyte reabsorption between the early distal convoluted tubules and the final urine could be detected. In contrast, a compensatory increase of reabsorption was observed in this part of the nephron. The activity of the tubuloglomerular feedback system was completely and reversibly blocked by torasemide. Torasemide did not differ from other typical loop diuretics with respect to the different renal actions studied here.     

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.     

DIURETIC EFFECT INDUCED BY INTRARENAL INFUSION OF NISOLDIPINE IN ANAESTHETIZED DOGS

1. Renal effects of nisoldipine, a potent calcium channel blocker, were examined in anaesthetized dogs. 2. Intrarenal arterial infusion of nisoldipine (10, 50 ng/kg per min) did not influence mean systemic blood pressure and renal haemodynamics, but did cause dose-related increases in urine flow and urinary excretion of electrolytes. During nisoldipine infusion at the higher dose, the levels of fractional excretion of sodium, potassium and chloride were significantly elevated. 3. In the lithium clearance study, fractional lithium excretion, an index of fractional sodium excretion in the proximal tubules, was unchanged even with the higher dose of nisoldipine, whereas fractional sodium excretion in the distal tubules markedly increased. 4. Nisoldipine elicited a significant increment in osmolar clearance without altering the reabsorption of free water. 5. Thus, intrarenal administration of nisoldipine at a non-hypotensive dose to anaesthetized dogs produced a significant diuretic effect without alteration in renal haemodynamics. Results in lithium clearance and free water clearance studies suggest that nisoldipine exerts a diuretic action by inhibiting sodium transport at the distal nephron segments beyond the proximal tubules.     

Pharmacological properties of the new potent diuretic torasemide in rats and dogs

Torasemide, a pyridine-3-sulfonylurea derivative, has potent diuretic activity in rats and dogs. In both species urinary volume and electrolyte excretion increased linearly with the logarithm of the dose, thus resembling the profile of a high ceiling diuretic. The minimum effective dose by oral route was 0.2 mg/kg in the rat and less that 0.1 mg/kg in the dog. Maximal effect was obtained with about 10 mg/kg. Experiments by oral and i.v. routes in the rat indicated that torasemide was equally potent by both oral and parenteral administration. In both rats and dogs, urinary excretions induced by torasemide were similar to those obtained with furosemide. However, for the same natriuretic effect, potassium losses with torasemide were significantly less than with furosemide. On a weight basis, torasemide was 9-40 times more potent than furosemide in the rat and about 10 times in the dog. After oral administration the diuretic effects of torasemide started within 20 min and lasted approximately 2 h in the rat and more than 8 h in the dog. The activity of torasemide was not decreased after a repeated daily oral dose of 10 mg/kg for 15 days in the rat. Torasemide at a daily oral dose of 5 mg/kg for 12 days effectively reduced the arterial blood pressure in desoxycortone induced hypertension in the rat. Besides the diuretic and antihypertensive effects no other significant pharmacological effects were observed with torasemide in the different in vitro and in vivo experiments. Torasemide was practically fully absorbed by the gastrointestinal tract, its bioavailability by oral route ranged from 80 to 100%.(ABSTRACT TRUNCATED AT 250 WORDS)     

Uricosuric and diuretic activities of DR-3438 in dogs and rabbits

The purpose of this study was to evaluate the uricosuric and diuretic properties of the new diuretic agent DR-3438. In the conventional clearance studies in urate-loaded dogs, intravenous injection of DR-3438 (3-30 mg/kg) resulted in dose-related increases in fractional excretion of urate (FEua), urine flow and sodium excretion. At doses causing similar natriuresis, tienilic acid (50 mg/kg, i.v.) markedly increased the FEua value, whereas indacrinone (1 mg/kg, i.v.) had no significant effect on it. Trichloromethiazide (1 mg/kg, i.v.) and furosemide (0.3 mg/kg, i.v.) tended to decrease the FEua. Thus, the uricosuric activity of DR-3438 (30 mg/kg) was 0.6-fold that of tienilic acid and 3.4-fold that of indacrinone. In contrast, in urate-loaded rabbits that exhibit net tubular secretion of urate, intravenous DR-3438 (30 mg/kg) produced a significant decrease in FEua. Stop-flow studies in dogs revealed that DR-3438 (30 mg/kg) blocks both urate reabsorption and p-aminohippurate secretion in the proximal segment of the nephron and strongly inhibits reabsorption of water, sodium and potassium in the distal segments. These results suggest that DR-3438 exerts uricosuric activity through blocking urate transport in the proximal tubules and diuretic and saluretic activities by inhibiting water and sodium reabsorption in the distal segment of the nephron.     

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)     

Torasemide (LUPRAC): a review of its pharmacological and clinical profile

Loop diuretics potently excrete water and electrolytes and therefore have been widely prescribed for the treatment of various kinds of edema for a long time. The potent diuretic action of loop diuretics, however, often causes hypokalemia, and therefore potassium sparing diuretics have also been supplied as a concomitant drug. Torasemide (LUPRAC), a novel diuretics, shows not only an effective loop diuretic action but also a potassium sparing action due to its anti-aldosteronergic effect. Torasemide also has a high bioavailability and is only slightly influenced by meals in humans. In addition, its pharmacodynamic features contribute to its stable diuretic action without any individual differences. In animal experiments, torasemide showed about a tenfold more potent diuretic action in comparison with furosemide, an authentic loop diuretic. On the one hand, the increase in the urinary potassium excretion by torasemide was relatively slight compared to the increase in urinary sodium excretion and, as a result, the urinary sodium to potassium (Na+/K+) ratio increased. The diuretic profile of torasemide was equal to that of the concomitant use of furosemide and an anti-aldosteronergic drug, spironolactone. Torasemide showed a significant efficacy and safety in comparison with furosemide in the patients with edema in both domestic and foreign clinical studies. Moreover, torasemide also showed a decreased rate of cardiac death in comparison to furosemide in patients with chronic heart failure in a large-scale clinical study (TORIC Study). The difference in cardiac death between these two diuretics has been suggested to depend on the anti-aldosteronergic effect of torasemide. In Japan, no new loop diuretics have been developed in over 10 years. Torasemide is therefore expected to be useful as an effective diuretic for diseases with edema.     

Anti-aldosteronergic effect of torasemide.

The diuretic actions of torasemide and furosemide were studied in normotensive rats and in deoxycorticosterone acetate (DOCA)-saline-loaded hypertensive rats. Torasemide (0.3-3 mg/kg) and furosemide (3-30 mg/kg) had a dose-dependent and significant diuretic action in normotensive rats. Potassium retention was only observed in the case of torasemide. Torasemide also had a dose-dependent and significant diuretic action in DOCA-saline-loaded hypertensive rats, whereas furosemide did not. Higher doses of torasemide (10 mg/kg) and furosemide (100 mg/kg) increased both plasma renin activity and aldosterone concentration in normotensive rats in a similar manner. In vivo aldosterone receptor binding was determined to test the possible anti-aldosteronergic effect of torasemide. Torasemide inhibited the binding of aldosterone to its receptor in the cytoplasmic fraction of rat kidney in a dose-dependent manner, while furosemide produced no effect. These results suggest strongly that an anti-aldosteronergic action of torasemide contributes to producing less kaliuresis.     

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.     

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.     

Diuretic action of metolazone in dogs.

Metolazone, the sulfonamide diuretic was investigated to determine the sites of action. We used a radioactive microsphere, clearance and stop-flow method in anesthetized dogs. Urine flow and urinary excretion of sodium and potassium were increased at 5--60 min when metolazone was given intravenously at doses of 0.2--5.0 mg/kg, while total renal blood flow, distribution of cortical renal blood flow and GFR did not change. The urinary excretion rate of sodium to potassium (Na/K) increased from 5.69 +/- 0.82 to 8.07 +/- 0.76 in a dose of 1.0 mg/kg, i.v. Osmolar clearance and free water reabsorption increased almost proportionally, indicating that metolazone has little effect on the medullary portion of the ascending limb of Henle and may have a proximal site of action. In stop-flow experiments, a significantly raised U/PNa/U/Pcreatinine was observed at the dip situated distally to the ascending limb of Henle. These findings indicate that the diuretic action of metolazone may be due to the inhibition of sodium reabsorption in the distal nephron segments, in addition to the absence of modification of the cortical regional blood flow.     

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.     

Effects of furosemide on the tubular reabsorption of nitrates in anesthetized dogs.

The present study was performed to determine the tubular sites of nitrite and nitrate (NO) reabsorption and the effects of furosemide on the renal handling of NOx in anesthetized dogs, using renal clearance and stop-flow methods. Furosemide (2 mg/kg, i.v.) increased the urinary excretion rates of Na+ (U(Na+)V) and NOx (U(NOx)V) with a reduction of tubular reabsorption rates of Na+ and NOx. During inhibition of renal nitric oxide (NO) synthesis by an intrarenal infusion of L-nitro arginine (30 microg/kg-min), furosemide also increased U(NOx)V and decreased tubular reabsorption rate of NOx from 96.5+/-0.8% to 86.6+/-1.7%. An intravenous infusion of 10% mannitol (0.5 ml/kg-min) also increased both U(Na+)V and U(NOx)V. In addition, after furosemide administration or mannitol infusion. U(NOx)V was correlated with U(Na+)V. In stop-flow experiments, the distal dip in NOx curve was observed and the site of the dip in NOx curve was identical to that of Na+ curve. Furosemide shifted upward the U/P(Na+)/U/P(Cr) and U/P(NOx)/U/P(Cr) at the distal dip, indicating inhibition of Na+ and NOx reabsorption at distal tubules. These results indicate that more than 96% of the filtered NOx is reabsorbed in the renal tubules, and that the tubular handling of NOx is very close to that of Na+. In addition, the stop-flow experiments demonstrate that furosemide inhibited the reabsorption of NOx as well as Na+ at the distal tubule.     

Torasemide. A review of its pharmacological properties and therapeutic potential.

Torasemide (torsemide) is a high-ceiling loop diuretic which acts on the thick ascending limb of the loop of Henle to promote rapid and marked excretion of water, sodium and chloride. Like furosemide (frusemide), its major site of action is from the luminal side of the cell. Torasemide is at least twice as potent as furosemide on a weight-for-weight basis, produces equivalent diuresis and natriuresis at lower urinary concentrations and has a longer duration of action, allowing once-daily administration without the paradoxical antidiuresis seen with furosemide. Torasemide also appears to promote excretion of potassium and calcium to a lesser extent than furosemide. In trials of up to 48 weeks' duration in patients with mild to moderate essential hypertension, torasemide, administered as a single daily dose, has been shown to achieve adequate blood pressure control reaching steady-state within 8 to 12 weeks. Those patients not responding initially have generally responded to a doubling of the dose. Comparative trials of up to 6 months show torasemide is as effective as indapamide, hydrochlorothiazide or a combination of triamterene/hydrochlorothiazide in maintaining control of blood pressure. Torasemide has also been used successfully to treat oedematous states associated with chronic congestive heart failure, renal disease and hepatic cirrhosis. In short term trials control of blood pressure, bodyweight and residual oedema has been sustained. Torasemide appears to be a useful alternative to furosemide in these patients, providing potent and long-lasting diuresis while being relatively potassium and calcium sparing. In clinical trials to date torasemide has been well tolerated with adverse effects of a mild, transient nature reported by only small numbers of patients. Changes in biochemical parameters have been common, including decreases in plasma sodium and potassium levels and increases in plasma creatinine and uric acid levels. These changes are typical of loop diuretics. No changes were clinically significant nor were clinically relevant changes noted in glucose metabolism, cholesterol or triglyceride levels or in haematological values. Thus, torasemide is an interesting new loop diuretic with potential use in the treatment of mild to moderate essential hypertension and of oedematous states in which diuretic therapy is warranted. Preliminary studies suggest it to be as efficacious as other diuretics in common use and to have some advantage over furosemide in duration of action and in effects on potassium and calcium. However, further long term trials in larger groups of patients are needed to delineate the place of torasemide in therapy fully, both as a single agent and in combination with other currently accepted drug regimens.     

Pharmacokinetics and pharmacodynamics of intravenous trasemide in mutant Nagase analbuminemic rats

The importance of plasma protein binding of intravenous furosemide in circulating blood for its urinary excretion and hence its diuretic effects in mutant Nagase analbuminemic rats (NARs, an animal model for human familial analbuminemia) was reported. Based on the furosemide report, the diuretic effects of another loop diuretic, torasemide, could be expected in NARs if plasma protein binding of torasemide is considerable in the rats. This was proven by this study. After intravenous administration of torasemide, 10 mg/kg, to NARs, the plasma protein binding of torasemide was 23.3% in the rats due to binding to alpha- and beta-globulins (this value, 23.3%, was greater than only 12% for furosemide), and hence the percentages of intravenous dose of torasemide excreted in 8-h urine as unchanged drug was 14.9% in the rat (this value was considerably greater than only 7% for furosemide). After intravenous administration of torasemide to NARs, the AUC (301 versus 2680 microg/min/ml) was significantly smaller [due to significantly faster both Cl(r) (4.81 versus 0.386 ml/min/kg) and Cl(nr) (28.3 versus 3.33 ml/min/kg)], terminal half-life (18.3 versus 73.5 min) and mean residence time (6.97 versus 61.8 min) were significantly shorter (due to faster Cl, 33.2 versus 3.74 ml/min/kg), and amount of 8-h urinary excretion of unchanged torasemide (446 versus 323 microg, due to increase in intrinsic renal excretion) was significantly greater than those in control rats. The 8-h urine output and 8-h urinary excretions of sodium and chloride were comparable between two groups of rats although the 8-h urinary excretion of torasemide was significantly greater in NARs. This could be explained by the following. The amount of urinary excretion of torasemide was significantly greater in NARs than that in control rats only between 0 and 30 min urine collection. In both groups of rats, the urinary excretion rate of torasemide during 0-30 min reached an upper plateau with respect to urine flow rate as well urinary excretion rates of sodium and chloride. Therefore, the diuretic effects (8-h urine output and 8-h urinary excretions of sodium and chloride) were not significantly different between the two groups of 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)     

Pharmacokinetics of torasemide and its metabolites in healthy controls and in chronic renal failure

Summary The pharmacokinetics of 20 mg torasemide i.v. has been studied in 7 healthy controls and 9 patients with varying degrees of renal impairment.Torasemide had a t_1/2 of about 4 h which was independent of kidney function, as the nonrenal clearance of torasemide was 3-times greater than its renal clearance. The active metabolite M1 and the main metabolite M5 were accumulated in chronic renal failure.In contrast to liver function, therefore, kidney failure does not have an important effect on the pharmacokinetics of torasemide.     

Effects of ozolinone,a diuretic active metabolite of etozoline,on renal function

Summary The renal action of 3-methyl-4-oxo-5-piperidino-thiazolidine-2-ylidine (ozolinone), a metabolite of the diuretic etozoline (Elkapin), was studied in anaesthetized dogs after i.v. injection and compared with the renal effects of furosemide. The diuretic action of ozolinone was rapid in onset and of short duration. Thesmallest effective i.v. dose was 1 mg\kg^–1. Maximal diuretic capacity was reached at 50 mg\kg^–1 i.v. Fractional tubular sodium reabsorption was depressed to 67% at maximal effective doses.Ozolinone had similar renal actions to those of furosemide. Like furosemide, ozolinone increased renal blood flow, slightly decreased glomerular filtration rate, depressed tubular chloride reabsorption more than sodium reabsorption, increased potassium excretion, lowered the pH of urine, decreased urinary osmolarity towards isotonicity and depressed tubular PAH secretion. As regards the effective doses and the maximal changes of tubular sodium excretion, ozolinone was somewhat less potent than furosemide.