Stimulation of renal sodium excretion in mature rats.

In adult rats a saline load is followed by an increase in renal excretion of sodium and by a low rate of ion exchange (hydrogen ions and potassium for sodium), caused by inhibited aldosterone secretion. Under analogous conditions a saline load provoked sodium retention and a distinct increase in renal excretion of hydrogen ions and potassium in young rats, which can be explained by a non-regulated, very intensive ion exchange. The repeated administration of NaCl solution alone and in combination with cyclopenthiazide produced an accelerated maturation of kidney function in 10- and 33-day-old rats measurable by an increase in sodium excretion and reduced ion exchange. In adult rats as well as immediately after birth (5-day-old rats) this effect cannot be provoked by the various pretreatments acting in mature rats.

Effect of slow oxprenolol and a combination of slow oxprenolol and cyclopenthiazide on plasma lipoproteins.

The effect of slow oxprenolol on plasma lipoprotein concentrations was compared to that of combined therapy with slow oxprenolol and cyclopenthiazide. The design of the study was a double blind between patient investigation in which 9 subjects with mild hypertension received slow oxprenolol and 11 slow oxprenolol and cyclopenthiazide. Plasma lipoproteins were analysed at 0, 2, 4, 8, 12 and 16 weeks. Slow oxprenolol given alone resulted in a significant rise in plasma and low density lipoprotein (LDL) cholesterol concentration whereas combined therapy with slow oxprenolol and cyclopenthiazide produced significant rises in plasma and very low density lipoprotein (VLDL) triglyceride. If one accepts that a rise in plasma or LDL cholesterol increases atherogenic risk more than a rise in plasma or VLDL triglyceride combined therapy is preferable.

Beta adrenergic blockade and diuretic therapy in benign essential hypertension: A dynamic assessment.

Beta adrenergic receptor antagonists (beta blockers) differ greatly in their cardioselectivity and intrinsic sympathomimetic activity, and these differences may have important therapeutic consequences. We have therefore studied the effect on blood pressure, heart rate and plasma renin activity of the beta blocking drug oxprenolol (Trasicor) which has considerable intrinsic sympathomimetic activity, both alone and in combination with the benzothiadiazine cyclopenthiazide. Eleven patients with mild to moderate benign essential hypertension were randomly allocated to one of two treatment groups. Oxprenolol was given as the first drug to Group 1, and cyclopenthiazide as the first drug to Group 2. The patients were assessed before the start of treatment, after 2 to 3 weeks of treatment with one drug and after a further 2 to 3 weeks of treatment with both drugs. Heart rate, blood pressure and plasma renin activity were measured with the patients recumbent and after a standardized tilt to 85 degrees to provide a reflection of day to day cardiovascular stress. Oxprenolol reduced arterial blood pressure without inducing significant bradycardia. The addition of cyclopenthiazide had little further effect. Oxprenolol alone suppressed plasma renin activity both at rest and during tilt and also abolished the increase in plasma renin activity after administration of cyclopenthiazide. The combination of (1) moderate reduction of blood pressure. (2) inhibition of the otherwise inevitable increase in plasma renin activity with the use of a diuretic drug, and (3) only moderate inhibition of overall sympathetic activity indicates that it is possible to achieve physiologic balance with the appropriate beta blocking drug.

p-Aminohippurate (PAH) transport and Na-K-ATPase activity in rat renal cortical slices during postnatal maturation and drug-induced stimulation.

PAH transport and Na-K-ATPase activity markedly increase during the first month of postnatal life. Pretreatment of rats with PAH or cyclopenthiazide induces a stimulation of in vitro PAH accumulation in renal cortical slices, whereas Na-K-ATPase activity is unchanged in comparison to saline-pretreated controls. 5 mM ouabain in the incubation medium reduces PAH accumulation. Developmental pattern and stimulation effects are pronounced as in controls. The ouabain-insensitive component of net PAH accumulation progressively increases with age and is significantly enhanced following drug pretreatment, whereas the ouabain-sensitive component of net PAH accumulation shows relatively slight modifications. Consequently, Na-K-ATPase seems not to be linked with postnatal maturation or drug-induced stimulation in tubular PAH transport.

[Concentration of p-aminohippuric acid in the serum and kidney tissue during stimulation of renal excretion of foreign materials]. / Konzentration an p-Aminohippursäure im Serum und im Nierengewebe bei Stimulation der renalen Fremdstoffausscheidung.

The renal excretion of p-aminohippuric acid (PAH) can be stimulated in adult rats by repeated applications of probenecid, cyclopenthiazide, and phenobarbital. The present studies have shown that this pretreatment significantly shortens the half-life for PAH too. In pretreated animals the PAH concentration decreases in the renal tissue more rapidly than in the control animals. These results were obtained in adult animals only but not in 5-day-old rats, in which the pretreatment had no effect upon the rate of renal PAH excretion. The pretreatment did not change the renal weight of 5-and 55-day-old rats.

Stimulation of renal excretion of p-aminohippurate (PAH) after unilateral nephrectomy in adult and ageing rats.

Unilateral nephrectomy (UNX) is followed by a significant decrease of excreted amount of PAH in rats. In 105 and 240-day-old rats, we characterized the time course of restitution of the PAH transport process., Furthermore, we studied whether or not the regeneration of kidney function can be accelerated by repeated administration of cyclopenthiazide. After stimulation of tubular transport of PAH by repeated administration of cyclopenthiazide, the loss of one kidney after UNX can be compensated more rapidly as in nephrectomized rats without pretreatment. In 105-day-old rats the regeneration and the extent of stimulation are more marked than in 240-day-old rats.

Stimulation of kidney function in rats injured by nephrotoxic agents.

After single administration of potassium dichromate or glycerol, renal PAH excretion was markedly reduced in adult, but not in newborn and infant rats. As already demonstrated in rats with intact kidney functions, repeated administration of PAH or cyclopenthiazide stimulates also renal PAH excretion in rats with acute renal failure. In detail, after PAH or cyclopenthiazide treatment of rats the duration of injury is shortened whereas the intensity of the nephrotoxic effects is not changed. However, the stimulation depends on the age of animals as well as on the nephrotoxic agent administered.

Relation between renal and hepatic excretion of drugs. XIV. Elimination of ioglycamic acid after nephrectomy, bile duct ligation, and after treatment with hormones or xenobiotics in young and adult rats.

Ioglycamic acid (IGA) is effectively eliminated in young and adult rats via urine and bile. After administration of low doses hepatic excretion dominates whereas following high supply renal elimination surpasses biliary excretion. Hepatic transport of IGA is active, indicated by the occurrence of a transport maximum in vivo and by a distinct accumulation of this drug within liver slices in vitro. Renal removal of IGA is preferentially caused by glomerular filtration. A tubular reabsorption obviously does not occur because forced diuresis (mannitol, furosemide) does not increase renal excretion of this substance. As calculated from our clearance data and as a result of accumulation experiments in vitro on renal cortical slices the active tubular secretion of this organic anion can be excluded. In principle there are no qualitative changes in IGA elimination between the 20th and 55th day of life, but active hepatic transport of the drug is significantly lower in young, immature rats. After bile duct ligation, renal excretion of IGA increases distinctly in both age groups, whereas in adult rats bilateral nephrectomy (NX) is followed by a significant decrease in its hepatic excretion in dependence on time after kidney removal. In young rats NX is without consequences on hepatic excretion of IGA. It is possible to stimulate renal and/or hepatic excretion of IGA by repeated administration of T3, dexamethasone, or phenobarbital. The effect of stimulation is different in kidney and liver and depends on age, too.

Relation between renal and hepatic excretion of drugs: X. Excretion of nalorphine in young and adult rats pretreated with hormones or xenobiotics.

Different processes are involved in renal and hepatic excretion of organic anions and cations. In contrast to our knowledge of anion excretion, information about cation transport in kidney and liver is relatively scarce. In this study, the elimination of nalorphine was investigated to characterize the relation between renal and hepatic excretion of organic cations. Nalorphine is excreted effectively both via kidney and liver. However, its hepatic excretion dominates in adult rats. In young, 20-day-old animals biliary nalorphine elimination is immature and the excreted amounts are significantly lower. Renal excretion of nalorphine is quite similar in rats of both ages. After bile duct ligation renal excretion of nalorphine increases significantly in adult rats whereas it remains unchanged in young ones. Remarkably, after bilateral nephrectomy hepatic elimination of nalorphine is even diminished in both age groups. In further experiments renal excretion of nalorphine could be stimulated in adult rats after repeated administration of trometamol, triiodothyronine, or dexamethasone; these treatments had no consequences on biliary secretion of nalorphine.

Increase of 14C-leucine uptake following stimulation of renal tubular transport processes.

Following treatment with cyclopenthiazide, triiodothyronine or dexamethasone the renal excretion of p-aminohippurate (PAH) as well as the accumulation of PAH in renal cortical slices from adult rats and from rats with immature kidney function are increased. There are differences with respect to the age of the rats as well as in dependence on the substance used for treatment. In 10- and 60-day-old rats the [14C]leucine uptake following such a stimulation of kidney function is increased, that means active tubular transport of amino acids can also be stimulated. Furthermore, the [14C]leucine content in the protein fraction of homogenized kidney tissue is increased, indicating a higher degree of incorporation of amino acids in kidney tissue following treatment with cyclopenthiazide, triiodothyronine or dexamethasone.

[Stimulation of renal excretion of p-aminohippuric acid by repeated administration of drugs in young and adult rats]. / Stimulierung der renalen Ausscheidung von-Aminohippursäure durch wiederholte Zufuhr von Pharmaka bei jungen und erwachsenen Ratten

The velocity of renal excretion of p-aminohippuric acid (PAH) could be raised by repeated administration of phenol red, probenecid and penicillin, which are actively transported by the acid carrier into the urine like PAH. These drugs produced an effect in fairly lower doses than PAH. The renal excretion of PAH can be accelerated by repeated pretreatment with the lipid-soluble drugs sulfaclomide, sulfamethoxypyridazine and cyclopenthiazide. It could be demonstrated that the stimulation of renal excretion of PAH by repeated administration of the investigated compounds is less pronounced in young rats than in adult animals.

[Stimulation of the renal transport of foreign substances following unilateral nephrectomy]. / Stimulation des renalen Fremdstofftransportes nach unilateraler Nephrektomie.

During the phase of compensation of parenchyma loss two different mechanisms can be stated causing an improvement of renal tubular transport capacity. Besides an increase of tubular transport ratio in kidney slices from nephrectomized rats an increased mass of kidney tissue participated in the augmented transport capacity. 24 h after unilateral nephrectomy TmPAH is elevated from 0.40 +/- 0.10 to 0.61 +/- 0.13 mg/min x g kidney weight. The simultaneous increase in slice-to-medium ratio of renal cortical slices demonstrate the increase in specific transport capacity of regenerating kidney tissue. Furthermore the increase in kidney mass is the reason for an elevated transport capacity. Stimulation of renal PAH excretion by repeated pretreatment with cyclopenthiazide shortened the phase of compensation and raised the extent of tubular transport capacity following partial loss of kidney tissue. The specific accumulation of PAH in renal cortical slices from nephrectomized, cyclopenthiazide pretreated rats is distinctly elevated 96 h after unilateral nephrectomy from 19.4 +/- 2.7 to 24.3 +/- 0.6 micrograms/g kidney weight. Obviously there are different mechanisms for the increased PAH transport caused by stimulation and by regeneration after unilateral nephrectomy, because additional effects can be stated in regenerating rats by additional stimulation of renal tubular transport.

Postnatal development of kidney function in rats receiving thyroid hormones.

In immature rats, renal excretion of p-aminohippurate (PAH) can be increased by daily pretreatment with triiodothyronine (T3) or tetraiodothyronine (T4) beginning on the 2nd day after birth (10 micrograms/100 g b.wt. i.p.). The increase of PAH excretion is nearly of the same extent, if 5-, 10-, 20-, 30-, 50-, and 105-day-old rats were pretreated with thyroid hormones (10 micrograms/100 g b.wt. i.p., 3 days, once daily). There is no strongly dose dependent renal effect of T3 and T4, respectively. The time course of stimulation of renal PAH excretion was also characterized in rats of different ages. Simultaneous pretreatment of young and adult rats with cyclopenthiazide and T3 is not distinctly more effective as both components given alone. Particularly the low degree of stimulation in young rats receiving cyclopenthiazide cannot be pronounced by additional T3 administration. Inhibitors of protein biosynthesis (azauracil, neomycin) can antagonize the stimulation of renal p-amino-hippurate excretion in rats receiving T3. The presented data indicate that T3 is effective in young rats. Furthermore, T4 can be converted to T3 in young rats, too. The importance of an intact protein synthesis seems to be a prerequisite to stimulate the kidney function by T3 pretreatment.

The antihypertensive and metabolic effects of low and conventional dose cyclopenthiazide in type II diabetics with hypertension.

The antihypertensive efficacy and metabolic effects of cyclopenthiazide 125 micrograms were compared with cyclopenthiazide 500 micrograms in patients with non-insulin dependent diabetes and hypertension in a double blind, randomized crossover study. After a 6-week placebo period 24 patients with non-insulin dependent diabetes mellitus, stabilized on diet or oral hypoglycaemic agents, who had a mean diastolic blood pressure between 90 and 120 mmHg after receiving placebo for 6 weeks were given 125 micrograms or 500 micrograms cyclopenthiazide for 12 weeks. Patients then received placebo for a further 6-week period, following which they received the alternate treatment dosage for 12 weeks. There were no differences between doses in their antihypertensive effects. While 500 micrograms significantly reduced systolic and diastolic blood pressures, only diastolic pressure was significantly reduced by 125 micrograms from pre-treatment values. The higher dose of cyclopenthiazide had greater effects on measures of diabetic control than did the 125 micrograms dose and the rise in blood glucose after 12 weeks' treatment with 500 micrograms was significantly different from pre-treatment values. Cyclopenthiazide 125 micrograms had significantly less effect on triglycerides, potassium and urate, than did 500 micrograms. Cyclopenthiazide 500 micrograms resulted in a significant fall in serum potassium from pre-treatment values. There were no intertreatment differences in the other variables measured. Cyclopenthiazide 125 micrograms is as effective as 500 micrograms in reducing diastolic blood pressure in mildly hypertensive non-insulin dependent diabetic patients. The higher dose had more pronounced adverse effects on glucose control and serum concentrations of triglycerides, potassium and urate.

Influence of diuretics on renal lithium excretion and tissue distribution of some cations in saline loaded young and adult rats.

In 5- and 105-day-old rats the effect of acetazolamide, cyclopenthiazide, and/or a saline load on renal lithium excretion as well as on lithium, sodium and potassium concentrations in serum and in various tissues (kidney, muscle, intestine, liver, brain) was investigated during the first 3 h after ip. administration of lithium. The administration of acetazolamide or saline led to a significant increase in renal lithium elimination in animals of both age groups, which could be stimulated additionally, when both substances were given simultaneously. In principle, increased renal lithium excretion is paralleled by enhanced sodium elimination. There was evidence for an inhibition of renal tubular lithium reabsorption and besides, extrarenal changes were observed in the lithium, sodium, and potassium distribution, which have consequences for lithium elimination as well. Lithium is accumulated to a different extent in each of the tissues investigated. Furthermore, tissue accumulation and efflux rate of lithium strongly depend on age. The influences of the diuretics and/or saline administration on possible mechanisms of renal and extrarenal lithium movements are discussed.

Compensation of renal drug excretion after unilateral nephrectomy.

Twenty hours after unilateral nephrectomy (uNX) the PAH excretion of uninephrectomized rats reaches about 80% of the controls. Immediately after removal of one kidney the parenchyma loss can be compensated by an intensification of glomerular filtration. Thereafter the active tubular secretion capacity raises. 24 h after uNX, a significant increase of renal mass could be measured. The specific PAH accumulation capacity per 1 g renal cortical tissue increases significantly 96 h after uNX if the animals had been pretreated with cyclopenthiazide before the operation. Administration of azauracil or fluoruracil or neomycin causes a dose-dependent reduction of PAH elimination in sham operated as well as in uNX-rats. The effect of stimulation by cyclopenthiazide, also occurring after uNX could be reduced significantly by the inhibitors. The relative extent of compensation (80 +/- 10%) was not influenced by the inhibitors of protein synthesis. The compensation after uNX and the stimulation of renal tubular function are mediated by different mechanisms.

[Extent and duration of drug-induced stimulation of renal excretion of p-aminohippuric acid]. / Ausmass und Dauer der Stimulation der renalen Ausscheidung von p-Aminohippursäure durch Pharmaka

Repeated pretreatment with p-aminohippuric acid (PAH), probenecide, cyclopenthiazide, and phenobarbital stimulates the renal excretion of PAH. For an interval of at least 6 hrs following i.p. application pretreated rats excrete more PAH excretion than the controls. All the drugs studied were found to stimulate renal PAH excretion within a period of 3 hrs by 50-60% of the control value. The required duration of pretreatment varies with the substance used. With cyclopenthiazide, the excretion of PAH is demonstrable for 2-3 weeks. Phenobarbital has a brief stimulating action. Correlations of a binding of drugs to structures of their tubular cell and the length of the stimulating action are discussed.

Influence of neomycin pretreatment on stimulated and maturative renal transport of p-aminohippurate (PAH).

Renal tubular transport of organic anions is immature at birth and can be stimulated in adult rats by repeated administration of xenobiotics. There is some evidence of an increased synthesis of carrier proteins in renal tubular cells following stimulation as well as during postnatal development of renal tubular transport processes. The effect of pretreatment with an inhibitor of protein biosynthesis (neomycin) on stimulated and maturative transport of p-aminohippurate (PAH) was measured. Neomycin has a dose dependent long acting and reversible effect on stimulated PAH transport and on postnatal maturation of PAH excretion, and increased protein biosynthesis is the likely common basic phenomenon of both processes.

Stimulation of kidney function in rats of different ages injured by nephrotoxic agents.

Intensity and duration of nephrotoxic effects can be characterized by measurement of renal p-aminohippurate (PAH) excretion. Single administration of potassium dichromate or glycerol is followed by a marked decrease of renal PAH excretion in dependence on the time after the administration as well as on the dosage used. Both agents are without effect in young rats with an immature tubular transport system for organic anions. As observed previously in rats with intact kidney function, renal PAH excretion can also be stimulated in rats with potassium dichromate or glycerol induced kidney damage. Stimulation of renal PAH excretion is possible in injured rats by repeated administrations of PAH and cyclopenthiazide, respectively. Exactly, the duration of injury is shortened whereas the intensity of the nephrotoxic effect is not changed. However, this effect depends on the age of rats as well as on the nephrotoxic agent administered.