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PubMed1975

Species variations among primates in responses to drugs which alter the renal excretion of uric acid.

The effects of salicylate, probenecid (Benemid) and pyrazinoate on uric acid excretion were determined in clearance experiments in the chimpanzee and Cebus monkey (C. albifrons and C. apella). The results were correlated with data from these species in the literature and where possible to analogous data in man. With salicylate, the rank order of responsiveness in terms of uricosuric action was chimpanzee greater than man greater than C. albifrons = C. apella. This was true when comparisons were made on the bases of drug concentration in plasma or the rate of drug excretion per milliliter of glomerular filtrate. A similar rank order was obtained with probenecid except that C. albifrons was slightly more responsive than C. apella. The latter comparisons were on the basis of plasma concentration of drug. The chimpanzee is more susceptible to the uricosuric action of pyrazinoate than is C. apella. With salicylate and pyrazinoate, there was urate retention at levels lower than those required for a uricosuric effect. The results suggest that in comparison with man, the chimpanzee is a hyperresponder to uricosuric drugs and Cebus monkeys are hyporesponders. Therefore, these findings limit extensions of quantitative results from one species to another.

Animals↗
PubMed1994

Beta-adrenergic receptor-mediated regulation of extracellular adenosine in cerebral cortex in culture.

Adenosine is an important inhibitory neuromodulator in the CNS, yet the sources of extracellular adenosine have yet to be well characterized. In this study we show that beta-adrenergic stimulation of cortical cultures results in the extracellular accumulation of cAMP as well as adenosine, and that the extracellular adenosine derives from extracellular cAMP. The concentration dependence of isoproterenol in evoking cAMP secretion was determined by radioimmunoassay, and the EC50 for this effect was found to be approximately 100 nM. In order to investigate the effect of beta-adrenergic stimulation on the regulation of extracellular adenosine, the effect of isoproterenol in stimulating the extracellular accumulation of adenine-containing compounds was examined by HPLC. Isoproterenol stimulated cAMP secretion in both astrocyte cultures and astrocyte-rich mixed cultures of astrocytes and neurons. However, no extracellular cAMP was detectable in neuron-enriched astrocyte-poor cultures. Extracellular adenosine increased in response to isoproterenol in the astrocyte-rich mixed cultures, but not in the neuron-enriched astrocyte-poor cultures. After 30 min exposure to isoproterenol, the concentration of adenosine in the extracellular medium increased by 47% in 56 experiments in the mixed astrocyte-rich cultures. In order to establish whether the adenosine that accumulates in response to isoproterenol stimulation actually derives from extracellular cAMP, phosphodiesterase inhibitors were tested for their ability to block isoproterenol-stimulated adenosine accumulation. Isobutylmethylxanthine (IBMX; 100 microM), RO 20-1724 (180 microM), carbazeran (10 microM), dipyridamole (10 microM), and trifluoperazine (10 microM) had no inhibitory effect on the isoproterenol-stimulated accumulation of extracellular adenosine. However 100 microM IBMX plus 180 microM RO 20-1724 effectively blocked isoproterenol-stimulated adenosine accumulation and, as expected, increased extracellular cAMP. As a further test of the origin of isoproterenol-stimulated adenosine accumulation, we attempted to block this phenomenon by blocking cAMP secretion itself. For this purpose probenecid, a known inhibitor of cAMP secretion in many different cell types, was used. We found that probenecid at 1 mM blocked isoproterenol-stimulated adenosine accumulation. These studies suggest that one potentially important source of extracellular adenosine in the cerebral cortex is endogenous extracellular cAMP, secreted from astrocytes in response to beta-adrenergic receptor stimulation. Since the receptors of neuromodulators other than norepinephrine may also be coupled to adenylyl cyclase in the cerebral cortex, there may be several neuromodulatory systems that regulate extracellular adenosine levels by this mechanism.

Adenine Nucleotides↗
PubMed1976

Progressive effects of cocaine on behavior and central amine metabolism in rhesus monkeys: relationship to kindling and psychosis.

Chronic administration of the same dose of cocaine to rhesus monkeys for up to 6 months was associated with progressive alterations in pathological behavior and increased susceptibility to seizures. Monkeys initially displaying prominent hyperactive stereotypic responses for up to 2 months began to demonstrate increasing amounts of inhibitory behavior, consisting of catalepsy, motor inhibition, and abnormal visual tracking and staring. Four of 13 animals developed increasing intensities of lingual-buccal dyskinesias after 10 weeks of chronic cocaine. Animals initially showing no convulsions to a given dose of cocaine eventually developed convulsions to the same dose, and then displayed an increased frequency of convulsions following subsequent injections. Levels of the dopamine metabolite, homovanillic acid (HVA), in the cisternal cerebrospinal fluid were significantly elevated during both excitatory stereotypic and inhibitory syndromes; a similar trend was observed for HVA after probenecid administration. Only the probenecid-induced accumulations of the serotonin metabolite 5-hydroxyindoleacetic acid, following acute cocaine administration, were significantly elevated. The progressive increases in convulsions, dyskinesias, and the inhibitory syndrome did not appear related to alterations in peak levels of cocaine in plasma or CSF, and a pharmacological kindling model is suggested as an alternate explanation of the data. The study extends the current models of stimulant-induced psychoses by highlighting the progressive alterations in behavior and neurological sequelae and in suggesting that this progressive mechanism may also be important in the development of psychosis in man.

Animals↗
PubMed1993

Transport of 2,4,5-trichlorophenoxyacetic acid across the blood-cerebrospinal fluid barrier of the rabbit.

Transport of the anionic herbicide, 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) across the blood-cerebrospinal fluid barrier was investigated using the isolated choroid plexus of the adult rabbit in vitro and ventriculocisternal perfusion in vivo. In vitro, 2,4,5-T transport was effective, with tissue concentrations 20 times those in the medium after only 5 min of incubation with 1 microM 2,4,5-T. The tissue to medium ratios reached steady state by 20 min at approximately 45-fold. Uptake was energy dependent and inhibited by ouabain, phloridzin and several organic anions (probenecid, 2,4-dichlorophenoxyacetic acid and octanoate). Neither tyrosine (transported by a separate system) nor the neurotoxin, quinolinic acid, inhibited 2,4,5-T transport. Kinetic analysis yielded an apparent Km of 58 microM and Vmax of 111 nmol g-1 min-1 in the lateral ventricular choroid plexus with similar values (57 microM and 87 nmol g-1 min-1) in the fourth ventricular plexus. In vivo, the steady-state clearance of 2,4,5-T from the cerebrospinal fluid exceeded that of inulin and was reduced in a dose-dependent fashion by 2,4-dichlorophenoxyacetic acid and probenecid. Together, these data indicate that 2,4,5-T is cleared from the brain and cerebrospinal fluid by the organic anion transport system and that alterations in such transport may have a significant impact on the toxicity of this agent in the central nervous system.

2,4,5-Trichlorophenoxyacetic Acid↗
PubMed1995

Pharmacokinetics of bacampicillin in equids.

Bacampicillin hydrochloride is an ester prodrug that is hydrolyzed to ampicillin after its absorption from the gastrointestinal tract. It was administered intragastrically at a dose rate of 13.5 mg/kg of body weight to ponies and horses, and was highly bioavailable (F = 41.0%), compared with other penicillins in adult horses. The high peak ampicillin plasma concentration of 6.1 +/- 0.5 micrograms/ml achieved and persistence of the antibiotic at concentration of 0.3 +/- 0.1 microgram/ml 6 hours after its intragastric administration, suggest that bacampicillin hydrochloride may reach suitable bactericidal concentrations for treatment of infections caused by susceptible microorganisms. In a separate experiment, dichlorvos, an organophosphate compound that inhibits some of the esterase activity in plasma, was administered orally to the same animals at a dose rate of 40 mg/kg, followed by intragastric administration of bacampicillin hydrochloride at a dose of 13.5 mg/kg. Plasma pseudocholinesterase and erythrocyte acetylcholinesterase activities were reduced to < 5% of reference (predichlorvos) values after dichlorvos administration. However, rate of hydrolysis of bacampicillin into ampicillin was not affected. Consequently, the disposition and fate of bacampicillin when administered intragastrically 1 day after dichlorvos administration were similar to the values obtained after administration of bacampicillin alone. Intragastric coadministration of probenecid at a dose rate of 75 mg/kg and bacampicillin at 13.5 mg/kg limited absorption of the antibiotic from the gastrointestinal tract. This suggests existence of a common transport mechanism for bacampicillin and probenecid in the gastrointestinal wall, and precludes use of this combination for treatment. The bioavailable fraction of ampicillin after combination treatment indicated prolonged residence time in the plasma, presumably as a consequence of reduced renal tubular secretion.

Ampicillin↗
PubMed1996

Mechanism of mobilization of cadmium by dithiocarbamates in rat primary hepatocyte cultures.

The mechanism of mobilization of cadmium (Cd) by N-benzyl-D-glucamine dithiocarbamate (BGD) and N-p-hydroxymethylbenzyl-D-glucamine dithiocarbamate (HBGD) in rat primary hepatocyte cultures was studied. Probenecid pretreatment increased Cd efflux from the hepatocytes by BGD, but did not affect Cd efflux by HBGD. p-Aminohippurate treatment had no effect on Cd efflux by the chelating agents. These results suggest that an enhancing effect of probenecid on the BGD-induced Cd mobilization is due to its inhibitory effect on the glucuronidation of BGD and not its specific action on BGD transport. Verapamil and nicardipine had no effect on the chelating agent-induced Cd mobilization. Phlorizin did not affect Cd efflux by BGD or HBGD. Phloretin and cytochalasin B inhibited Cd efflux by the chelating agents. These results seem to be evidence that BGD and HBGD may be transported by a facilitated diffusion system in the hepatocytes.

Animals↗
PubMed1997

Effects of uricosuric and antiuricosuric agents on urate transport in human brush-border membrane vesicles.

Inhibition of [14C]-urate uptake by uricosuric and antiuricosuric agents was investigated in human brush-border membrane vesicles, urate being transported either by anion exchange mechanisms or by voltage sensitive pathway. The IC50 for drugs on [14C]-urate uptake in vesicles loaded with 1 mM cold urate or with 5 mM lactate was, respectively: 0.7 and 0.3 microM for benzbromarone; 6 and 4 microM for salicylate; 133 and 13 microM for losartan; 520 and 190 microM for sulfinpyrazone and 807 and 150 microM, for probenecid. The IC50 ratio for [14C]-urate uptake in exchange for cold urate or for lactate varied from about 1 for salicylate to 10 for losartan, supporting the hypothesis that two distinct anion exchangers are involved in urate transport. Application of Hill equation revealed that urate/anion exchangers have more than one binding site, possibly two binding sites with high cooperativity, for benzbromarone and sulfinpyrazone, but only one for probenecid, salicylate and losartan. The uricosuric diuretic, tienilic acid was 10 to 50 times more potent than hydrochlorothiazide, chlorothiazide and furosemide, for inhibiting [14C]-urate uptake in exchange for cold urate. This higher potency is the reason of its uricosuric properties. All uricosuric agents, as well as the antiuricosuric agents, pyrazinoate and ethambutol, had a much lower potency for inhibiting [14C]-urate uptake through the voltage sensitive pathway (apical secretory step) than through the urate/anion exchangers. This suggests that antiuricosuria, induced by pyrazinoate and ethambutol, as well as by low concentrations of uricosuric agents, does not result from an inhibition of the apical voltage sensitive pathway.

Aged↗
PubMed1997

Metabolism of cAMP to adenosine in the renal vasculature.

We recently demonstrated that cAMP added to the perfusate increased the renal venous recovery of adenosine in the isolated rat kidney, an effect blocked by inhibition of ecto-phosphodiesterase and ecto-5'-nucleotidase. Although our previous study established the cAMP-adenosine pathway, i.e., the conversion of cAMP to adenosine, as a viable metabolic pathway within the kidney, that study did not determine whether conversion of arterial cAMP to adenosine recoverable in the venous effluent occurred in the tubules versus nontubular sites. In the current study, we addressed this issue by determining the effects of blocking cAMP transport into the renal tubules with probenecid (0.1, 0.3 and 1 mM) on the increase in renal venous output of adenosine induced by adding cAMP (30 microM) to the perfusate of isolated rat kidneys. Addition of cAMP to the perfusate caused a marked increase in renal venous secretion of adenosine, an effect that was augmented, rather than inhibited, by probenecid. To test the hypothesis that the renal vasculature supports a cAMP-adenosine pathway, cultured rat preglomerular vascular smooth muscle cells were incubated with cAMP (30 microM) for 1 hr in the presence and absence of 3-isobutyl-1-methylxanthine (a phosphodiesterase inhibitor). Incubation with cAMP increased extracellular adenosine levels 41-fold, and this effect was abolished by 3-isobutyl-1-methylxanthine. In a third experimental series, addition of cAMP (0.3, 1, 3, 10 and 30 microM) to the perfusate of isolated rat kidneys and mesenteric vascular beds increased the renal venous, but not mesenteric venous, output of AMP, adenosine and inosine. We conclude that the renal vasculature supports a cAMP-adenosine pathway, that administering cAMP into the renal artery and measuring adenosine in the venous effluent of the perfused rat kidney most likely monitors primarily the renal vascular cAMP-adenosine pathway and that the quantitative importance of the cAMP-adenosine pathway is not equivalent in all vascular compartments.

1-Methyl-3-isobutylxanthine↗
PubMed1976

Penetration of phenylacetic acid across the blood-cerebrospinal fluid barrier.

Labeled phenylacetic acid (14C-PAA) penetrates blood-cerebrospinal fluid (CSF) barrier in cats only under a high gradient of concentration; under these conditions the administration of large doses of either PAA or probenecid decreases the plasma:CSF 14C-PAA ratio. 14C-PAA is quickly removed from the CSF and blood and is excreted into urine; this excretion is blocked by probenecid. It appears, therefore, that PAA crosses the blood-CSF barrier with difficulty and that is secreted by the kidney.

Animals↗
PubMed1976

14C-homovanillic acid in the cerebrospinal fluid of parkinsonian patients after intravenous 14C-L-dopa.

Six patients with Parkinson's disease and five controls were premedicated with probenecid and the peripheral decarboxylase inhibitor alpha-methyldopathydrazine (Carbidopa) before intravenous administration of 50 muc of 14C-L-dopa in tracer quantity. Seven-and-one-half hours later lumbar CSF was obtained. 14C-homovanillic acid (HVA), a major metabolite of brain dopamine, was isolated by thin-layer chromatography and measured. The statistically significant positive correlation between endogenous HVA and 14C-HVA in the entire patient group and the slightly lower values of endogenous HVA and 14C-HVA in the CSF of the parkinsonians support the assumption that the concentration of HVA in the CSF after probenecid treatment reflects brain dopamine turnover. Measurement of labeled HVA here seems to have little advantage over measurement of endogenous HVA alone.

Aged↗
PubMed2000

Functional expression of P-glycoprotein and multidrug resistance-associated protein (Mrp1) in primary cultures of rat astrocytes.

Although it has been well established that the drug efflux pump P-glycoprotein (P-gp) protects the brain against the entry of cytotoxic drugs, its real in situ localization, i.e., at brain capillary endothelial cells or on astrocyte foot processes, is still controversial. The aim of this study was to compare the expression of P-gp and of multidrug resistance-associated protein (Mrp1), another drug efflux pump, in cultured neonatal rat brain astrocytes and in cultured brain capillary endothelial cells. Reverse transcriptase-polymerase chain reaction (RT-PCR) analysis showed that the mdr1b gene was preferentially expressed in astrocytes, whereas both mdr1a and mdr1b mRNA were detected in endothelial cells. Moreover, the mrp1 gene encoding Mrp1 was expressed in both cell types. Western blotting analysis revealed higher expression of P-gp in endothelial cells as compared with astrocytes, but higher expression of Mrp1 in astrocytes. Moreover, P-gp and Mrp1 expression was not modified in more differentiated astrocytes obtained when cultured with db-cAMP for 48 hr. Our functional analysis of P-gp showed a modest effect of P-gp modulators (CsA, verapamil, PSC 833) on the uptake of colchicine (a substrate of P-gp) by astrocytes, whereas they increased by about 50% the uptake of vincristine (a common substrate of P-gp and MRP) by astrocytes. MRP modulators (genistein, probenecid, and sulfinpyrazone) did not modify the uptake of colchicine but increased that of vincristine with a major effect found for sulfinpyrazone. Moreover, indomethacin, probenecid, and sulfinpyrazone increased the uptake of fluorescein (a substrate of MRP but not of P-gp). Taken together, our results provide the first biochemical and functional evidence supporting the expression of P-gp and Mrp1 in rat cultured astrocytes.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2000

Interventions for treating gonorrhoea in pregnancy.

BACKGROUND: Neisseria gonorrhoeae can be transmitted from the mother's genital tract to the newborn during birth and can cause gonococcal opthalmia neonatorum. OBJECTIVES: The objective of this review was to assess the effects of antibiotic regimens in the treatment of genital infection with gonorrhoea during pregnancy with respect to neonatal and maternal morbidity. SEARCH STRATEGY: The Cochrane Pregnancy and Childbirth Group trials register and the Cochrane Controlled Trials Register were searched. Date of last search: October 1998. SELECTION CRITERIA: Randomised trials of one regimen of antibiotic versus another in pregnant women with culture confirmed genital gonococcal infection. DATA COLLECTION AND ANALYSIS: Eligibility and trial quality were assessed by one reviewer. MAIN RESULTS: Two trials involving 329 women were included. Amoxycillin with probenicid or spectinomycin or ceftriaxone have a similar effect on microbiological cure, defined by negative gonococcal culture. REVIEWER'S CONCLUSIONS: Any of the antibiotic regimens tested in these trials appear to be effective for the treatment of gonorrhoea in pregnancy in terms of their effect on microbiological cure. For women who are allergic to penicillin, this review provides reassurance that treatment with ceftriaxone or spectinomycin appears to be at least as equally effective in producing microbiological cure.

Anti-Bacterial Agents↗
PubMed1983

Cerebrospinal fluid monoamine metabolites in narcolepsy and hypersomnia.

Two groups of patients with the common complaint of excessive daytime sleepiness were examined. One group fulfilled the criteria for narcolepsy. The other had the sole symptom of excessive daytime sleepiness, confirmed by sleep latency tests, which was unaccompanied by systemic illness. Spinal fluid examinations for homovanillic acid, 3,4-dihydroxyphenylacetic acid, 3-methoxy-4-hydroxyphenylethylene glycol, and 5-hydroxyindoleacetic acid were carried out before and after administration of probenecid on the 20 patients and 40 controls. Probenecid-corrected accumulation of the dopamine metabolites was significantly increased in each of the patient groups, suggesting an association between pathological sleepiness and elevated dopamine turnover in the central nervous system.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1983

Physiologically based pharmacokinetic model for beta-lactam antibiotics I: Tissue distribution and elimination in rats.

The disposition characteristics of beta-lactam antibiotics in rats were investigated, and a physiologically based pharmacokinetic model capable of predicting the tissue distribution and elimination kinetics of these drugs was developed. Protein-binding parameters in rat serum were determined by equilibrium dialysis. Linear binding was found for penicillin G, methicillin, dicloxacillin, and ampicillin; however, nonlinear binding was observed for penicillin V and cefazolin. After intravenous bolus dosing, cefazolin was recovered almost completely in urine and bile, while for the penicillins, penicilloic acid was found to be the major metabolite. Biliary excretion of cefazolin followed Michaelis-Menten kinetics, and no significant inhibition of urinary secretion was observed after probenecid administration. The renal clearance of unbound drug was 0.82 ml/min with a reabsorption ratio (R) of 0.22. Tubular secretion was inhibited for the penicillins by probenecid plasma concentrations of 50 micrograms/ml, resulting in an R-value of 0.32. Erythrocyte uptake, serum protein binding, and tissue-to-plasma partition coefficient (Kp) were measured. Theoretical Kp values were calculated and found to be in good agreement with the Kp values for three of the antibiotics. Plasma and tissue concentrations (lung, heart, muscle, skin, gut, bone, liver, and kidney) were measured as a function of time at various doses for inulin and cefazolin in rats after an intravenous bolus dose, and were found to be in reasonable agreement with concentrations predicted by the model. These correlations demonstrate that the proposed model can accurately describe the plasma and tissue contributions of inulin and cefazolin in the rat and suggest that this model could have utility in predicting drug distribution in humans.

Animals↗
PubMed1994

Organic anion transport and reabsorptive fluid flux in diabetic retinal vessels: a microperfusion study.

Microperfusion techniques were used to characterize in vitro the fluorescein transport and fluid movement across isolated diabetic rabbit retinal vessels. Unbranched segments of arterioles of alloxan-induced diabetic rabbits were isolated and cannulated on a microperfusion apparatus. Movement of 3H-inulin, the reference tracer, and 14C-fluorescein, the test tracer, across the vascular walls was studied using microperfusion techniques adapted by us to study vascular permeability. The diabetic retinal vessels showed a fluid flux from bath to lumen of 3.6 +/- 0.6 nl min-1 mm-1 with perfusion rates of 7.1 +/- 0.3 nl min-1. This value was 43% (P < or = 0.05) lower when compared with normal values obtained in previous work. Bath to lumen fluorescein fluxes were 2.1 +/- 0.5 and 7.6 +/- 1.6 x 10(-12) mol min-1 mm-1, for fluorescein concentrations of 0.87 x 10(-4) and 1.5 x 10(-4) M, respectively. These values are 23% (P < or = 0.05) and 38.7% (P < or = 0.05), respectively, lower when compared to values obtained from normal retinal vessels. Probenecid, a competitive inhibitor of organic anion transport, added to the bath, had no effect. Increasing bath concentrations of fluorescein caused increasing fluid flux from bath to lumen, and again, probenecid added to the bath has no effect. These results show a significant decrease of fluorescein transport and of net fluid flux across diabetic retinal vessel walls from outside into the lumen, suggesting that in experimental alloxan-induced diabetes there is an early, probably functional, involvement of the retinal vessels in the initial alteration of the blood-retinal barrier (BRB).

Absorption↗
PubMed1983

Characteristics of the accumulation of methotrexate polyglutamate derivatives in Ehrlich ascites tumor cells and isolated rat hepatocytes.

The intracellular synthesis and retention of polygammaglutamyl derivatives of methotrexate and their interactions with H2 folate reductase was evaluated in the Ehrlich ascites tumor cell and the isolated rat hepatocyte. Methotrexate polyglutamates were detected within 15 minutes in hepatocytes exposed to 1 microM methotrexate, and continued to accumulate for at least 60 minutes producing a large transmembrane gradient. These derivatives appeared to be preferentially retained within the cell even under conditions where release of intracellular methotrexate was induced by dibutyryl cyclic AMP or isobutyl methyl xanthine. Deoxycholate and bromosulfophthalein, compounds which inhibited methotrexate influx into hepatocytes, reduced the ratio of methotrexate polyglutamates to methotrexate, suggesting that these agents also inhibit the metabolism of methotrexate. In studies with the Ehrlich ascites tumor accumulation of methotrexate polyglutamates was increased over 5-fold by the addition of 5 mM L-glutamine or L-glutamate and exhibited a positive correlation with the extracellular concentration of methotrexate. Vincristine and probenecid, agents that increase the intracellular levels of methotrexate by inhibiting efflux, also produced a marked increase in methotrexate polyglutamates. When Ehrlich ascites tumor cells were exposed to 10 microM methotrexate and 5 mM L-glutamine intracellular polyglutamates were detected within 10 minutes and their levels increased linearly over 4 hours. As these derivatives accumulated, there was a decline in intracellular methotrexate due at least in part to a replacement of methotrexate on H2 folate reductase by polyglutamates and subsequent efflux of the previously bound methotrexate from the cell. When ppolyglutamate derivatives were in excess of the H2 folate reductase binding capacity and extracellular methotrexate removed, methotrexate rapidly exited the cell whereas the majority of its metabolites were retained and eventually saturated the major portion of the enzyme. These studies indicate that (1) intracellular methotrexate is rapidly converted to polygammaglutamyl derivatives, (2) these metabolites effectively compete with methotrexate for binding sites on H2 folate reductase, (3) these derivatives are retained within the cell more effectively than methotrexate, and (4) vincristine and probenecid may be potentially useful for selectively increasing methotrexate polyglutamates in tumor cells.

Animals↗
PubMed1987

The diuretic effect of muzolimine.

Muzolimine produces a diuresis in the loop of Henle. Unlike other diuretics of this kind, the effect of muzolimine is slow and its action is long lasting. The present study was designed to examine the mechanism of action of muzolimine in isolated in vitro perfused rabbit cortical thick ascending limb segments (cTAL). In a first series it was confirmed that muzolimine itself in a concentration of up to 10(-4) mol/l had no effect on the equivalent short circuit current (Isc), corresponding to the rate of active NaCl reabsorption, in cTAL segments neither from the lumen nor from the bath side. In a second series of experiments, muzolimine was administered intravenously (70 mumol/kg) to male Wistar rats, and the clearances of inulin, Na+ and K+ were calculated. Muzolimine, after a lag phase of 5 to 20 min caused a marked diuresis and natriuresis, but had only a minor effect on glomerular filtration rate and on K+ excretion. The urines of these animals were diluted with isotonic saline, and were examined in rabbit cTAL segments for their ability to block Isc. It was found that the urines of the antidiuretic period were devoid of effects, whereas the diuretic urines inhibited Isc strongly down to a dilution of 300 times when they were perfused in the lumen. The same diluted urines had no effect from the bath side. In a third series, probenecid (100 mumol/kg) was administered i.v. to rats undergoing a muzolimine induced saluresis. It was found that probenecid inhibited the diuresis and saluresis.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1976

On the nature of brain stem disorders in severe head injured patients.

In head injured patients changes were found in the CSF levels of metabolites of the dopaminergic and the serotonergic neurotransmission (HVA and 5-HIAA). After the fifth day following trauma a significant decrease of the HVA levels in the lumbar CSF after probenecid treatment was found. The intensity of this decrease was found to be related to the severity of the trauma (period of unconsciousness), but not to the state of consciousness. Also the probenecid-induced 5-HIAA levels in conscious patients were decreased after the fifth post-traumatic day. In unconscious patients, the period of unconsciousness, particularly in the period of 5-20 days after trauma. Between 21 and 60 days after trauma the 5-HIAA concentrations in unconscious patients decreased remarkably, but they were still significantly higher than in the conscious patients. It can be concluded that during unconsciousness serotonergic neurons have a high rate of turnover, but that both neurotransmitter systems are damaged by the direct or indirect consequences of the injury.

Adolescent↗