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PubMed1994

Chloride dependence of pH modulation by beta-adrenergic agonist in rat cardiomyocytes.

The effects of beta-adrenergic agonists on pHi were studied on single ventricular myocytes isolated from adult rat heart and loaded with the acetoxymethyl ester (AM) form of the pH indicator SNARF-1. In modified Krebs' solution containing 20 mmol/L HEPES and 4.4 mmol/L HCO3-, isoproterenol (1 mumol/L) caused a significant decrease of steady-state pHi from 7.20 +/- 0.02 to 7.13 +/- 0.02 (mean +/- SEM) within 2 minutes. This acidification, which was also observed in myocytes that were preloaded with the Ca2+ chelator BAPTA and superfused with nominally Ca(2+)-free solution, was blocked by propranolol as well as by the specific beta 1-antagonist CGP 20712 A but not by the beta 2-antagonist ICI 118,551. Forskolin (10 mumol/L) induced a similar reversible decrease of pHi (average decrease, 0.11 +/- 0.02 pH unit). Furthermore, adenosine (100 mumol/L) substantially attenuated the isoproterenol-induced decrease of pHi. The effect of isoproterenol was not prevented by inhibitors of the Na(+)-H+ antiport, amiloride (1 mmol/L) and 2-N,N-hexamethylene amiloride (20 mumol/L). On the other hand, blockers of Cl- transport mechanisms, DIDS (200 mumol/L) and probenecid (100 mumol/L), inhibited this acidification, Isoproterenol also failed to induce a decrease of steady-state pHi in myocytes incubated in Cl(-)-free medium. Rather, the initial rate of rise of pHi observed on removal of external Cl- ions was significantly increased in the presence of isoproterenol or dibutyryl cAMP. Because the alkalinization induced by removal of Cl- ions is mainly due to reversal of the Cl(-)-HCO3- exchanger, the augmentation of this initial rate of pHi rise directly points to a beta-adrenergic stimulation of the exchanger. Furthermore, the pHi recovery following NH4Cl exposure was accelerated by isoproterenol in the presence of probenecid, indicating that the Na(+)-HCO3- cotransport and/or the Na(+)-H+ antiport also could be activated.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine↗
PubMed1978

Renal tubular transport of organic acids. Studies with oxalate and para-aminohippurate in the rat.

The renal handling of oxalate was examined by free-flow micropuncture, intratubular microinjection, and droplet precession techniques in the rat. After the sustained i.v. infusion of [(14)C]oxalate, the fractional delivery of oxalate from the early portions of the proximal tubule was 120.1+/-4.4%, indicating net secretion. Fractional delivery rates from the late proximal tubule (124.6+/-6.1), distal tubule (120.9+/-2.9), and final urine (126.2+/-2.9%) were not different from that of the early proximal tubule. Direct intratubular microinjections of oxalate into the early proximal tubule and late proximal tubule yielded urinary recovery rates of 85+/-3% and 101+/-2%, respectively, suggesting that oxalate absorption does occur in the mid-portions of the proximal tubule. Droplet precession studies confirmed a secretory flux for oxalate. In contrast to oxalate, para-aminohippurate (PAH), the more traditional marker for organic acid transport, was secreted in the late portions of the proximal tubule and in large measure at a site between the late proximal and distal tubules, presumably the pars recta. Probenecid inhibited PAH secretion but was without effect on net oxalate transport, oxalate absorption, or oxalate secretion. These studies demonstrate that net oxalate secretion occurs in the early portions of the proximal convoluted tubule, undergoes bidirectional transport of approximately equal magnitude in later segments of the proximal tubule, and probably is not transported in more distal nephron sites. The secretory mechanism for oxalate differs from that of PAH in that it is located in a different segment of the nephron and is not inhibited by probenecid. These differences suggest that the early portions of the proximal tubule are important in the renal metabolism of some organic acids.

Aminohippuric Acids↗
PubMed1996

Basolateral localization and export activity of the human multidrug resistance-associated protein in polarized pig kidney cells.

The human multidrug resistance-associated protein MRP confers resistance to various cytotoxic drugs by lowering the intracellular drug concentration. Recent evidence indicates that MRP can also transport glutathione S-conjugates across membranes. To study the transport properties of MRP in intact cells, we have expressed human MRP cDNA in the polarized pig kidney epithelial cell line LLC-PK1. MRP mainly localized to the basolateral plasma membrane of these cells, and not to the apical membrane, as determined by immunocytochemistry using confocal laser scanning and electron microscopy. In accordance with this localization, MRP caused increased transport of the glutathione S-conjugate S-(2, 4-dinitrophenyl)-glutathione and of the anticancer drug daunorubicin to the basal side of the epithelial cell layer. Sulfinpyrazone and probenecid, known inhibitors of multispecific organic anion transport, inhibited this basolateral transport, but not the apical transport of daunorubicin mediated by the apically localized human MDR1 P-glycoprotein in MDR1-transfected LLC-PK1 cells. Probenecid and sulfinpyrazone may therefore be useful lead compounds for the development of clinical reversal agents specific for MRP-mediated drug resistance.

ATP-Binding Cassette Transporters↗
PubMed2004

Response of HIV-infected patients with asymptomatic syphilis to intensive intramuscular therapy with ceftriaxone or procaine penicillin.

The objective of this prospective pilot study was to evaluate the response of HIV-infected patients with asymptomatic syphilis to one of two intensive antibiotic treatment regimens. Thirty-one HIV-infected patients with serum rapid plasma reagin titre > or =1:4 and no clinical findings of syphilis were randomized to receive daily intramuscular injections of ceftriaxone or procaine penicillin (plus oral probenecid) for 15 days; 24 returned for follow-up study. Seven of 10 (70%) procaine penicillin-treated patients and 10 of 14 (71%) ceftriaxone-treated patients had a > or =4-fold decline in RPR (P=0.94); two penicillin-treated and one ceftriaxone-treated patient relapsed. Two patients failed ceftriaxone therapy. Three penicillin-treated, and two ceftriaxone-treated patients were serofast. Serological responses were similar in those patients with and without asymptomatic neurosyphilis. There was no difference in the serologic response to daily treatment with ceftriaxone vs that with procaine penicillin plus probenecid; both treatments were associated with comparatively high rates of serological non-response and relapse.

Adult↗
PubMed2001

Cidofovir for cytomegalovirus infection and disease in allogeneic stem cell transplant recipients. The Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation.

A retrospective study was performed to collect information regarding efficacy and toxicity of cidofovir (CDV) in allogeneic stem cell transplant patients. Data were available on 82 patients. The indications for therapy were cytomegalovirus (CMV) disease in 20 patients, primary preemptive therapy in 24 patients, and secondary preemptive therapy in 38 patients. Of the patients, 47 had received previous antiviral therapy with ganciclovir, foscarnet, or both drugs. The dosage of CDV was 1 to 5 mg/kg per week followed by maintenance every other week in some patients. The duration of therapy ranged from 1 to 134 days (median, 22 days). All patients received probenecid and prehydration. Ten of 20 (50%) patients who were treated for CMV disease (9 of 16 with pneumonia) responded to CDV therapy, as did 25 of 38 (66%) patients who had failed or relapsed after previous preemptive therapy and 15 of 24 (62%) patients in whom CDV was used as the primary preemptive therapy. Of the patients, 21 (25.6%) developed renal toxicity that remained after cessation of therapy in 12 patients. Fifteen patients developed other toxicities that were potentially due to CDV or the concomitantly given probenecid. No toxicity was seen in 45 (61.6%) patients. Cidofovir can be considered as second-line therapy in patients with CMV disease failing previous antiviral therapy. However, additional studies are needed before CDV can be recommended for preemptive therapy.

Adolescent↗
PubMed2006

Uptake of 3H-cAMP by retinal pigment epithelium isolated from bluegill sunfish (Lepomis macrochirus).

BACKGROUND: In bluegill sunfish, the melanin-containing pigment granules of the retinal pigment epithelium undergo cyclic movements in response both to ambient lighting and circadian cues. Pigment granules aggregate into the cell body at night (in the dark), and disperse into apical processes during the day (in the light). Regulation of pigment granule aggregation in a number of fishes depends on modulating the intracellular levels of cyclic adenosine monophosphate. RESULTS: Here we show isolated RPE takes up cyclic adenosine monophosphate (cAMP) in a saturable manner, exogenously applied cAMP induces pigment granule aggregation in retinal pigment epithelium isolated from bluegill, and aggregation induced in this manner is inhibited by treatment with probenecid, an organic anion transport inhibitor. CONCLUSION: Our results raise the possibility that cAMP functions as a messenger secreted from the neural retina to signal darkness to the RPE, which takes it up. It further suggests that organic anion transport systems are the route by which cAMP crosses RPE cell membranes since probenecid inhibits extracellular cAMP from causing pigment granule aggregation.

Animals↗
PubMed1987

Transport mechanism of cephalexin in isolated hepatocytes.

By using isolated rat hepatocytes, the mechanism of uptake of a zwitterionic beta-lactam antibiotic, cephalexin, was clarified. The uptake followed the combination of saturable carrier-mediated and nonsaturable first-order rate processes. The kinetic parameters were estimated as follows (mean +/- SD): maximum uptake rate (Vmax), 2.28 +/- 0.24 nmol/min/mg of protein; Michaelis constant (Kt), 6.28 +/- 0.31 mM and first-order rate constant (kd), 0.11 +/- 0.012 nmol/min/mg of protein/mM. There was no inhibitory effect by amino acids, dipeptides or organic cations, whereas an organic anion, probenecid, markedly inhibited the hepatic uptake of cephalexin. Several beta-lactam antibiotics including zwitterionic and anionic derivatives inhibited cephalexin uptake significantly. The inhibition kinetics revealed that benzylpenicillin and the stereo-isomer l-cephalexin competitively inhibited cephalexin uptake. Furthermore, the efflux of cephalexin from the cells was stimulated by adding benzylpenicillin in the extracellular medium. These results demonstrated that all beta-lactam antibiotics have a common transport system with an organic anion such as probenecid, irrespective of their ionic charges, though a cationic charge on the molecule is less advantageous for being recognized by the carrier system.

Amino Acids↗
PubMed1986

Inhibition by cyclic GMP of p-aminohippurate uptake by basolateral membrane vesicles isolated from rat kidney cortex.

We studied the effect of cyclic guanosine 3',5'-monophosphate (cyclic GMP) on p-aminohippurate (PAH) uptake by basolateral membrane vesicles isolated from rat kidney cortex. Cyclic GMP inhibited PAH uptake dose-dependently. Dibutyryl cyclic GMP inhibited the uptake of PAH to the same extent. However, cyclic adenosine 3',5'-monophosphate, cyclic cytidine 3',5'-monophosphate and guanosine monophosphate had no effect on PAH uptake by membrane vesicles. Therefore, the inhibition of PAH uptake was specific to cyclic GMP and not common to nucleotides. In the presence of probenecid, an inhibitor of PAH transport, cyclic GMP did not affect PAH uptake. Thus, cyclic GMP had an inhibitory effect on probenecid-sensitive PAH transport. Inhibition by cyclic GMP of PAH uptake by basolateral membrane vesicles as described this study may contribute to the decrease in PAH accumulation in kidney cortical slices caused by the cyclic nucleotide which we previously reported.

Aminohippuric Acids↗
PubMed1992

[The mechanism of the renal excretion of disopyramide in rats. I].

The mechanism involved in the renal excretion of disopyramide (DPM) is still incompletely understood. The purpose of this study was to examine the renal handling of DPM and the interactions between DPM and several organic anionic or cationic drugs related to the renal tubular secretion, using the renal clearance and renal cortical slices uptake techniques in rats. The clearance ratio of DPM was greater than that of glomerular filtration and this suggests the tubular secretion of DPM. The clearance ratio of DPM did not change after infusion of either anionic drugs (p-aminohippurate and probenecid) or a cationic drug (cimetidine). The results of time and concentration-dependent experiments using renal cortical slices demonstrated that DPM was accumulated against a concentration gradient by a saturable process. Inhibition of uptake by 2,4-dinitrophenol and cyanide indicated an energy dependence. DPM uptake was considerably inhibited by the cationic drugs, cimetidine and quinine, suggesting that DPM was transported by the cation transport mechanism. Probenecid, a competitor for the anion transport mechanism, moderately inhibited DPM uptake.

Animals↗
PubMed1986

[Effect of S-adenosyl-L-methionine on cerebral monoamine turnover after hypoxia in rats].

The effects of S-Adenosyl-L-methionine (SAMe) on cerebral monoamine turnover at 60 min of reoxygenation after hypoxia (PaO2, 31-35 mmHg) for 15 min were studied in 44 rats anesthetized with nitrous oxide. The accumulations of monoamine metabolites: 3-methoxy 4-hydroxyphenylglycol (MHPG), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) were determined after probenecid. The accumulations of noradrenaline (NA) and dopamine (DA) were also determined after pargyline. In the non-treated group, there was an impairment of degradation of NA to MHPG and of DA to DOPAC or HVA in the control group (no hypoxia). These changes were accompanied by higher levels of NA and DA in the cerebral cortex, hypothalamus and striatum than those of the control group. In the group treated with 100 mg/kg SAMe plus 38 mg/kg mannitol 3 min after the start of reoxygenation, there were no significant changes in these metabolites and amines. Mannitol alone did not cause significant changes. There were no changes in serotonin and 5-HIAA in any of the groups studied. The effects of SAMe were studied in an additional 16 awake rats. MHPG in all regions measured after probenecid in the rats treated with SAMe was higher than that without SAMe. It appears that SAMe ameliorates perturbation of cerebral catecholamine turnover produced by reoxygenation after hypoxia.

Animals↗
PubMed1980

Hyperuricemia induced by some antihypertensives and uricosuric drugs in oxonate-treated rats.

Effects of antihypertensive and uricosuric drugs were studied on the plasma and urinary levels of uric acid in oxonate-treated rats. We made use of animals with a catheterized aorta to successfully collect blood samples and this procedure simplified the evaluation of progressive changes of plasma uric acid, under successive loading with potassium oxonate. The plasma uric acid level of the oxonate-treated rats was increased even with a single administration of diuretic chlorothiazides, furosemide, diazoxide and also uricosuric drugs such as tienilic acid and probenecid. On the other hand, a wellmaintained plasma uric acid level was also produced by exogenously administered uric acid in rats which had been given allopurinol and potassium oxonate. Diazoxide, tienilic acid and probenecid increased the plasma uric acid, while diuretic chlorothiazides did not. Furosemide tended to decrease the plasma uric acid level at the early stage of administration to rats treated with allopurinol, oxonate and uric acid, but increased these levels several hours later when the effect was studied by uric acid loading test wit rats treated with allopurinol and oxonate. These effects also appeared as changes in the urine-excreted uric acid. Thus, the oxonate-treated rats demonstrated an acutely induced hyperuricemia not only with certain antihypertensives, but also with uricosuric drugs. The utility of these procedures for evaluating the hyperuricemic and uricosuric effects of drugs is discussed.

Allantoin↗
PubMed1987

A new uricosuric diuretic, S-8666, in rats and chimpanzees.

5-Dimethylsulfamoyl-6,7-dichloro-2,3-dihydrobenzofuran-2-carboxyli c acid (S-8666) was studied as a possible new uricosuric diuretic agent using rats and chimpanzees. Various new compounds belonging to the 5-sulfamoyl-6,7-dichloro-2,3-dihydrobenzofuran-2-carboxylic acids were clearly diuretic with uricosuric activity in intraperitoneally oxonate-treated rats. S-8666 was chosen as a favorable candidate because its uricosuric activity due to the effects of tubular transport of uric acid were apparently more marked than those of known uricosuric agents such as probenecid, benzbromarone, tienilic acid and indacrinone in oxonate-treated rats. S-8666 was also uricosuric in rats not given urate oxidase inhibitor. The diuretic effect of S-8666 in oxonate-treated rats was as high-ceilinged as that of furosemide, while those of tienilic acid, indacrinone and a known compound of a 5-carbonyl-6,7-dichloro-2,3-dihydrobenzofuran-2-carboxylic acid were rather low-ceilinged. These uricosuric and diuretic activities of S-8666 were manifested by two enantiomers, of which the (+)-enantiomer displayed predominantly uricosuric activity and the (-)-enantiomer, diuretic activity like furosemide. The new compound was also uricosuric and diuretic in chimpanzees, although the potency of the uricosuric activity was similar to that of probenecid and less than that of indacrinone. Thus, it seems that S-8666 is a different type of uricosuric diuretic from known agents which have already been tried in humans.

Animals↗
PubMed1993

Leakage of the fluorescent Ca2+ indicator fura-2 in smooth muscle.

The movement of a fluorescent intracellular Ca2+ indicator, fura-2, in smooth muscle was examined. Strips of rat and rabbit aortas and bovine trachea were loaded with the acetoxymethyl ester of fura-2 (fura-2/AM), followed by washing with normal physiological solution. Not only fura-2/AM but also fura-2 was detected in the washout solution. The amount of fura-2 in the cells, measured fluorometrically, decreased gradually during the washout. The decrease was fastest in rat aorta followed by rabbit aorta > bovine trachea. In rat aorta, fura-2 leakage was inhibited by an inhibitor of anion transport, probenecid, or by a decrease in bath temperature. The Ca2+ ionophore ionomycin (10 microM) increased the leakage of fura-2, which was not inhibited by probenecid, possibly because a high concentration of ionomycin nonselectively increased membrane permeability. These results suggest that fura-2/AM is cleaved to fura-2 in the cell which gradually leaked out of the cell mainly by an anion transport system. The amount of fura-2 in the cell seemed to be determined mainly by the rate of leakage of fura-2, which is the largest in rat aorta followed by rabbit aorta and bovine trachea.

Animals↗
PubMed2002

The MRP4/ABCC4 gene encodes a novel apical organic anion transporter in human kidney proximal tubules: putative efflux pump for urinary cAMP and cGMP.

The cyclic nucleotides cAMP and cGMP play key roles in cellular signaling and the extracellular regulation of fluid balance. In the kidney, cAMP is excreted across the apical proximal tubular membrane into urine, where it reduces phosphate reabsorption through a dipyridamole-sensitive mechanism that is not fully understood. It has long been known that this cAMP efflux pathway is dependent on ATP and is inhibited by probenecid. However, its identity and whether cGMP shares the same transporter have not been established. Here the expression, localization, and functional properties of human multidrug resistance protein 4 (MRP4) are reported. MRP4 is localized to the proximal tubule apical membrane of human kidney, and membrane vesicles from Sf9 cells expressing human MRP4 exhibit ATP-dependent transport of [(3)H]cAMP and [(3)H]cGMP. Both probenecid and dipyridamole are potent MRP4 inhibitors. ATP-dependent [(3)H]methotrexate and [(3)H]estradiol-17beta-D-glucuronide transport by MRP4 and interactions with the anionic conjugates S-(2,4-dinitrophenyl)-glutathione, N-acetyl-(2,4-dinitrophenyl)-cysteine, alpha-naphthyl-beta-D-glucuronide, and p-nitrophenyl-beta-D-glucuronide are also demonstrated. In kidneys of rats deficient in the apical anionic conjugate efflux pump Mrp2, Mrp4 expression is maintained at the same level. It is concluded that MRP4 is a novel apical organic anion transporter and the putative efflux pump for cAMP and cGMP in human kidney proximal tubules.

Adenosine Triphosphate↗
PubMed1994

Role of intracellular pH during cytoprotection of proximal tubule cells by glycine or acidosis.

Lowering extracellular pH to less than 7.0 strongly protects isolated proximal tubules against ATP depletion and Ca(2+)-induced injury, but there is little information about alterations of intracellular pH (pHi) in renal tubules during either injury or its modification by decreasing medium pHi or other potent protective factors such as glycine. pHi was assessed with 2',7'-bis-(2-carboxyethyl)-5-carboxyfluorescein during proximal tubule injury produced by simple ATP depletion with the electron transport inhibitor antimycin or by large increases of cytosolic free Ca2+ induced by treatment with the calcium ionophore ionomycin, alone and in combination with antimycin. Freshly isolated rabbit proximal tubules studied under superfusion conditions in the presence of probenecid were suitable for monitoring pHi during relatively prolonged and severe injury states. Probenecid, used to promote the retention of intracellular fluorophores, only minimally modified the injury response by transiently delaying lactate dehydrogenase release during antimycin treatment. The tubules did not exhibit spontaneous decreases of pHi during simple ATP depletion, but pHi fully equilibrated with cytoprotective decreases of medium pH. Irrespective of the presence of antimycin, ionomycin induced intracellular alkalinization in Ca(2+)-replete medium, which may have further enhanced the severity of injury. When medium Ca2+ was buffered to 100 nM, ionomycin induced intracellular acidification, which likely resulted from a combination of Ca2+/H+ exchange activity of the ionophore and H+ uptake during Ca(2+)-ATPase-mediated extrusion of Ca2+ released by ionomycin from intracellular pools. Alterations of pHi did not contribute to glycine cytoprotection because glycine did not affect the behavior of pHi during treatment with antimycin, ionomycin, or both agents in combination.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphate↗
PubMed1977

Benzbromarone: a review of its pharmacological properties and therapeutic use in gout and hyperuricaemia.

Benzbromarone1 is a benzofuran derivative which lowers serum urate and increases urinary urate excretion in normal, hyperuricaemic and gouty subjects. In open short- and long-term studies benzbromarone reduced serum uric acid levels by one-third to one-half and maintained its effectiveness for periods of up to 8 years. Single-dose experimental studies have shown benzbromarone to have a urate-lowering effect similar to that of a therapeutic dose of probenecid or sulphinpyrazone, but unlike these drugs benzbromarone can be administered in a once daily regimen. In 2 short-term comparative therapeutic trials in a small number of patients with hyperuricaemia, 80mg of micronised benzbromarone daily was at least as effective as 1000mg of probenecid or 300mg of allopurinol daily in lowering serum uric acid levels. Side-effects during benzbromarone administration are usually mild and primarily gastrointestinal in nature.

Aspirin↗
PubMed1994

Movement of carboxyfluorescein across the isolated rabbit iris-ciliary body.

The movement of carboxyfluorescein across the isolated iris-ciliary body of the albino rabbit was analyzed using an Ussing chamber under short-circuit conditions with carboxyfluorescein concentrations ranging from 10 to 100 microM. At a concentration of 50 microM, the outward permeability (from the aqueous to the stromal side) was 4.0 +/- 0.2 x 10(-6) cm/sec and the inward permeability (from the stromal to the aqueous side) was 1.3 +/- 0.2 x 10(-6) cm/sec (Mean +/- SE, N = 6). The former was significantly greater than the latter (P < 0.001). Inward movement of carboxyfluorescein showed a linear increase in relation to the concentrations tested. Neither ouabain (100 microM), 2,4-dinitrophenol (10 microM) nor probenecid (100 microM) significantly inhibited the inward movement of carboxyfluorescein. The net outward movement of carboxy-fluorescein became saturated, as concentration was increased, and a Lineweaver--Burke plot gave an apparent Km of 28 microM and Vmax of 0.67 x 10(-9) mole/hr/cm2. In addition, outward carboxyfluorescein movement was significantly inhibited by ouabain (100 microM), 2,4-dinitrophenol (10 microM), probenecid (100 microM), iodipamide (1.0 mM), hippurate (1.0 mM), low temperature or low external Na+ concentration. These results suggest that outward carboxyfluorescein movement across the tissue largely depends on carrier-mediated active transport, while inward movement occurs by passive diffusion.

Animals↗
PubMed1987

Some effects of metolazone on electrolyte transport.

Metolazone action was studied 1) in vitro on isolated operculum of Fundulus heteroclitus (active chloride transport) using an Ussing chamber (metolazone conc 500 microM) and in vivo 2) using the modified Sperber technique in the hen (metolazone infusion rate 0.75-1.2 micrograms/kg/min) and 3) in healthy volunteers using clearance techniques (metolazone infusion rate 10 mg/h). Metolazone reduced (p less than 0.05) short circuit current potential differences with 20% from average control values (p less than 0.05), while direct current resistance was unchanged. This is comparable to thiazide but much lower than loop diuretic effects. True tubular excretion fraction of metolazone before and after novobiocin (2.7 mumol/kg/min coinfusion averaged 14.1 and 4.5%, resp. (p less than 0.01; n = 8). Thus metolazone is partly eliminated by renal tubular secretion. However, the diuretic effect (sodium, chloride and potassium excretion)--and clearances of Cr51-EDTA and I125-Na-o-iodohippurate--were symmetrical, i.e. independent of metolazone urinary excretion rate, as previously shown for thiazides. Renal clearance of metolazone in healthy volunteers. (HPLC-method) averaged 173 +/- 20 ml/min (n = 8). Probenecid (1 g iv.) significantly reduced the renal clearance of metolazone to 33 +/- 7 ml/min and potassium excretion with maximum 30%, while diuretic and saluretic effects were significantly increased with maximum 30%. Thus, also in humans the diuretic effect of metolazone is not coupled to the urinary excretion rate of the drug, but suggests that its diuretic effect is elicited primarily from the peritubular side of the nephron. Probenecid apparently dissociates sodium from potassium excretion effects of metolazone. This implies a luminal, sodium-independent kaliuretic effect of the drug.

Adult↗