Isolated perfused rat kidney as a tool in the investigation of renal handling and effects of nonsteroidal antiinflammatory drugs

Cox, P. Gerard; Moons, Miek M.; Slegers, J. F. G.; Rüssel, Frans G. M.; Ginneken, C. A. M. Van

doi:10.1016/0160-5402(90)90020-l

Cited by 30 publications

(31 citation statements)

References 23 publications

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“…Although some parameters were slightly changed after pretreatment with one of the inhibitory agents, no severe effects on kidney functioning could be determined. In agreement with previous investigations (Cox et al,, 1990), the system remained stable and viable during the whole experimental period. Addition of rhodamine 123 slightly increased renal functioning as compared to control experiments, which could be concluded from a slightly decreased fractional excretion of sodium, calcium and glucose throughout the whole experimental period (P < 0.05).…”

Section: Effect On Kidney Functionsupporting

confidence: 93%

“…Urine and perfusate samples were analyzed for glucose and various electrolytes as described previously (Cox et al, 1990). Inulin was determined according to a previously published method (Heyrovski, 1956).…”

Section: Discussionmentioning

confidence: 99%

“…The isolation and perfusion of the rat kidney and stabil ity of the perfused kidney system were described in detail previously (Cox et al, 1990). Briefly, male Wistar-Hannover rats (225-275 g) were anesthetized intraperitoneally with pentobarbital (6 mg/ 100 g) and furosemide was injected intraperitoneally (1 mg/ 100 g) to prevent deterio ration of the distal nephron.…”

Section: Jj Kidney Isolation and Perfusionmentioning

confidence: 99%

“…This in vitro technique has been shown useful for the investiga tion of renal organic anionic and cationic drug excretion (Cox et al, 1990;Boom et aL, 1994). Previous investiga tions in various carcinoma cells showed that the mitochon drial dye with anticarcinoma activity, rhodamine 123 , is effectively pumped out of these cells via P-glycoprotein (Neyfakh et al, 1989;Lee et al, 1994;Denis-Gay et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

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Rhodamine 123 accumulates extensively in the isolated perfused rat kidney and is secreted by the organic cation system

Masereeuw

Moons

Rüssel

1997

European Journal of Pharmacology

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Rhodamine 123 has been shown to be a substrate for P-glycoprotein in multidrug resistant cells, In the present investigation the disposition of rhodamine 123 was studied in the isolated perfused rat kidney, After exposing the kidneys to perfusate concentrations ranging from 10 to 1000 n g/m l, the renal clearance was 4-1 times the clearance by glomerular filtration, respectively, indicating active and saturable secretion of rhodamine 123. The rate-limiting step in secretion was found to be membrane passage from cell to tubular lumen. Suprisingly, renal clearance was not influenced by the P-glycoprotein inhibitors cyclosporin A or digoxin. However, pretreatment o f the kidneys with verapamil and quinidine (inhibitors of both P-glycoprotein and organic cation transport) or cimetidine (organic cation transport inhibitor) resulted in a significantly reduced rhodamine 123 clearance, indicating that the renal organic cation carrier may be involved in active secretion. Rhodamine 123 accumulated extensively in the isolated perfused rat kidney; tissue concentrations o f 2 7 0 -3 6 0 times the perfusate concentration were determined. Similar accumulation ratios at different perfusate concentrations were found, suggesting that the compound enters the tubular cells by (facilitated) diffusion. In conclusion, rhodamine 123 accumulated extensively in the isolated perfused rat kidney and active renal secretion appears to be pi*eferentially mediated by the organic cation carrier and not by P-glycoprotein.

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Section: Effect On Kidney Functionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Jj Kidney Isolation and Perfusionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Rhodamine 123 accumulates extensively in the isolated perfused rat kidney and is secreted by the organic cation system

Masereeuw

Moons

Rüssel

1997

European Journal of Pharmacology

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“…Rat kidneys of Wistar-Hannover (WH) and TR Ϫ rats were isolated and perfused as described in detail previously (25,26). Research was undertaken under the auspices of a protocol approved by the local university animal care and usage committee.…”

Section: Kidney Isolation and Perfusionmentioning

confidence: 99%

Contribution of Multidrug Resistance Protein 2 (MRP2/ABCC2) to the Renal Excretion of p-aminohippurate (PAH) and Identification of MRP4 (ABCC4) as a Novel PAH Transporter

Smeets¹,

Aubel²,

Wouterse³

et al. 2004

Journal of the American Society of Nephrology

139

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Abstract. p-Aminohippurate (PAH) is the classical substrate used in the characterization of organic anion transport in renal proximal tubular cells. Although basolateral transporters for PAH uptake from blood into the cell have been well characterized, there is still little knowledge on the apical urinary efflux transporters. The multidrug resistance protein 2 (MRP2/ ABCC2) is localized to the apical membrane and mediates ATP-dependent PAH transport, but its contribution to urinary PAH excretion is not known. In this report, we show that renal excretion of PAH in isolated perfused kidneys from wild-type and Mrp2-deficient (TR Ϫ ) rats is not significantly different. Uptake of [14 C]PAH in membrane vesicles expressing two different MRP2 clones isolated from Sf9 and MDCKII cells exhibited a low affinity for PAH (Sf9, 5 Ϯ 2 mM; MDCKII, 2.1 Ϯ 0.6 mM). Human MRP4 (ABCC4), which has recently been localized to the apical membrane, expressed in Sf9 cells had a much higher affinity for PAH (K m ϭ 160 Ϯ 50 M). Various inhibitors of MRP2-mediated PAH transport also inhibited MRP4. Probenecid stimulated MRP2 at low concentrations but had no effect on MRP4; but at high probenecid concentrations, both MRP2 and MRP4 were inhibited. Sulfinpyrazone only stimulated MRP2, but inhibited MRP4. Realtime PCR and Western blot analysis showed that renal cortical expression of MRP4 is approximately fivefold higher as compared with MRP2. MRP4 is a novel PAH transporter that has higher affinity for PAH and is expressed more highly in kidney than MRP2, and may therefore be more important in renal PAH excretion.

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Safety Pharmacology of Drugs for the Urinary Tract

Hart

2006

Drug Discovery and Evaluation

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Isolated perfused rat kidney as a tool in the investigation of renal handling and effects of nonsteroidal antiinflammatory drugs

Cited by 30 publications

References 23 publications

Rhodamine 123 accumulates extensively in the isolated perfused rat kidney and is secreted by the organic cation system

Rhodamine 123 accumulates extensively in the isolated perfused rat kidney and is secreted by the organic cation system

Contribution of Multidrug Resistance Protein 2 (MRP2/ABCC2) to the Renal Excretion of p-aminohippurate (PAH) and Identification of MRP4 (ABCC4) as a Novel PAH Transporter

Safety Pharmacology of Drugs for the Urinary Tract

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