Aprotinin, a substance to measure zonal glomenilar filtration rate

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PM439

In a searchfar a substanceto delerminezonai glomerularfibion

~tes. ;lprotininhas bxn wdun~d This compound,MW6513,is a polypeptidewhich is a protteaseinhibItorthai has been empkyedin the tr~ment of acute pancrcatitis. In earlier studies(Tenstadet al., 1989),it ~3s foundthat apprcrximately9% of apratinin in plasma is boundprotein.The renal removal(renalexcretionplus renaltubularup!&) was668 of glomerularfilcntion~11: whencorrectedfor proteinbinding,Maleate,a metabolicinhibiter,was found to incre;lseIhe renalremoval of aprotinin.initiallythe increw in removalwasbelievedto be due to inhibitiona[ rapidIransportof aprotinin across the tubules,However, reevaluation of theexperiments revealedthat plasmaproteins ww markedly dilutedbeewusr: largevolumesof salinewererequiredto administerthe maleate.To deterrnmcthe efkct nPdifferentconxnltaticlnsof plasmaproteii on tie renalremovalof aprotinin,levelsof pltima protein wrre altcr~din Inactinanesthetized ra!s, Albuminwasadministered to increaseihs plasmaconcentration of protdn whereasplasmawasremovedand replaced withRinger’ssolutionto decreasethe plasmaconcentration of protein.i”51-aprc:irlio and51Cr4DTAwereinfusedi.v. for 20 minutesand radioactivitywasmeasuredin kidney,urine,plasmaaad in gelCillration fracticms of plasma.The kidneys wereusuti~ removed at theendof the infusionperiod,but in someexperiments, thk wasnot doneuntil40 minuteslater, Althoughthe petcentof aptotinin boundto plasmaproteinwas not markedlyalteredby these procedures, therenalremoval of aprotininMSfound to vary inverselywiththe plasmaconcentration of protein.Sines: aprotininis a positivescharFedpolypeptide,its filtrationcouldalsobe dependentuponGibbs-Uonnan equilibrium. Whenthe renalremovalof ayrocstinin was evaluated for differentchargeson the moltiule, a chargeohsixwasfound to fit with the data on the assumption of completetubularuptakeand retentionof filteredapcotinin.Thisagrm withtile chargeestimatedfromthe aminoacidcomposition of aprotinin.Furthermore,acetylationof aprotinin,whichreduces the numberd positive chaseson the mc~lecule, increzszd thecle~anceof aprotitin ta 0.9of the gIomcrulat filtration rate, Thus, it appearsthat therenalremoval df aprotininis decreased by proteinbindingas *ill as by GibbsDorman equilibrium, Whenthe removalof aprotininis cor~ectsdfor theseFactors,a valueequalto :hat of the glomerular filtrationestimated by EDTA is obtained. In conclusion, renal removal of aprotininconsistsof &me&r filtntigrr2 an amountnlJtbcnmdta plasma proteiis or limkd by Gibbs-Donnan equilibriumthat can be calculatedand whichis nearlycom$etelytakenup by no evicknclefor loss of proximaltubularcek Lessthm 1%of filteredaprotininis excretedin the urine.Cll**herrnore, - -.. aprotininfromproximaltubularcellsws obtainedovera periodof 60 minutes,Thus,aprorininw&d appear10IXa usefulagentto estimateglomerular filtration rates in outer andinnx corticalzonesof thekidney Reference Tend, O,,Williamson, H.E.and Aukland, K., 1989, Fwceeding of the IntemationnlUnional PhysidogicdSC~~LKIS Abancts. 17,372,