Micropuncture evaluation of the site of action of 2-aminomethyl-4-(1,1-dimethylethyl)-6-iodophenol hydrochloride (MK447) in the rat kidney.
Free-flow micropuncture and in situ microperfusion techniques were used to define the site of action and relative effect of MK447 [2-aminomethyl-4-(1,1-dimethylethyl)-6-iodophenol hydrochloride] vs. furosemide in the rat kidney. MK447 was administered i.v. at 5 mg/kg/hr. Infusion of this drug had little effect on proximal tubule reabsorption of water, Na+ and K+. In contrast, reabsorption of these constituents by the loop of Henle was significantly reduced. There was a tendency for water and Na+ reabsorption to rise and for K+ secretion to fall along the distal tubule. These latter effects can be explained by the contributions of an increased distal flow rate and increased tubule fluid K+ concentration. Net addition of K+ beyond the distal tubule was observed. This may be due to effect of the drug on the collecting duct system or juxtamedullary nephrons. The effects of MK447 and furosemide on loop of Henle reabsorption were compared in microperfusion experiments. Furosemide reduced Na+, K+ and water reabsorption by the loop, whereas MK447 had no effect. A 6-bromophenol sulfate ester of MK447 significantly reduced loop reabsorption. From these observations, we conclude that MK447 affects water and electrolyte reabsorption by the loop of Henle and beyond the superficial late distal tubule. The fact that a potential metabolite, but not MK447, significantly reduced reabsorption by the in situ, perfused loop of Henle supports the hypothesis that the p.o. and i.v. effects of MK447 are dependent on metabolism.
Johnston
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Department of Pharmacology, ICI Pharmaceutical Group, ICI Americas, Inc., Wilmington, Delaware.
Kau
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D000042:Absorption; D000818:Animals; D002084:Butylated Hydroxytoluene / Q000494:pharmacology* / Q000031:analogs & derivatives; D004232:Diuretics / Q000494:pharmacology*; D005665:Furosemide / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D010477:Perfusion; D011188:Potassium / Q000378:metabolism; D011677:Punctures; D051381:Rats; D011919:Rats, Inbred Strains; D012964:Sodium / Q000378:metabolism
D004232:Diuretics; D002084:Butylated Hydroxytoluene; C013753:2-aminomethyl-4-t-butyl-6-iodophenol; D005665:Furosemide; D012964:Sodium; D011188:Potassium