A micropuncture study on the renal site of action of ICI 206,970, a unique eukalemic diuretic.
The site of action of ICI 206,970, an aminomethylphenol pyrazine derivative, with effects on Na+ and water excretion similar to hydrochlorothazide, was determined using free-flow micropuncture and in vivo microperfusion techniques. Furosemide and ICI 206,970 were perfused into the loop of Henle, at a concentration of 10(-4) M. Furosemide reduced water, Na+ and K+ reabsorption by the loop, but ICI 206,970 had little effect. Amiloride and ICI 206,970 were perfused into the distal nephron at a concentration of 10(-4) M. Both compounds reduced the reabsorption of Na+ and secretion of K+, ICI 206,970 having a somewhat greater effect than amiloride at this dose. ICI 206,970 also reduced water reabsorption by the distal tubule. ICI 206,970 was infused i.v. at a dose of 10 mg/kg/hr into anesthetized rats, and its effect on reabsorption by various nephron segments was determined. This compound tended to reduce proximal reabsorption of Na+, K+ and water, but had little effect on reabsorption of electrolytes and water by the loop of Henle, or distal tubule reabsorption of Na+ and water. Distal K+ secretion decreased after administration of ICI 206,970. Reabsorption of electrolytes and water beyond the late distal nephron was not affected by the drug. Urinary excretion of Na+ and water was elevated, but K+ excretion remained unchanged after treatment with ICI 206,970. The sites of action of ICI 206,970 appear to be the proximal and distal nephron. Urinary excretion of Na+ and water was largely dependent on the effect of ICI 206,970 on proximal reabsorption, as this compound had little effect on loop of Henle or distal tubule reabsorption.(ABSTRACT TRUNCATED AT 250 WORDS)
Johnston
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PA
Department of Pharmacology, ICI Pharmaceuticals Group, A Business Unit of ICI Americans Inc., Wilmington, Delaware.
Kau
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D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004232:Diuretics / Q000494:pharmacology*; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D007684:Kidney Tubules / Q000187:drug effects / Q000378:metabolism; D008297:Male; D010477:Perfusion; D011188:Potassium / Q000378:metabolism*; D011677:Punctures; D011719:Pyrazines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D004232:Diuretics; D011719:Pyrazines; C079771:ICI 206970; D011188:Potassium