Effects of amiloride and a novel diuretic, 7-chloro-2,3-dihydro-1-(2-methylbenzoyl)-4(1H)-quinolinone-4-oxime-o-su lfonic acid, potassium salt (M17055), on calcium transport in the rabbit connecting tubule.
To elucidate the mechanisms of relative anticalciuric effect of a diuretic, 7-chloro-2,3-dihydro-1-(2-methylbenzoyl)-4(1H)-quinolinone-4-oxime-o-sul fonic acid, potassium salt (M17055), having sites of action on the Henle's loop plus the distal nephron segments, we measured intracellular calcium concentration ([Ca++]i) of the rabbit connecting tubule perfused in vitro by using the microscopic fluorometry with fura 2. First, we confirmed that parathyroid hormone increases [Ca++]i by a mechanism mediated by cyclic AMP. We also confirmed that the Na+/Ca++ exchanger in the basolateral membrane is essential for the extrusion of Ca++ across this membrane. In the presence of 10 nM parathyroid hormone in the bath, the elimination of Na+ from the lumen decreased [Ca++]i, supporting the view that a decrease in Na+ supply from the apical membrane enhances the Na+/Ca++ exchanger in the basolateral membrane. Under a similar condition, the addition of 10 microM amiloride in the lumen also decreased [Ca++]i, further supporting the view that the inhibition of Na+ entry across the apical membrane causes similar effect as does Na+ elimination. Under a similar condition, the addition of 1 mM M17055 in the lumen exerted a similar effect on [Ca++]i as did amiloride. Because M17055 did not further decrease [Ca++]i when Na+ was eliminated from the lumen, the effect of M17055 is mediated by an inhibition of Na+ entry across the apical membrane. From these observations we conclude that either inhibition or diminution of Na+ entry across the apical membrane of the connecting tubule increases the Ca++ extrusion across the basolateral membrane via the Na+/Ca++ exchanger.(ABSTRACT TRUNCATED AT 250 WORDS)
Yamasaki
F
F
Department of Pharmacology, Jichi Medical School, Tochigi, Japan.
Yoshitomi
K
K
Shinkawa
T
T
Imai
M
M
D000584:Amiloride / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000187:drug effects / Q000378:metabolism*; D002463:Cell Membrane Permeability; D005576:Colforsin / Q000494:pharmacology; D004232:Diuretics / Q000494:pharmacology*; D066298:In Vitro Techniques; D007424:Intracellular Fluid / Q000378:metabolism; D007684:Kidney Tubules / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D009399:Nephrons / Q000187:drug effects / Q000378:metabolism; D010091:Oximes / Q000494:pharmacology*; D010281:Parathyroid Hormone / Q000494:pharmacology; D015363:Quinolones / Q000494:pharmacology*; D011817:Rabbits; D012964:Sodium / Q000378:metabolism / Q000493:pharmacokinetics
D002135:Calcium-Binding Proteins; D004232:Diuretics; D010091:Oximes; D010281:Parathyroid Hormone; D015363:Quinolones; D005576:Colforsin; C079648:7-chloro-2,3-dihydro-1-(2-methylbenzoyl)-4(1H)-quinolinone 4-oxime-O-sulfonic acid; D000584:Amiloride; D012964:Sodium; D002118:Calcium