AVP-sensitive cAMP production is dependent on calmodulin in both MTAL and MCT.
Vasopressin (AVP) plays a key role in maximal urine concentration by stimulating NaCl reabsorption in the medullary thick ascending limbs of Henle (MTAL) and by increasing water permeability in the medullary collecting tubules (MCT). These effects of AVP in MTAL and MCT are mediated by activation of adenylate cyclase. Because effects of high ambient Ca2+ on AVP-sensitive adenosine 3',5'-cyclic monophosphate (cAMP) production are quite different in MTAL and MCT, we examined whether the Ca2+-calmodulin system is involved differently in AVP-sensitive cAMP production in MTAL and MCT of mouse kidney using two dissimilar calmodulin inhibitors, trifluoperazine (TFP) and W-7. TFP and W-7 inhibited AVP-sensitive cAMP production in both nephron segments in a dose-dependent manner with maximal inhibition of both agents being greater than 90%. A half-maximal inhibition by TFP and W-7 was about 45, 100 microM in MTAL and about 40, 40 microM in MCT, respectively. The inhibitory effect of W-5, a chemically similar to W-7 but less potent calmodulin inhibitor, was significantly less than that of W-7 in both nephron segments. TFP and W-7 but not W-5 also inhibited glucagon-sensitive cAMP production in MTAL. W-7 inhibited forskolin-sensitive cAMP production but the inhibition by W-5 was significantly less than that by W-7 in MTAL and MCT. Results suggest that AVP-sensitive cAMP production is MCT.(ABSTRACT TRUNCATED AT 250 WORDS)
Takaichi
K
K
Fourth Department of Internal Medicine, University of Tokyo, School of Medicine, Japan.
Kurokawa
K
K
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D001127:Arginine Vasopressin / Q000494:pharmacology*; D002147:Calmodulin / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000096:biosynthesis*; D004789:Enzyme Activation / Q000187:drug effects; D005934:Glucagon / Q000494:pharmacology; D007684:Kidney Tubules / Q000378:metabolism*; D007685:Kidney Tubules, Collecting / Q000187:drug effects / Q000378:metabolism*; D008138:Loop of Henle / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D013449:Sulfonamides / Q000494:pharmacology; D014268:Trifluoperazine / Q000494:pharmacology
D002147:Calmodulin; D013449:Sulfonamides; D001127:Arginine Vasopressin; D005576:Colforsin; D014268:Trifluoperazine; C017967:W 7; C034700:N-(6-aminohexyl)-1-naphthalenesulfonamide; D005934:Glucagon; D000242:Cyclic AMP; D000262:Adenylyl Cyclases