Loop diuretics: from the Na-K-2Cl transporter to clinical use.
The diuretic response to loop diuretics in various disease states has consistently been found to be subnormal. One of the key determinants of the degree of diuretic response is the functional integrity of the sodium-potassium-chloride transporter in the loop of Henle. Studies in animal models suggest that expression/activity of the transporter may be affected by factors such as altered natural splicing events of NKCC2 (the gene encoding for the renal transporter), renal prostanoids, vasopressin, and other autacoids. We have reviewed the pharmacokinetics and pharmacodynamics of loop diuretics in health and in edematous disorders for which they are used. On the basis of evidence reviewed in this paper, we propose that altered expression or activity of the sodium-potassium-chloride transporter in the loop of Henle, in conjunction with events occurring in other segments of the nephron, possibly accounts for the altered diuretic response to these agents. Thus the modulators of this altered expression/activity could serve as important therapeutic targets for alternative diuretic regimens in these conditions.
Shankar
Sudha S
SS
Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indianapolis 46202-5124, USA.
Brater
D Craig
DC
D000818:Animals; D004232:Diuretics / Q000627:therapeutic use*; D006333:Heart Failure / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D008138:Loop of Henle / Q000378:metabolism*; D028021:Sodium-Potassium-Chloride Symporters / Q000378:metabolism*
D004232:Diuretics; D028021:Sodium-Potassium-Chloride Symporters