Site and Mechanism of Diuretic Action

Peter A. Friedman and Steven C. Hebert

Dartmouth Medical School, Department of Pharmacology and Toxicology, Hanover,

New Hampshire 03755-3835; and Vanderbilt University Medical School, Division of Nephrology,

Nashville, Tennessee 37215

INTRODUCTION

Diuretics are a diverse group of chemical compounds that share the ability to augment net renal sodium excretion. These agents are widely used in clinical medicine for the treatment of hypertension, pulmonary or cerebral edema, and other disorders that are characterized by the accumulation of fluid in the interstitial or extracellular compartments. Detailed discussions of the therapeutic use of diuretics can be found elsewhere in this text. The goal of the present chapter is to provide the reader with an understanding of the site and mechanisms of diuretic effects, with particular emphasis on recent insights into their cellular mechanisms of action and the molecular biology of the transport proteins that they inhibit.

Diuretics can be conveniently divided into four classes: osmotic diuretics and carbonic anhydrase inhibitors like mannitol and acetazolamide, respectively, which act in proximal tubules; loop diuretics such as furosemide that inhibits sodium transport in thick ascending limbs of Henle's loop; thiazide and thiazide-type diuretics that act in distal tubules; and the weak diuretics amiloride and triamterene that act in collecting ducts and are used primarily for their potassium-sparing action. The nephron sites of action of these different agents are summarized in Fig. 1.

Diuretic Agents: Clinical Physiology and Pharmacology

Copyright © 1997 by Academic Press. All rights of reproduction in any form reserved.

PROXIMAL

distal

PROXIMAL

distal

COLLECTING □ UCT

AmilorideiTramterene-Type Diuretics

Loop of HENLE

FIGURE 1. Sites of action of the four classes of diuretics.

AmilorideiTramterene-Type Diuretics

Loop of HENLE

COLLECTING □ UCT

FIGURE 1. Sites of action of the four classes of diuretics.

When these compounds were initially developed there was little understanding of cellular ion transport mechanisms and hence few details known of how they work. Physiological investigations over the past 25 years, however, have revealed that each class of diuretic inhibits a specific ion transport protein in the kidney. Moreover, the NaCl absorption mechanisms along the mammalian nephron from proximal tubule to papillary collecting duct have been defined and characterized. In this regard, the most exciting new information has come from the cloning of members of each class of diuretic-sensitive Na+ transporter, as well as other transporters or enzymes important to salt absorption and diuretic action. Many laboratories are currently engaged in research focusing on defining the structural sites for ion transport and diuretic binding and the molecular mechanisms of transport regulation. This information may enable the design of new diuretics and provide the basis for improved use of diuretics.

Drugs that owe their diuretic effects to the physical retention of fluid within the nephron rather than to a direct action on cellular sodium transport are called osmotic diuretics. Osmotic diuretics are nonelectrolytes that are freely filtered at the glomerulus and not reabsorbed to a significant extent. Any poorly absorbable solute whose transport maximum is exceeded can also effect such a diuretic action. For instance, in severe hyperglycemia the filtered load of glu

Was this article helpful?

0 0
Reducing Blood Pressure Naturally

Reducing Blood Pressure Naturally

Do You Suffer From High Blood Pressure? Do You Feel Like This Silent Killer Might Be Stalking You? Have you been diagnosed or pre-hypertension and hypertension? Then JOIN THE CROWD Nearly 1 in 3 adults in the United States suffer from High Blood Pressure and only 1 in 3 adults are actually aware that they have it.

Get My Free Ebook


Post a comment