X

urinary H;Os space

urinary H;Os space ft IMWIHIMMBB

basolateral space

FIGURE 7. Model for NaCl absorption in the thick ascending limb of Henle.

Ascending Limb

Model of NaCl Transport

The mechanism of all salt reabsorption by the thick ascending limb of Henle is well understood and is shown schematically in the model depicted in Fig. 7. The thick ascending limb reabsorbs about 10-15% of the filtered NaCl. The entry of each sodium ion across the apical membrane of thick ascending limb cells is directly and tightly coupled to one potassium ion and two chloride ions by the Na/K/2C1 cotransporter, a process that is electroneutral. The entry of these ions is a secondary active transport process since it depends on the low intracellular Na+ that is maintained by the primary active extrusion of Na+ from the cell by the basolateral (Na+/K+/ATPase (Na+-pump). Since the luminal membrane is relatively impermeable to water, NaCl absorption is responsible both for urinary dilution and for generating the classic "single" effect (active transport step) for countercurrent multiplication that is essential for urine concentration.

Much of the potassium that enters the cell by Na/K/2C1 cotransport recycles back to the tubular urine through potassium channels, a process that has two major consequences. First, it replenishes the urinary K+ that would otherwise be lost through absorption by the Na/K/2C1 cotransporter. This step ensures a virtually inexhaustible supply of tubular K+ necessary for reabsorption of the large fraction of Na+ load transported by the thick ascending limb. Thus, without K+ recycling, tubular fluid K+ concentrations in the thick ascending limb would fall to levels that would limit the amount of NaCl that could be reabsorbed by this nephron segment. In addition, K+ recycling across the apical membrane produces an electrical current that results in a lumen-positive trans-epithelial voltage. This voltage, in turn, provides the driving force for a para-cellular current that carries 50% of the total Na+ reabsorbed by the thick ascending limb (see Fig. 7). Studies of the rabbit, rat, and mouse thick ascending limb have shown that blockade of these apical K+ channels both abolishes the transepithelial voltage and substantially reduces net NaCl reabsorption.

From the salt transport model of the thick ascending limb shown in Fig. 7 it is evident that pharmaceutical agents could function as loop diuretics if they effectively interfered with any of the steps crucial for transepithelial NaCl movement. Although this can be accomplished in isolated thick ascending limb cells or tubule segments by the application of drugs that inhibit basolateral transport processes (e.g., inhibition of the Na+/K+/ATPase by cardiac glycosides such as ouabain or inhibition of the CI" channel by a variety of anion channel blockers) no such compounds have yet been found that are clinically useful as diuretics. On the other hand, certain pharmaceutical agents affecting apical transport processes do make clinically useful diuretics. These apical transport processes are especially vulnerable to inhibition in the clinical setting because they face a specialized compartment (urinary space) in which the concentrations of diuretic drugs can achieve effective inhibitory levels as a result of both proximal tubular secretion and proximal volume reabsorption. Only drugs directly inhibiting the apical Na/K/2C1 cotransporter [i.e., furosemide (Lasix), bumetanide (Bumex), torsemide (Demadex), and ethacrynic acid (Edecrin)] have found their way into clinical practice in this country. Several others, notably, piretanide, and azosemide, have comparable action but have not been approved for clinical use in the United States.

These drugs are extensively bound to plasma proteins. Nonetheless, the primary mode of elimination is urinary excretion. Because they are bound to plasma proteins, their entry into the tubular fluid is dependent on active secretion of the diuretics by the proximal tubule. Systemic effects of these agents on Na/K/2C1 cotransport processes in nonrenal tissues are generally absent or minimal since plasma concentrations usually are below effective inhibitor levels. High plasma concentrations leading to systemic toxic effects such as deafness can result, however, when large quantities of these loop diuretics are given to patients with impaired renal function. Potassium channel inhibitors should also make potent diuretics but clinically effective and selective agents are not yet available. One class of agents, sulfonylureas, which can inhibit these K+ channels (see discussion below) have been shown in loop perfusion studies to inhibit NaCl absorption in the thick ascending limb and result in natriuresis and chloruresis.

Other Physiological Consequences of Inhibiting NaCl Absorption in the Thick Ascending Limb

A number of other transport processes are affected by inhibition of NaCl reabsorption by the thick ascending limb. Some of these effects can be readily understood from the transport model of the thick ascending limb shown in Fig. 7. First, since NaCl absorption is essential to both the concentrating and the diluting processes loop diuretics result in excretion of urine with an osmolality approaching that of plasma. Second, the NaCl transport-related lumen-positive transepithelial voltage drives passive calcium and magnesium reabsorption through the paracellular pathway. Thus, loop diuretics can result in frank cal-ciuria and magnesuria, with attendant hypomagnesemia in some instances. Comparable effects on serum calcium do not occur. Conversely, because of their effects on calcium and magnesium excretion, loop diuretics are used clinically in treating hypercalcemia or hypermagnesemia.

The action of loop diuretics on the thick ascending limb also results in increased delivery of NaCl to more distal nephron segments. A variable fraction of this salt is reabsorbed by the distal convoluted tubule and collecting duct. This additional NaCl reabsorption can modulate the magnitude of the natriuresis produced by diuretics like furosemide. During clinical conditions resulting in heightened renal NaCl absorption (such as states of extracellular fluid volume depletion from vomiting, diarrhea, or blood loss; congestive heart failure; or cirrhosis) this distal reabsorption may severely limit loop diuretic-mediated natriuresis. The reduced effectiveness of loop diuretics is due to at least two consequences of volume-depletion states. First, as described earlier, the increased fraction of NaCl and volume reabsorbed by proximal tubules reduces the delivery of NaCl to the thick ascending limb and consequently the amount of NaCl that can be inhibited by diuretics is diminished. Second, NaCl reabsorption by the distal convoluted tubule and collecting duct (see Figs. 11 and 14), which, like that in the thick ascending limb, is also load-dependent, is enhanced so that larger absolute and fractional amounts of delivered NaCl are reabsorbed. The interplay of many hormonal systems (e.g., renin-aldosterone, atrial natriuretic peptides, antidiuretic hormone, kinins, and prostaglandins) can alter these distal NaCl reabsorption processes and affect the natriuretic effectiveness of loop diuretics.

There are two major physiological consequences of the increased delivery of NaCl to more distal nephron segments. First, NaCl reabsorption in the distal convoluted tubule is load- and flow-dependent so that increased delivery results in greater NaCl reabsorption by this nephron segment. Second, calcium reabsorption by both the distal convoluted tubule and connecting tubule, in contrast, is inversely related to NaCl reabsorption. Thus, increased NaCl delivery results in reduced reabsorption of calcium by both these nephron segments. This latter effect significantly enhances the calciuric potential of loop diuretics. Moreover, increased NaCl delivery to the cortical collecting duct (see Fig. 14) enhances K+ secretion and increases kaluresis (see Diuretics Affecting Collecting Duct Salt Transport, below, for further details). The loop diuretic-induced kaluresis and extracellular fluid volume depletion can, in turn, lead to significant hypokalemia and metabolic alkalosis.

Was this article helpful?

0 0
Supplements For Diabetics

Supplements For Diabetics

All you need is a proper diet of fresh fruits and vegetables and get plenty of exercise and you'll be fine. Ever heard those words from your doctor? If that's all heshe recommends then you're missing out an important ingredient for health that he's not telling you. Fact is that you can adhere to the strictest diet, watch everything you eat and get the exercise of amarathon runner and still come down with diabetic complications. Diet, exercise and standard drug treatments simply aren't enough to help keep your diabetes under control.

Get My Free Ebook


Post a comment