Sites And Modes Of Action

Proximal convoluted tubule

Some 65% of the filtered sodium is actively transported from the lumen of the proximal tubule by the sodium pump (Na+, K+-ATPase). Chloride is absorbed passively, accompanying the sodium; bicarbonate is also absorbed, through the action of carbonic anhydrase. These solute shifts give rise to the iso-osmotic reabsorption of water, with the result that > 70% of the glomerular filtrate is returned to the blood from this section of the nephron. The epithelium of the proximal tubule is described as 'leaky' because of its free permeability to water and a number of solutes. Osmotic diuretics such as mannitol are solutes which are not reabsorbed in the proximal tubule (site 1. Fig. 26.1) and therefore retain water in the tubular fluid. Their effect is to increase water rather than sodium loss, and this is reflected in their special use acutely to reduce intracranial or intraocular pressure and not states associated with sodium overload.

Loop of Henle

The tubular fluid now passes into the loop of Henle where 25% of the filtered sodium is reabsorbed. There are two populations of nephron: those with short loops that are confined to the cortex, and the juxtamedullary nephrons whose long loops penetrate into the inner parts of the medulla and are principally concerned with water conservation;1 the following discussion refers to the latter. The physiological changes are best understood by considering first the ascending limb. In the thick segment (site 2, Fig. 26.1), sodium and chloride ions are transported from the tubular fluid into the interstitial fluid by the three-ion co-transporter system (i.e. Na+/K+/ 2CT) driven by the sodium pump. Since the tubule epithelium is 'tight' here i.e. impermeable to water, the tubular fluid becomes dilute, the interstitium becomes hypertonic and fluid in the descending limb, which is permeable to water, becomes more concentrated as it approaches the tip of the loop, because the hypertonic interstitial fluid sucks water out of this limb of the tubule. The 'hairpin' structure of the loop thus confers on it the property of a countercurrent multiplier, i.e. by active transport of ions a small change in osmolality laterally across the tubular epithelium is converted into a steep vertical osmotic gradient. The high osmotic pressure in the medullary interstitium is sustained by the descending and ascending vasa recta, long blood vessels of capillary thickness which lie close to the loops of Henle and act as countercurrent exchangers, for the incoming blood receives sodium from the outgoing blood.2 Frusemide (furosemide), bumetanide, piretanide, torasemide and ethacrynic acid act principally at site 2 by inhibiting the three-ion transporter system, thus preventing sodium ion reabsorption and lowering the osmotic gradient between cortex and medulla; this results in the formation of large volumes of dilute urine. These drugs are called the loop diuretics.

As the ascending limb of the loop re-enters the renal cortex, sodium continues to be removed from the tubular fluid by the sodium pump, accompanied electrostatically by chloride. Both ions pass into the interstitial tissue (site 3) from which they are rapidly removed because cortical blood flow is high and there are no vasa recta present; consequently the urine becomes more dilute. Thiazides act principally at this cortical diluting segment of the ascending limb, preventing sodium reabsorption. They inhibit the NaCl co-transporter (called NCCT).

Distal convoluted tubule and collecting duct

In the distal tubule (site 4), sodium ions are exchanged for potassium and hydrogen ions. The sodium ions are transported across the epithelial Na channel (called ENaC), which is stimulated by aldosterone. The aldosterone (mineralocorticoid)

1 Beavers occupying a watery habitat have nephrons with short loops, while those of the desert rat have long loops.

2 The most easily comprehended countercurrent exchange mechanism (in this case for heat) is that in wading birds in cold climates whereby the veins carrying cold blood from the feet pass closely alongside the arteries carrying warm blood from the body and heat exchange takes place. The result is that the feet receive blood below body temperature (which does not matter) and the blood from the feet which is often very cold, is warmed before it enters the body so that the internal temperature is more easily maintained. The principle is the same for maintaining renal medullary hypertonicity.

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