Collecting tubules

Potassium-Sparing Diuretics. Potassium-sparing diuretics act on the aldosterone-sensitive portion of cortical collecting tubules, and partially in the distal convoluted tubules of the nephron. The commonly used potassium-sparing diuretics are triamterene, amiloride, and spironolactone (Table 3). Spironolactone is a competitive aldosterone receptor antagonist, whereas triamterene and amiloride are not (44,45). 

The answer is c. (Katzung, p 493.) Lithium treatment frequently causes polyuria and polydipsia. The collecting tubule of the kidney loses the capacity to conserve water via anti diuretic hormone. This results in significant free-water clearance, which is referred to as nephrogenic diabetes insipidus. 

Grenier, F.C. (1986). Characteristics of renal collecting tubule cells in primary culture. Mineral Electrolyte Metab. 12 58-63. 

Sodium reabsorption Much less than 10% of the filtered load of NaCl reaches the distal nephron. Regulation of Na uptake, occurring mainly in the principal cells of the cortical collecting tubule, is controlled by the steroid hormone aldosterone (see Section 4.4). The net effect of aldosterone is the reclamation of NaCl and potassium excretion in to the luminal fluid. 

Renal effects have been observed in both male and female rats in a chronic-duration oral study. Male Fischer 344 rats exposed to 1,4-dichlorobenzene at 150 and 300 mg/kg/day for 2 years exhibited nephropathy, epithelial hyperplasia of the renal pelvis, mineralization of the collecting tubules in the renal medulla, and focal hyperplasia of the tubular epithelium. Each of these effects was associated with hyalin droplet formation. There were also increased incidences of nephropathy in female Fischer 344 rats dosed with 1,4-dichlorobenzene at 300 and 600 mg/kg/day. Histopathologically, the nephropathy was characterized by degeneration and regeneration of the tubular epithelium, tubular dilatation with attenuation and atrophy of the epithelium, granular casts in the tubules of the outer stripe of the medulla, thickening of the basement membranes, and minimal accumulation of interstitial collagen (NTP 1987). 

The smallest functional unit of the kidney is the nephron. In the glomerular capillary loops, ultrafiltration of plasma fluid into Bowman s capsule (BC) yields primary urine. In the proximal tubules (pT), approx. 70% of the ultrafiltrate is retrieved by isoosmotic reabsorption of NaCl and water. In the thick portion of the ascending limb of Henle s loop (HL), NaCl is absorbed unaccompanied by water. This is the prerequisite for the hairpin countercurrent mechanism that allows build-up of a very high NaQ concentration in the renal medulla In the distal tubules (dT), NaCl and water are again jointly reabsorbed. At the end of the nephron, this process involves an aldosterone-controlled exchange of Na+ against 1C or H. In the collecting tubule (C), vasopressin (antidiuretic hormone, ADH) increases the epithelial permeability for water, which is drawn into the hyperosmolar milieu of the renal medulla and thus retained in the body. As a result, a concentrated urine enters the renal pelvis. 

After a single exposure of rabbits to 17 ppm for 6 hours, the sensory trigeminal nucleus was severely affected. Other effects included tubular and focal necrosis in the collecting tubules of the kidney and fatty degeneration of the liver. ... 

Amiloride and triamterene-Am or 6e and triamterene not only inhibit sodium reabsorption induced by aldosterone, but they also inhibit basal sodium reabsorption. They are not aldosterone antagonists, but act directly on the renal distal tubule, cortical collecting tubule and collecting duct. They induce a reversal of polarity of the transtubular electrical-potential difference and inhibit active transport of sodium and potassium. Amiloride may inhibit sodium, potassium-ATPase. 

Aldosterone acts on the late distal tubules and collecting tubule cells by combining with an intracellular receptor which induces the formation of aldosterone induced protein, which promotes Na+ reabsorption and K+ secretion. 

Figure 12.1 Site of action of diuretics on the nephron. PCT, proximal convoluted tubule LoH, Loop of Henie DCT, distal convoluted tubule CT, collecting tubule.

Figure 12.6 Mechanism of action of mineralocortjcoid receptor antagonists in the collecting tubule. Aldosterone enters the tubular cell by the basolateral surface and binds to a specific mineralocorticoid receptor (MNR) in the cytoplasm. The hormone receptor complex triggers the production of an aldosterone-induced protein (AlP) by the cell nucleus (NUC). The AIP acts on the sodium ion channel (ic) to augment the transport of Na+across the basolateral membrane and in to the cell. An increase in AIP activity leads to the recruitment of dormant sodium ion channels and Na pumps (P) in the cell membrane. AIP also leads to the synthesis of new channels and pumps within the cell. The increase in Na+conductance causes electrical changes in the luminal membrane that favour the excretion of intracellular cations, such as K+and H-h. Spironolactone competes with aldosterone for the binding site on the MNR and forms a complex which does not excite the production of AIP by the nucleus.

Acidosis and alkalosis are infrequent. Metabolic acidosis is a side effect of acetazolamide therapy and is due to bicarbonate loss in the PCT. All the K+-sparing diuretics can cause metabolic acidosis by H+ retention in the cells of the collecting duct. Metabolic alkalosis is associated with the loop and thiazide drugs. Reflex responses to volume depletion cause reabsorption of HCO-3 in the PCT and H+ secretion in the collecting tubule. 

Spironolactone Block aldosterone receptor in renal collecting tubule Increase Na and decrease excretion poorly understood reduction in heart failure mortality Aldosteronism, heart failure, hypertension ... 

Spironolactone Block cytoplasmic aldosterone receptors in collecting tubules of nephron possible membrane effect Increased salt and water excretion reduces remodeling reduces mortality Chronic heart failure aldosteronism (cirrhosis, adrenal tumor) hypertension Oral duration 24-72 h (slow onset and offset) Toxicity Hyperkalemia, antiandrogen actions... 

Cortical collecting tubule (CCT) Na+ reabsorption (2-5%) coupled to K+ and H+ secretion Variable2 Na channels (ENaC), channels,1 H transporter,1 aquaporins K+-sparing diuretics... 

Ion transport pathways across the luminal and basolateral membranes of collecting tubule and collecting duct cells. Inward diffusion of Na+ via the epithelial sodium channel (ENaC) leaves a lumen-negative potential, which drives reabsorption of and efflux of K+. (R, aldosterone receptor.)... 

Potassium-sparing diuretics prevent K+ secretion by antagonizing the effects of aldosterone at the late distal and cortical collecting tubules. Inhibition may occur by direct pharmacologic antagonism of mineralocorticoid receptors ( spironolactone, eplerenone ) or... 

Amiloride and triamterene are direct inhibitors of Na+ influx in the CCT (cortical collecting tubule). Triamterene is metabolized in the liver, but renal excretion is a major route of elimination for the active form and the metabolites. Because triamterene is extensively metabolized, it has a shorter half-life and must be given more frequently than amiloride (which is not metabolized). 

Spironolactone and eplerenone bind to mineralocorticoid receptors and blunt aldosterone activity. Amiloride and triamterene do not block aldosterone, but instead directly interfere with Na+ entry through the epithelial Na+ channels (ENaC) in the apical membrane of the collecting tubule. Since K+ secretion is coupled with Na+ entry in this segment, these agents are also effective potassium-sparing diuretics. 

Antidiuretic hormone antagonists inhibit the effects of ADH in the collecting tubule. Conivaptan is a pharmacologic antagonist at Via and V2 receptors. Both lithium and demeclocycline appear to reduce the formation of cyclic adenosine monophosphate (cAMP) in response to ADH. 

Another serious toxicity of diuretic use, particularly in the cardiac patient, is hypokalemia. Hypokalemia can exacerbate underlying cardiac arrhythmias and contribute to digitalis toxicity. This can usually be avoided by having the patient reduce Na+ intake, thus decreasing Na+ delivery to the K+ -secreting collecting tubule. Patients who are noncompliant with a low Na+ diet must take oral KCI supplements or a K+-sparing diuretic. 

Certain forms of renal disease, particularly diabetic nephropathy, are frequently associated with development of hyperkalemia at a relatively early stage of renal failure. In these cases, a thiazide or loop diuretic will enhance K+ excretion by increasing delivery of salt to the K+-secreting collecting tubule. 

Amiloride Blocks epithelial sodium channels in collecting tubules Reduces Na retention and wasting increases lithium clearance Hypokalemia from other diuretics reduces lithium-induced polyuria Orally active duration 24 h Toxicity Hyperkalemic metabolic acidosis... 

Vasopressin activates two subtypes of G protein-coupled receptors (see Chapter 17). Vi receptors are found on vascular smooth muscle cells and mediate vasoconstriction. V2 receptors are found on renal tubule cells and reduce diuresis through increased water permeability and water resorption in the collecting tubules. Extrarenal V2-like receptors regulate the release of coagulation factor VIII and von Willebrand factor. 

The ureteric bud develops into the ureter, and the swelling at its end becomes the renal pelvis. The repeated branching of the ureteric bud results in the formation of the major and minor calyces (the large ducts that empty into the renal pelvis) and the system of collecting tubules. The two major calyces form from the first branching of the ureteric bud, around the end of the 6th week. 

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