Agents Which Primarily Increase Free Water Clearance

The kidney increases plasma osmolality by excreting a urine which is dilute with respect to the plasma (increased free water excretion) and reduces plasma osmolality by excreting a urine which is concentrated with respect to the plasma (increased free water reabsorption). As shown in Fig. 1, the nephron dilutes the urine by reabsorbing solute (predominantly NaCl) without water primarily in the thick ascending limb (TAL). In the absence of ADH, this dilute urine is mostly excreted. The reabsorption of solute in the absence of water in the thick ascending limb, coupled with the action of the countercurrent ar-

Diuretic Agents: Clinical Physiology and Pharmacology

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Apical

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FIGURE 1. Schematic of the nephron with principal pathways of salt and water transport shown for several key segments. AA, afferent arteriole; EA, efferent arteriole; PT, proximal tubule; TAL, thick ascending limb; DCT, distal convoluted tubule; CCD, cortical collecting duct; MCD medullary collecting duct. For PT, TAL, DCT, CCD, and MCD, representative epithelial cells with transport pathways are shown, including the Na/K-ATPase in all cell types, the Na+/H+ exchanger in the PT, the Na+/K+/2C1~ cotransporter in TAL, the Na+/Cl~ cotransporter in DCT, as well as apical Na+, K+, and water channels in collecting duct segments.

rangement of the vasculature and tubules in the medulla, lead to the development of an interstitial osmolality which is markedly hypertonic with respect to the plasma. In response to increases in plasma osmolality, a fall in blood pressure, and reduced effective circulating volume, ADH is released from the posterior pituitary. ADH stimulates insertion of water channels into the apical membranes of the collecting duct (see Fig. 2), permitting reabsorption of water from the lumen into the hypertonic interstitium and excretion of a concentrated urine. In some species ADH also promotes the development of a hypertonic interstitium by stimulating thick ascending limb salt reabsorption.

Image Camp Aquaporin

the association of the three subunits of the stimulatory G protein heterotrimer (as, (3, and -y sub-units) with adenylate cyclase (AC), leading to stimulation of cAMP generation. cAMP augments transcription of Aquaporin II mRNA chronically, increading the levels of water channel proteins. cAMP acutely augments insertion of water channel containing vesicles into the apical membrane as well.

the association of the three subunits of the stimulatory G protein heterotrimer (as, (3, and -y sub-units) with adenylate cyclase (AC), leading to stimulation of cAMP generation. cAMP augments transcription of Aquaporin II mRNA chronically, increading the levels of water channel proteins. cAMP acutely augments insertion of water channel containing vesicles into the apical membrane as well.

Most diuretic agents increase urine volume by reducing net reabsorption of NaCl and obligating excretion of increased water. However, in salt-retentive conditions such as congestive heart failure, cirrhosis, and nephrotic syndrome, effective circulating volume is decreased. The neurohypophyseal and renal responses to reduced effective circulating volume include increased circulating levels of ADH, resulting in increased free water reabsorption and hyponatremia. The availability of agents which block specifically free water reabsorption in response to ADH would prevent hyponatremia in these conditions and also in patients with the syndrome of inappropriate ADH secretion [31]. As shown in Fig. 2, there are several sites at which agents could potentially block the water-reabsorptive response, including antagonists of ADH, agents which disrupt the transmission of the ADH signal via cAMP and protein kinase A, and agents which block water channels [60].

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  • martha
    How to increase free water clearance?
    11 months ago

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