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Adenosine is an unphosphorylated ribonucleoside whose actions in the kidney have been intensively studied. As in all tissues, renal adenosine concentrations rise in response to hypoxia and ATP consumption. In most tissues, hypoxia results in compensatory vasodilation and, if cardiac output is sufficient, increased blood flow. The kidney has different requirements because increased blood flow leads to an increase in GFR and greater solute delivery to the tubules. This increased delivery would increase tubule work and ATP consumption. In contrast, in the hypoxic kidney, ade-nosine actually decreases blood flow and GFR. Because the medulla is always more hypoxic than the cortex, adenosine increases Na+ reabsorption from the reduced flow in the cortex, so that delivery to medullary segments will be even further reduced.
There are four distinct adenosine receptors (A1, A2a, A2b, and A3), all of which have been found in the kidney. However, prob-ably only one of these (A1) is of importance with regard to the pharmacology of diuretics. The adenosine A1 receptor is found on the pre-glomerular afferent arteriole, as well as the PCT and most other tubule segments. Adenosine is known to affect ion transport in the PCT, the medullary TAL, and collecting tubules. In addi-tion, adenosine (via A1 receptors on the afferent arteriole) reduces blood flow to the glomerulus (and GFR) and is also the key signal-ing molecule in the process of tubuloglomerular feedback (, under Heart Failure).
In addition to its effects on GFR, adenosine significantly alters Na+ transport in several segments. In the proximal tubule, adenos-ine has a biphasic effect on NHE3 activity: enhancement at low concentrations and inhibition at very high concentrations. However, adenosine receptor antagonists have generally been found to block the enhancement of NHE3 activity and thus exhibit diuretic activity . It is particularly interesting that unlike other diuretics that act upstream of the collecting tubules, adenosine antagonists do not cause wasting of K. This important finding suggests that in addition to their effects on NHE3, adenosine antagonists must also blunt K+ secretion in the cortical collecting tubule. Adenosine A1 receptors have been found in the collecting tubule, but the precise mechanism by which adenosine blunts K+ secretion is not well understood.
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