urea transporter UT] (UT-A, UTA-1) molecules into the apical

membranes of collecting duct cells in the medulla.

Urea concentration in the medulla plays an important role

maintaining the high osmolarity of the medulla and in the concen-
tration of urine. ADH secretion is regulated by serum osmolality
and by volume status. A new class of drugs, the vaptans (see Agents
That Alter Water Excretion), are ADH antagonists.

RENAL AUTACOIDS

A number of locally produced compounds exhibit physiologic

effects within the kidney and are therefore referred to as autacoids,
or paracrine factors. Several of these autacoids (adenosine, the pros-
taglandins, and urodilatin) appear to have important effects on the
pharmacology of diuretics. Since these effects are complex, they
will be treated independently of the individual tubule segments
discussed above.

ADENOSINE
iene Se eee
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 zlome-ule: fltcetion vate (GPR)
and greater solute delivery to the iubules. This sncressed delivery
would increase tubule work and Ai? consumption. In contrast,
in the hypoxic kidney, adenosine actualiy 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 (A;, Az, Ayp

and A), all of which have been found in the kidney. However,
probably only one of these (Aj) is of importance. The nile
A, 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 addition, adenosine (via A, recep di
on the afferent arteriole) reduces blood flow to the glomeru us
(and GFR) and is also the key signaling molecule in the p nis s
tubuloglomerular feedback. Adenosine receptor Se a
generally been found to block the enhancement oid :; sla
ity and thus exhibit diuretic activity (see below). Ic is ses’ ie
collecting tubules, adenosine antagonists do no
of kK’,

PROSTAGLANDINS

d to
Prostaglandins contribute importantly to renal phyicroBy OY
the function of many other organs a ae thromboxane
glandin subtypes (PGE, PGI,, PGDz PGhow