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

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 glomerular filtration rate (GFR)
and greater solute delivery to the tubules. This increased delivery
would increase tubule work and A}? consumption. In contrast,
in the hypoxic kidney, adenosine actually decreases blood flow
and GFR. Because the medulla is alvays more hypoxic than the
cortex, adenosine increases “.." scatsorption from the reduced
flow in the cortex, so that c«!:veiy co medullary segments will be
even further reduced.

There are four distinct adenosine receptors (Ay, Ap, Agps

and A), all of which have been found in the kidney. However,
probably only one of these (A,) is of importance. The adenosine
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, receptors
on the afferent arteriole) reduces blood flow to the glomerulus
(and GFR) and is also the key signaling molecule in the process of
tubuloglomerular feedback. Adenosine receptor antagonists have
generally been found to block the enhancement of NHE3 activ-
ity and thus exhibit diuretic activity (see below). It is particularly
interesting that unlike other diuretics that act upstream of the
collecting tubules, adenosine antagonists do not cause wasting
of K’,

PROSTAGLANDINS

scaled chr ee eat eisai

Prostaglandins contribute importantly to renal physiology and to
the function of many other organs (see Chapter 18). Five prosta-
glandin subtypes (PGE), PGI,, PGD,, PGF,,, and thromboxane