Page 273 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 15 Diuretic Agents 259

urea transporter UT1 (UT-A, UTA-1) molecules into the apical [TXA ]) are synthesized in the kidney and have receptors in this
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membranes of collecting duct cells in the medulla. organ. The role of some of these receptors in renal physiology is
Urea concentration in the medulla plays an important role not yet completely understood. However, PGE (acting on EP ,
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maintaining the high osmolarity of the medulla and in the concen- EP , and possibly EP receptors) has been shown to play a role in
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tration of urine. ADH secretion is regulated by serum osmolality the activity of certain diuretics. Among its many actions, PGE
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and by volume status. A new class of drugs, the vaptans (see Agents blunts Na reabsorption in the TAL of Henle’s loop and ADH-
That Alter Water Excretion), are ADH antagonists. mediated water transport in collecting tubules. These actions
of PGE contribute significantly to the diuretic efficacy of loop
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RENAL AUTACOIDS diuretics. Blockade of prostaglandin synthesis with NSAIDs can
therefore interfere with loop diuretic activity.
A number of locally produced compounds exhibit physiologic
effects within the kidney and are therefore referred to as autacoids, PEPTIDES
or paracrine factors. Several of these autacoids (adenosine, the pros-
taglandins, and urodilatin) appear to have important effects on the The natriuretic peptides (ANP, BNP, and CNP, see Chapter 17)
pharmacology of diuretics. Since these effects are complex, they induce natriuresis through several different mechanisms. ANP and
will be treated independently of the individual tubule segments BNP are synthesized in the heart, while CNP comes primarily
discussed above.
from the CNS. Some of these peptides exert both vascular effects
(see Chapter 17) and sodium transport effects in the kidney,
ADENOSINE which participate in causing natriuresis. A fourth natriuretic pep-
tide, urodilatin, is structurally very similar to ANP but is synthe-
Adenosine is an unphosphorylated ribonucleoside whose actions sized and functions only in the kidney. Urodilatin is made in distal
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in the kidney have been intensively studied. As in all tissues, renal tubule epithelial cells and blunts Na reabsorption through effects
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adenosine concentrations rise in response to hypoxia and ATP on Na uptake channels and Na /K -ATPase at the downstream
consumption. In most tissues, hypoxia results in compensatory collecting tubule system. In addition, through effects on vascular
vasodilation and, if cardiac output is sufficient, increased blood smooth muscle, it reduces glomerular afferent and increases
flow. The kidney has different requirements because increased glomerular efferent vasomotor tone. These effects cause an
blood flow leads to an increase in glomerular filtration rate (GFR) increase in GFR, which adds to the natriuretic activity. Ularitide
and greater solute delivery to the tubules. This increased delivery is a recombinant peptide that mimics the activity of urodilatin.
would increase tubule work and ATP consumption. In contrast, The cardiac peptides ANP and BNP increase GFR through
in the hypoxic kidney, adenosine actually decreases blood flow effects on glomerular arteriolar vasomotor tone and also exhibit
and GFR. Because the medulla is always more hypoxic than the diuretic activity. CNP has very little diuretic activity. Three agents
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cortex, adenosine increases Na reabsorption from the reduced in this group are in clinical use or under investigation: nesiritide
flow in the cortex, so that delivery to medullary segments will be (BNP), carperitide (ANP, available only in Japan), and ularitide
even further reduced. (urodilatin, under investigation). Intravenous ularitide has been
There are four distinct adenosine receptors (A , A , A , studied extensively for use in acute heart failure. Experimentally,
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and A ), all of which have been found in the kidney. However, it can improve cardiovascular function and promote diuresis with-
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probably only one of these (A ) is of importance. The adenosine out reducing creatinine clearance, but it has not yet proved to be
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A receptor is found on the pre-glomerular afferent arteriole, as clinically useful. There is also evidence that nesiritide (simulating
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well as the PCT and most other tubule segments. Adenosine is BNP) may enhance the activity of other diuretics while helping
known to affect ion transport in the PCT, the medullary TAL, to maintain stable renal function. However, the Acute Study
and collecting tubules. In addition, adenosine (via A receptors of Clinical Effectiveness of Nesiritide in Decompensated Heart
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on the afferent arteriole) reduces blood flow to the glomerulus Failure (ASCEND-HF) study did not show an improvement in
(and GFR) and is also the key signaling molecule in the process of outcomes with nesiritide compared with regular care in patients
tubuloglomerular feedback. Adenosine receptor antagonists have with heart failure.
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 ■ BASIC PHARMACOLOGY OF
collecting tubules, adenosine antagonists do not cause wasting DIURETIC AGENTS
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of K .
CARBONIC ANHYDRASE
PROSTAGLANDINS INHIBITORS

Prostaglandins contribute importantly to renal physiology and to Carbonic anhydrase is present in many nephron sites, but the
the function of many other organs (see Chapter 18). Five prosta- predominant location of this enzyme is the epithelial cells of the
glandin subtypes (PGE , PGI , PGD , PGF , and thromboxane PCT (Figure 15–2), where it catalyzes the dehydration of H CO
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