Circulation Research
NOVEMBER
VOL. XXXIII
1973
NO. 5
An Official Journal of the American Mi ear t Association
Brief Reviews
Prostaglandins and the Kidney
By John C. McGiff and Harold D. Itskovitz
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• Although prostaglandins were discovered four
decades ago, definition of their remarkable range of
biological activity was delayed until the past decade
when Bergstrom et al. (1) identified the structures
of the major prostaglandins and set the foundation
for their synthesis. What has happened thereafter is
only too familiar: a full-scale invasion by prostaglandins into disciplines as disparate as demography and neurophysiology has resulted in a rapid
accumulation of information, much of which
appears contradictory and resists meaningful classification. For example, prostaglandins of the E series
can either attenuate or augment the vasoconstrictor
response to nerve stimulation, although augmentation occurs only at high doses (2). PGE2, the major
renal prostaglandin, can modulate the renal response to antidiuretic hormone (ADH) by inhibiting stimulation of adenyl cyclase by ADH, although
a prostaglandin of the E series can itself
activate adenyl cyclase (3). Therefore, when
considering biological activities, the prostaglandin
in question must be unequivocally identified among
the more than 14 naturally occurring prostaglandins
and its dose and route of administration must be
noted, since major differences in the effects of a
prostaglandin depend on these factors in a way that
appears to be unique for biological systems even in
comparison with steroids.
CHEMISTRY, BIOSYNTHESIS, AND METABOLISM
The prostaglandins are 20-carbon unsaturated
fatty acids containing a five-membered ring. The
particular biological properties of a prostaglandin
depend primarily on the substituents of the ring. In
the 9-position, a ketone group characterizes prostaglandins of the E series and a hydroxyl group
From the Section of Clinical Pharmacology, Departments
of Pharmacology and Medicine, The Medical College of
Wisconsin, Milwaukee, Wisconsin 53233.
Dr. McGifF is a Burroughs Wellcome Fund Scholar in
Clinical Pharmacology.
Circulation Reiearch, Vol. XXXIII, November 19/'i
characterizes those of the F series (Fig. 1).
Prostaglandins of the A series differ from those of
the E series by the absence of a hydroxyl group in
the 11-position and the presence of a double bond
in the ring. The subscript numeral indicates the
degree of unsaturation of the side chains, e.g., PGE2
has two double bonds in its side chains and PGEj
has one. Prostaglandins having similar degrees of unsaturation possess common precursors: arachidonic
acid is the precursor for PGE2 and PGF2a and dihomo-y-linolenic acid is the precursor for PGE, and
PGFia. PGE compounds readily undergo dehydration within the ring resulting in the formation of
PGA compounds. Because of the instability of the
former, it is difficult to be certain that prostaglandins of the A series occur naturally (4), except in
human seminal vesicular fluid (5). Lee et al. (6)
isolated three prostaglandins from the rabbit renal
medulla: PGE2, PGF2«, and PGA2. However they
thought that PGA2 was a possible artifact produced
from PGE2 during extraction of the prostaglandins.
Concurrently, Daniels et al. (7) identified PGE2 as
the principal renal prostaglandin. Within a series of
prostaglandins, quantitative differences in their
biological activities occur, whereas qualitative
differences are exceptional. Qualitative differences
between prostaglandins of the F series and those of
the E and the A series are encountered frequently.
The latter two groups of prostaglandins resemble
each other in their biological actions. However,
PGE compounds are more potent than PGA
compounds, and, unlike the PGA compounds, they,
as well as the PGF compounds, are almost entirely
removed from the blood on passage across the lung
(8). PGE2 has a renal vasodilator potency fivefold
that of PGA2 (9). In contrast, PGF.a does not
affect renal blood flow under the same conditions.
The renal vasodilator actions of prostaglandins of
the E and the A series have not been dissociated
from concurrent natriuresis (8). The demonstration
that PGE compounds oppose vasoconstrictor stimuli
479
McGIFF, ITSKOVITZ
480
HD
H
H
OH
OH
PGAj
ISOHISASE
PK0STW3LANDIN /
A.RACH100N1C
PGC,
HO
H H
OH
cow
PGB,
FIGURE 1
PGE2 and PGFec[ arise from a common cyclic endoperoxide
intermediate (not shown). If it is naturally occurring, PGAS
must arise from PGES. Conversion of PGAS to PGCS may be
a species-dependent phenomenon.
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is vital to the proposal that endogenous prostaglandins modulate autonomic nervous activity generally
(10) and renal pressor systems specifically (11).
Prostaglandins of the E series are more potent in
this regard than are those of the A series (2). In
contrast, PGF2« augments vasoconstriction produced by pressor stimuli in some vascular beds (2),
although the renal bed is exempted from this action
(9).
The prostaglandin concentrations reported in
tissues are more an indication of biosynthetic
activity than of endogenous prostaglandin content.
In the rabbit renal medulla, concentrations of PGE2
as high as 17 fig/g (12) have been reported; this
concentration approaches that in human seminal
vesicular fluid where the highest concentrations are
found (13). However, if the kidney is quick-frozen,
concentrations of PGE2 are only 0.005 /xg/g. The
interstitial cells of. the renal medulla are considered
to be the site of synthesis and storage of renal
prostaglandins. Moreover, changes in ultrastructure and granularity of interstitial cells have been
related to hypertension and altered renal function
(14). Although interstitial cells can synthesize
prostaglandins, this function may not be invested
exclusively in this type of cell within the kidney in
view of the lesser biosynthetic capacity (15) of
these cells compared with that of slices of renal
medulla (16) and the identification by a histochemical method of the cells of the collecting
ducts as the site of the most active prostaglandin
synthesis (17). The studies of Anggard et al. (12)
also suggest that renal prostaglandins do not
accumulate in any subcellular particle, indicating
that they are not stored. Release of prostaglandins
by the kidney in response to a stimulus such as
infusion of angiotensin II, then, denotes increased
prostaglandin synthesis which results in the immediate entry of the prostaglandin into the extracellular
compartment. After their release within the renal
medulla, prostaglandins are not degraded appreciably locally because of the virtual exclusion of
metabolizing enzymes from this zone. The absence
of the major metabolizing enzyme, 15-hydroxy
prostaglandin dehydrogenase, from the inner medulla (18) where synthesizing enzymes have been
shown to be most active has intriguing implications
concerning duration and sites of activity of
prostaglandins after their release intrarenally. The
question of prostaglandin synthesis by the renal
cortex, which could have large functional implications, is complicated by the presence of very active
metabolizing enzymes in the cortex. Although only
trace quantities of PGE2 and PGF 2a have been
detected in rabbit renal cortex (19), prostaglandin
synthesis in this zone, although low, may be sig-'
nificant. The recent report by Larsson and Anggard
(20) of prostaglandin synthesis by the rabbit renal
cortex equal to less than 10% of that of the medulla
involved the use of a microsomal fraction which
excluded metabolizing enzymes. Crowshaw (personal communication), using a purified acetone
powder preparation of rabbit renal cortex, has
confirmed these observations. Furthermore, it is
unlikely that the release within the cortex of newly
synthesized prostaglandins has major extracellular
effects beyond a sharply circumscribed area due to
their rapid and efficient metabolism to 15-keto
derivatives (20). This situation contrasts sharply
with the much larger quantities of PGE2 and
PGF 2a synthesized and released within the renal
medulla, as discussed above.
The initial step in the synthesis of prostaglandins
presumably is activation of an acyl hydrolase, such
as phospholipase A, which releases from a phospholipid an unsaturated fatty acid, e.g., arachidonic
acid, the precursor of PGE2 and PGF2« (21). The
precursor is rapidly converted to prostaglandins E
and F after undergoing oxidative cyclization. One
of the intermediates in the synthesis of prostaglandins, a cyclic endoperoxide, may possess independent biological activity. Gryglewski and Vane (22)
have suggested that a series of vasoactive substances
results from activation of acyl hydrolases of which
prostaglandins are the end products. A by-product,
the lysophospholipid, resulting from phospholipaseinduced release of prostaglandin precursors from
phospholipids possesses potent biological actions
(23). A lysophospholipid has been proposed to be a
Circulation Research, Vol. XXXIII, November
1973
PROSTAGLANDINS AND THE KIDNEY
naturally occurring inhibitor of renin (24). Those
factors operating in vivo which determine whether
the synthesis of PGE2 or PGF2a will predominate
have not been identified, although selective formation of PGE2 occurs intrarenally in response to
those vasoactive hormones which have been examined thus far (25).
PRQSTAGLANDINS:
LOCAL HORMONES OR CIRCULATING HORMONES?
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To appreciate the sphere of activity of prostaglandins, it is useful to assign them to that class of
endogenous substances called local or tissue hormones. A local hormone may be synthesized or
activated in many organs or tissues; however, the
activity of a local hormone is usually restricted to
the site of its formation, the venous system, and
those cardiopulmonary structures proximal to its
degradation in the lung. PGE2 and PGF2a, although
stable in blood, are almost completely inactivated
on passage across the lung (26). The other
prostaglandin isolated from the kidney, PGA2,
could function as a circulating hormone, since
prostaglandins of the A series escape destruction in
the lung (8). However, PGA2 must originate from
conversion of PGE2, since the breakdown of the
biosynthetic intermediate, the cyclic endoperoxide,
results in PGE2 and PGF2a, not PGA2 (27).
Crowshaw (28), using rabbit and dog renal
medullary preparations, has consistently failed to
demonstrate biosynthesis of PGA2 after addition of
either labeled arachidonic acid or PGE2. These
findings support those of Hamberg (4), who also
has been unable to show formation of PGA2 in
rabbit renal medulla under conditions which promote synthesis of PGE2 and PGF2a. Davis and
Horton (29) have reported relatively high concentrations of PGE2 and PGF 2a in renal venous blood
of the rabbit, but a PGA-Iike substance was not
recovered from renal venous blood in sufficient
quantity, in contrast to PGE- and PGF-like
material, to permit its definitive identification. If
one assumes that the PGA-like material was PGA,
although it could have been a PGB or a PGC
compound (Fig. 1), then its concentration was
considerably less than one-tenth of that of PGE2.
Since the renal vasodilator-diuretic activity of PGA2
is one-fifth of that of PGE2 (9), differences in their
concentrations in renal venous blood expressed in
terms of equivalency of their vasodilator-diuretic
actions exceed fiftyfold. We conclude that PGA2, if
present in the kidney, is present in amounts which
are not readily detected and that this problematic
renal production of PGA2 could not account for the
Circulation Research, Vol. XXXlll,
November 1973
481
high peripheral blood levels reported for PGA
compounds in man (30, 31). Nonetheless, the
proposal that a prostaglandin of the A series is a
circulating hormone (32) should be considered an
open issue in view of two recent studies. In the first,
Jones and Cammoek (33) have demonstrated in
plasma the enzymatic conversion of PGAj and PGA2
to isomers designated PGCi and PGC2, respectively, which are more potent than their PGA
precursors and share with them the ability to escape
pulmonary degradation (Fig. 1). However, the
activity of this isomerase in many species including
man is low or absent. In the second study, a
substance (s), which is immunoreactive with antibodies to PGA compounds, has been described in
peripheral plasma of normal adults (30) at
concentrations, about 1.5 ng/ml, severalfold greater
than those of prostaglandins of the E series (31).
Inasmuch as information on the identification, fate,
and biological activity of prostaglandin precursors
and metabolites is incomplete, experience dictates
caution when considering the possibility of circulating prostaglandins. This consideration has particular pertinence to the claims of specificity for
measurements of prostaglandins by radioimmunoassay, since one or more metabolites of the parent
compound or related substances may cross-react
with the antibody to the prostaglandin being
measured. There are sufficient precedents in the
convoluted story concerning the development of a
radioimmunoassay for angiotensin II (34) to make
one wary of radioimmunoassay procedures in the
early phases of their development. We interpret the
evidence presently available to support primary
local actions for renal prostaglandins. Bradykinin is
also a local hormone which shares with prostaglandins potent vasoactive properties and an uncertain
intrarenal status. Bradykinin-prostaglandin interactions have recently been described within the kidney (25); these interactions may herald identification of another intrarenal regulatory system in
addition to the adrenergic nervous-renin-angiotensin system.
Although arterial concentrations of prostaglandins of the E and the F series are probably less than
0.02 ng/ml under resting conditions (35), precipitous increases in the arterial levels of prostaglandins
can occur, e.g., in response to pulmonary embolism
(36). In addition, in advanced lung disease,
particularly when it is associated with extensive
shunting of blood, arterial levels of prostaglandins
can approach venous levels. The localization of the
major prostaglandin-metabolizing enzymes in the
482
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cortex of the kidney (18) would diminish considerably the threat to body fluid homeostasis presented
by sudden increases in the arterial levels of
prostaglandins.
Since prostaglandins possess diverse actions and
affect most biological systems, construction of their
intrarenal actions based on their intravascular
administration demands recognition that blood
levels rarely, if ever, exceed 10 10 moles/ml (< 35
ng/ml). Concentrations of this magnitude would be
expected only in the venous effluent from organs
having large biosynthetic capacity, representing
peak levels which are not maintained. Arterial
levels which are less than one-fiftieth those occurring in renal venous blood probably rarely exceed
20 pg/ml blood (35). When blood levels of administered prostaglandins are excessive, a sought-for
direct renal action may be superseded or obscured
by their systemic effects. Questionable purposes are
served by studies of the effects of administration of
prostaglandins by bolus injection or in amounts
which establish blood levels in excess of 100 ng/ml.
Furthermore, no route of administration of prostaglandins reproduces the effects evoked by release of
endogenous prostaglandins from an organ in terms
of either concentrations achieved at their sites of
action, vascular elements initially affected, or the
sequence of vascular elements affected. These
considerations are frequently overlooked when tentative physiological roles are inferred on the basis
of the reported effects of exogenous prostaglandins
on renal function. For example, since administration of a PGA compound reduces renal medullary
blood flow and increases cortical blood flow, it has
been reasoned that a deficiency of prostaglandins
intrarenally will result in cortical ischemia (32). On
the contrary, release of prostaglandins within the
renal medulla where metabolizing enzymes are
deficient or absent (20) should primarily increase
medullary blood flow. Furthermore, the presence of
the major prostaglandin-metabolizing enzymes in
the cortex should assure a primary medullary action
of renal prostaglandins (20). Thus, deficiency of
renal prostaglandins induced by inhibition of
prostaglandin synthetase should result primarily in
ischemia of the renal medulla, not the renal cortex.
Studies directed towards examination of the physiological roles of renal prostaglandins are scarce
because of (1) the considerable difficulties involved in measuring levels of prostaglandins in
biological fluids and (2) the absence of agents
which block effector responses efficiently and
predictably. However, the important discovery that
McGIFF, ITSKOVITZ
anti-inflammatory acids such as salicylates and
indomethacin inhibit synthesis of prostaglandins
(37) has already resulted in several findings of
major importance, namely, PGE-. is vital to the
maintenance of resting blood flow to the kidney
(35) and acts as a determinant of the intrarenal
distribution of blood flow (38).
PGEs MODULATES
PRESSOR
SYSTEMS
The studies of Hedqvist (10) are an excellent
introduction to the role of prostaglandins as
intrarenal modulators of vasoconstrictor-antidiuretic
systems. These studies suggest a negative feedback
mechanism whereby a PGE compound is released
on nerve stimulation in addition to the neruotransmitter; the prostaglandin then inhibits further release of the neurotransmitter. Hedqvist (10) has
shown that stimulation of the adrenergic nerves
supplying the heart and the spleen releases a PGE
compound and norepinephrine simultaneously
from these organs. A primary prejunctional action
of PGE compounds seems likely, since (1) the release of norepinephrine is increased after inhibition
of prostaglandin synthesis and (2) exogenous
PGE2 inhibits the response to nerve stimulation
more readily than it does that to injected norepinephrine. Increasing the concentration of calcium
reverses prostaglandin inhibition of the neuroeffecttor response to adrenergic stimulation (39). Involvement of prostaglandins at this fundamental level,
translocation of ionic calcium (40) and facilitation
of its binding (41), may explain the nonspecific
nature of prostaglandin modulation of pressor hormones. Thus, PGE2 inhibits not only adrenergicinduced renal vasoconstriction, but also vasoconstriction effected by angiotensin II (9). Since
vasoconstrictor responses to angiotensin II (42)
and adrenergic nerve stimulation (43) are calcium
dependent, the demonstration that a prostaglandin
of the E series affects binding of calcium ions appears vital to its activity as a modulator. Because
ionic calcium may be required for expression of the
activity of hormones and appears to be involved
in the initial hormone-receptor interaction (44),
the importance of a substance which affects disposition of calcium ions cannot be overestimated.
Changes in cellular binding of ionic calcium produced by prostaglandins may be pivotal in prostaglandin-adenyl cyclase interactions.
PROSTAGLANDINS AND THE ANTIHYPERTENSIVE FUNCTION
OF THE KIDNEY
The antihypertensive function of the kidney may
depend on the secretion of an antipressor subCirculation Research. Vol. XXXlll,
November
1973
PROSTAGLANDINS AND THE KIDNEY
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stance(s) by the kidney in response to elevated
blood pressure rather than the regulation by the
kidney of extracellular fluid volume. The continuous
secretion of this substance(s) is thought to be
responsible for maintaining blood pressure at
normal levels (45), since bilateral nephrectomy
results in hypertension which is not necessarily
dependent on changes in extracellular fluid volume.
Demonstration that a prostaglandin opposes
constriction of renal blood vessels produced by
pressor hormones is a necessary first step in relating
renal prostaglandins to the antihypertensive function of the kidney. Norepinephrine shares with
angiotensin II (46) the ability to release a PGE-like
substance from the kidney, associated with blunting
of the renal vasoconstrictor-antidiuretic action of
the pressor hormone (47). When this substance is
not released during infusion of the pressor hormone,
renal blood flow and urine flow do not recover. In
addition, stimulation of the renal nerves so as to
effect moderate reductions in renal blood flow does
not release a PGE compound from the kidney, and
blood flow and urine flow remain depressed. Release
of renal prostaglandins is not, then, obligatory in
response to nerve stimulation, suggesting that their
release is dependent on a critical change in either
renal function or the extracellular concentration of
a substance resulting from nerve stimulation. However, under other conditions, such as increased renal
perfusion pressure, stimulation of the renal nerves
releases prostaglandins from the kidney (48). An
important additional finding, which will be expanded later to establish a relationship between
the capacity of the kidney to release PGE2 and the
state of sodium balance, is that the increases in the
concentration of the PGE-like substance encompass
a fiftyfold range (47). Although the PGE-like
substance is indistinguishable from a PGE compound by physicochemical, chromatographic, and
pharmacological criteria, the amounts released preclude definitive identification (46, 47). However,
two recent studies have strengthened the tentative
identification of PGEo as the mediator of these
effects. In the first study, inhibition of prostaglandin
synthesis has been shown to enhance the renal
vasoconstrictor action of angiotensin II and norepinephrine associated with failure of the pressor
hormones to release prostaglandins intrarenally (49).
In the second study, PGE2 has been shown to
inhibit the vasoconstrictor and antidiuretic actions
of angiotensin II and norepinephrine when it is
infused into the renal artery at rates which
establish concentrations, about 0.5 ng PGE2/ml
Circulation Research, Vol. XXX11I, November 1975
483
blood, comparable to those of a PGE-like substance
reported in venous effluent of the kidney during
escape from the renal effects of pressor hormones
(9).
The mechanism operating through prostaglandins
which modulates the renal actions of pressor
hormones may also account for the natriuresis
produced by increased renal perfusion pressure
(50). The capacity of the kidney to increase
synthesis of prostaglandins in response to increased
renal perfusion pressure is deduced from comparison of two recent studies. In the first, in which renal
blood flow was allowed to vary during nerve
stimulation, reductions in renal blood flow v/ere not
associated with release of prostaglandins from the
kidney (47). In contrast, in the second study, renal
blood flow was kept constant and renal perfusion
pressure was allowed to vary. Under these conditions, nerve stimulation which greatly increased
renal perfusion pressure was associated with an
increased efflux of prostaglandins from the kidney
(48). Thus, increased renal perfusion pressure
appears to be a sufficient condition for release of
renal prostaglandins.
Unilateral renal ischemia has also been shown to
be associated with increased concentrations of
prostaglandins in the venous blood of both ischemic
and contralateral kidneys, acutely in dogs (51), as
well as in hypertensive subjects (52). Angiotensin
II presumably mediates the release of prostaglandins from the contralateral kidney, since infusion of
angiotensin II in anesthetized dogs, at a rate which
establishes concentrations in blood within the range
of those reported in renovascular hypertension,
< 0.5 ng/ml blood (53), releases a PGE compound
into renal venous blood (46). Although prostaglandin-angiotensin interactions may affect the development of renovascular hypertension, other antihypertensive lipids of renal origin may prove decisive in
aborting those events which culminate in hypertension, namely an antihypertensive neutral lipid (54)
and a renin inhibitor (24). Either or both of these
substances may operate in concert with renal
prostaglandins in preventing hypertension. The
work of Muirhead et al. (54) in particular compels
consideration of a circulating antihypertensive
substance originating from the renal medulla and
challenges invocation of a mechanism having a
primary locus of action intrarenally (55) such as
would be required for investing the renal antihypertensive function in PGEo. The question of PGA2 of
renal origin functioning as an antihypertensive
484
substance has been dealt with previously and
answered in the negative.
PROSTAGLANDINS AND REACTIVITY OF RENAL
BLOOD VESSELS TO PRESSOR HORMONES
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Interactions of pressor hormones and prostaglandins which are sodium dependent may be major
determinants of vascular reactivity. Contrary to the
generally accepted relationship that an increased
concentration of sodium enhances vascular reactivity (56), Kilcoyne and Cannon (57) have found
that sodium restriction potentiates the renal vasoconstrictor response to norepinephrine. This observation is not unexpected, if it is recognized that the
regional vasoconstrictor response to a pressor
stimulus is affected by the capacity of the stimulus
to release a PGE compound from the vascular
territory. The amount of PGE2 released from the
kidney by pressor hormones may be related to the
state of sodium balance or some function of it such
as extracellular fluid volume or renal medullary
tonicity. Plasma renin activity has been used as an
index of the state of sodium balance (58). The
norepinephrine-induced increase in concentration
of a PGE compound in renal venous blood, which
ranges from 0.5 to 24.2 ng/ml, is unrelated to the
dose of the amine but is inversely related to plasma
renin activity (59). Thus, norepinephrine releases
the largest amount of a PGE compound when
plasma renin activity is low (positive sodium
balance) and the least when plasma renin activity is
high (negative sodium balance). A similar relationship to sodium balance may exist for the vasoconstrictor action of angiotensin II (60). However,
Hollenberg et al. (61), having confirmed in man
the observations of Kilcoyne and Cannon (57)
concerning vascular responsiveness to norepinephrine as affected by sodium balance, have shown that
the renal vasoconstrictor response to angiotensin II,
unlike the response to norepinephrine, is potentiated by positive sodium balance. These findings
emphasize the need, in future studies on vascular
reactivity, to define the capacity of the pressor
stimulus to release prostaglandins, since the latter
will, in large part, determine the degree of residual
vasoconstriction. Since increased vascular reactivity has been reported to precede the onset of
hypertension (62), these studies suggest that
deficiency of prostaglandin production may initiate
hypertension. Hypertension, then, may be considered to result from uncompensated deficiencies or
excesses of one or more components of the vasodepressor and vasopressor systems, respectively.
McGIFF, ITSKOVITZ
MAINTENANCE OF RENAL BLOOD FLOW
AND DETERMINANTS OF ITS DISTRIBUTION
The evidence presented thus far suggests that
renal prostaglandins do play a role in defending
renal function against excesses of vasoconstrictorantidiuretic hormones. However, a basal efflux of
prostaglandins from the kidney persists in the
absence of any challenge to the renal circulation
(25). Inhibition of prostaglandin synthesis by
either indomethacin or meclofenamate results in
decreased renal blood flow closely correlated with a
decline in renal efflux of a PGE compound, in spite
of increased renal perfusion pressure (35). Changes
in renal efflux of a PGF compound are unrelated to
reductions in renal blood flow. Femoral blood flow
and cardiac output are not affected. The interpretation that PGE2 contributes to resting renal blood
flow is strengthened by demonstrating identical
effects of indomethacin on the isolated canine kidney, thereby excluding the operation of extrarenal
factors. Thus, renal vascular tone at rest, heretofore
considered to be determined by "autonomous,
intrinsic activity of the renal arterioles" (63),
depends, in large part, on continued production of a
renal prostaglandin. However, the mean reduction
of 45% in renal blood flow produced by inhibition of
prostaglandin synthesis (35) cannot be accounted
for in terms of changes in blood flow to the renal
medulla or to that zone, the juxtamedullary cortex,
from which the medullary blood vessels take origin.
In considering these results, it is important to
recognize that the vascular architecture of the
canine kidney might partially determine the magnitude of these changes, since nephrons having long
loops predominate in the dog, in contrast to man in
whom they constitute less than 20% of the nephrons
(64). Furthermore, renal prostaglandins may affect
cortical structures via tubular fluid, since PGEi> and
PGFoa, considered to originate intrarenally, have
been identified in the urine (65). In addition, a
cortical site of action for renal prostaglandins seems
probable in view of the important findings of
Herbaczynska-Cedro and Vane (66) that renal
autoregulation is dependent on the activity of
prostaglandin synthetase. In this study, reduction of
renal perfusion pressure resulted in release of
prostaglandinlike material into renal venous effluent
coincident with compensatory renal vasodilation.
Indomethacin abolished simultaneously the release
of prostaglandinlike material by the kidney and the
renal autoregulatory response to decreased renal
perfusion pressure. Since inhibition of prostaglandin synthesis by anti-inflammatory drugs affects all
Circulation Research, Vol. XXXIII, November
1973
485
PROSTAGLANDINS AND THE KIDNEY
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products of prostaglandin synthetase, as well as
other enzymes (67), it is important to confirm any
study which depends on this action of antiinflammatory agents by alternate methods, e.g.,
prostaglandin antagonists of high specificity which
are presently unavailable. Thus, the availability of
agents which effectively block cellular responses to
endogenous prostaglandins in vivo is indispensable
for the fullest definition of the nature and the range
of prostaglandin-effector mechanisms and would
yield information analogous to that obtained from aand /J-receptor blockade of adrenergic neuroeffector responses. A similar relationship between basal
production of prostaglandins and resting blood flow
may be anticipated wherever transporting epithelia
of large capacity are present, such as the gut and
lung. In addition, functional and reactive hyperemia of the kidney, gut, and exocrine tissue may
depend on their capacity to increase synthesis of a
PGE compound in response to either metabolic or
vasoactive hormonal signals (68).
The sector of activity of renal prostaglandins has
been tentatively identified by measuring the distribution of blood flow to the inner and the outer
cortex with radioactive microspheres before and
after inhibition of prostaglandin synthesis in the
isolated canine kidney (38). This technique allows
estimation of changes in medullary blood flow, since
blood vessels of the renal medulla are derived primarily from the efferent arterioles of the inner cortex. Thus, changes in inner cortical blood flow reflect changes in medullary blood flow. Inasmuch as
prostaglandin synthetase is located in the renal
medulla and the major degradative enzyme, the 15hydroxy prostaglandin dehydrogenase, is located
primarily in the renal cortex (20), the actions of
renal prostaglandins in the medulla will be
relatively unopposed (Fig. 2). The consequences of
increased medullary vascular resistance resulting
from inhibition of synthesis of PGE2, if the medulla
is the primary site of action of PGE2, will be
reduction in blood flow to the inner cortex. This
proposal has been validated: after indomethacin
administration, blood flow and its fractional distribution to the inner cortex are invariably decreased
and the decreases correlate with the reduction in
concentration in blood of a PGE compound. In
contrast, outer cortical blood flow does not
decrease, and fractional distribution to this zone
increases. However, these results in the isolated
canine kidney may partially depend on the relatively high blood levels of PGE compound in this preparation; namely, greater than tenfold those of the in
Circulation Reieatch, Vol. XXXIII, November
197i
II
uo
si
£3
VASCULAR
X - SECTION
o
e
PREPOSTINDOMETHACIN
INCREASED PGE,
SYNTHESIS BY: 2
1 . NOREPINEPHRINE
2. ANGIOTENSIN
3 . ADH ( ? )
4 . 8RADYKIMIN
5 . INCREASED
PERFUSION
PRESSURES)
INNER
MEDULLA
FIGURE 2
Nephrons having long and short loops of Henle are shown on
the left. The origin of the renomedullary blood vessels
(vasa recta) from the efferent arterioles of the juxtameduUary
glomeruli is schematized on the right {after Fourman, J.,
and Moffat, D. B.: Blood Vessels of the Kidney. Oxford,
Blackwell Scientific Publications, 1971). The primary effect
of inhibition of prostaglandin synthesis is indicated by a
decrease in the diameter of the vasa recta as schematized
in the vascular cross sections. The prostaglandin-metabolizing
and the prostaglandin-synthesizing enzymes are segregated,
the former to the cortex and the latter to the medulla.
situ kidney, thereby facilitating any demonstration
of the effects of an intervention dependent on elimination of endogenous prostaglandins. In addition,
these observations cannot be extrapolated to other
mammals because of the aforementioned species
differences in the vascular architecture of the
kidneys. These objections notwithstanding, the
study supports the proposal that PGE2 functions in
the renal medulla as a local hormone which
participates in the regulation of medullary and,
thereby, deep cortical blood flow with all the
attendant effects on renal function. In this regard,
the renin-angiotensin system has been shown to
participate in the regulation of blood flow to the
same zone, the inner cortex, affected by PGE2 but
in a reciprocal fashion (69). Thus, the antagonism
of PGE2 and angiotensin intrarenally is reaffirmed.
RENAL PGF?«: A DETERMINANT OF CARDIAC PERFORMANCE?
PGF2a, the second most abundant renal prostaglandin, neither amplifies neurogenic renal vasoconstriction (9) nor affects renal vascular resistance in
concentrations as high as 40 ng/ml blood (25). In
contrast, changes in the concentration of PGE2 in
arterial blood of 0.1 ng/ml produce renal vasodilation and diuresis (8). The determinants of PGF2«
McGIFF, ITSKOVITZ
486
synthesis intrarenally remain undefined, since both
pressor and depressor hormones result in a selective
release in PGE2. The systemic pressor action of
PGF2a may be primarily related to increased
cardiac output consequent to enhanced venomotor
tone (70). In this regard, Hinman (71) first
suggested in 1967 that PGF2« may fulfill a coupling
role between renal function and cardiac performance, i.e., PGFoo may be released in response to
depressed renal function to increase cardiac output.
A substance affecting venous return and synthesized
intrarenally may account for the earliest hemodynamic changes in experimental hypertension, i.e.,
increased cardiac output preceding heightened
arteriolar tone (72).
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This Review benefited from the criticism of Dr. K.
Crowshaw, Dr. A. Nasjletti, and Mr. J. C. Strand. We thank
Miss P. Welsch and Mrs. K. Houde for typing the
manuscript.
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Circulation Research, Vol. XXXIII, November 1973
Prostaglandins and the Kidney
JOHN C. MCGIFF and HAROLD D. ITSKOVITZ
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Circ Res. 1973;33:479-488
doi: 10.1161/01.RES.33.5.479
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