Converting Enzyme Inhibition and the Kidney
L E O N A R D G. M E G G S , M . D . , A N D N O R M A N K. HOLLENBERG, M.D., P H . D .
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SUMMARY We review information on the renal response to converting enzyme inhibition, and attempt to
evaluate the evidence that a reduction in angiotensin II formation is responsible for the renal response. There is
little response to converting enzyme inhibitors in animals or man when the renln-angk>tensin system is suppressed by a literal sodium intake. With restriction of sodium intake, an increase in renal blood flow occurs;
because a quantitatively similar response occurs to the angiotensin II analogs it is likely that the response
reflects reversal of the local action of angiotensin II. In other settings it is not yet dear whether the renal response to converting enzyme inhibitor reflects only a reduction in angiotensin II formation or an additional action such as potentiation of the local actions of bradykinin or enhanced prostaglandin formation. Because these
agents induce a potentiated increase in renal blood flow in the patient with essential hypertension, and with it
an increase in glomerular filtration rate and sodium excretion in some patients, despite a fall in arterial
pressure these questions have considerable importance. (Hypertension 2: 551-557, 1980)
KEY WORDS
•
sodium excretion
gk>menilar filtration rate
• renal blood flow
angiotensin II antagonists
M
classes of pharmacologic agents that have made the
major contribution have been the angiotensin analogs
(All A), which act as competitive antagonists or partial agonists," and the converting enzyme inhibitors
(CEI).e> 7 In the case of the angiotensin analogs, the
major problem has involved not their specificity — for
it appears they have no action in addition to those anticipated from an angiotensin analog — but as partial
agonists their angiotensin-like activity may well have
led to an underestimate of angiotensin's role in specific
situations."
In the case of the converting enzyme inhibitors, a
host of actions in addition to their well-documented
impact on angiotension II generation have been uncovered: under some circumstances, inhibition of
kininase II has led to bradykinin accumulation, and
bradykinin is a renal vasodilator.* More circumstantial evidence suggests that activation of prostaglandin
synthetase, at least under some circumstances, may
have led to the generation of yet another potent endogenous vasodilator.'-10 Whether these actions apply
to the kidney has often been unclear from available information. In the special circumstance when an angiotensin analog and a converting enzyme inhibitor have
produced a quantitatively identical result, the results
are very likely to have been due to pharmacologic interruption of the renin-angiotensin system, in view of
the clear differences in structure, mechanism of action, and potentially misleading influences between
these two classes of agent. Under many other circumstances, the responses to the two classes of agent either
ULTIPLE observations over the years have
suggested that angiotensin, in addition
to its systemic effect on blood pressure
(BP) and on sodium homeostasis through control of
aldosterone secretion, may have a direct action on the
renal blood supply.18 The important conceptual role
played by ablation in defining the action of a hormone
in an effector system was pointed out by Haber.4 In
the special case of the interaction of the renin-angiotensin system and the kidney, the kidney is both the
source of the hormone and the responding organ. The
ablation experiment, therefore, has clearly been impossible. For that reason, the development of several
classes of agent that have made it possible to interrupt the renin-angiotensin system pharmacologically
has made a major contribution to the evolution of our
ideas.
Before we convert pharmacologic responses to a
physiologic interpretation, it is important that we
assess the specificity of the available agents. The two
From the Departments of Medicine and Radiology, Harvard
Medical School and Peter Bent Brigham Hospital, Boston,
Massachusetts.
Supported by Grants HL 14944, HL 07236, HL 11668, and GM
18674 from the National Institutes of Health, and Grant NSG 9078
from the National Aerospace Agency. Metabolic balance studies*
were performed in the Clinical Research Center supported by a
separate grant from the National Institutes of Health (RR 00888).
Address for reprints: Dr. Norman Hollenberg, Department of
Medicine, Peter Bent Brigham Hospital, 721 Huntington Ave.,
Boston, Massachusetts 02115.
551
552
HYPERTENSION
appear to differ or have not been clearly documented,
and it is by no means clear at this time by which
mechanism renal perfusion and function have been
altered. We will attempt to make clear, in this review,
where such evidence is available and where it is still
lacking.
Renal Response to Pharmacologic Interruption in the
Normal State
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In healthy, recumbent animals and man, in the
absence of a deficit of extracellular fluid volume and
while ingesting a typical, liberal salt intake, the administration of neither angiotensin analogs nor CEI
influences renal perfusion or glomerular filtration
rate.' Even the modest challenge to extracellular fluid
volume engendered by a diet restricted in sodium content, however, results in a striking change in the renal
response to CEI and All A.
It has long been known that restriction of sodium
intake not only activates the renin-angiotensin system,
but also reduces renal perfusion and glomerular filtration rate." In addition, as renal blood flow fell, the
renal vascular response to angiotensin II was also
reduced.12 Circumstantial evidence, which raised the
interesting possibility that the renal response was due
to the direct action of angiotensin on the renal blood
supply, was quickly tested in a number of species when
pharmacologic antagonists became available. Many
studies have documented an increase in renal blood
flow in the dog and the rabbit when either class of
agent is employed,1'"" but the interpretation of the
functional response to the pharmacologic agents was
complicated by the drop in arterial blood pressure
when these agents were administered to animals in
balance on a low salt diet.
Perhaps the least equivocal study among the many
reported was that performed by Kimbrough et al," in
which they studied unanesthetized, trained dogs, to
avoid the complicating effects of anesthesia,1* and infused the All A and CEI into the renal artery, to
avoid the accompanying drop in blood pressure. They
documented a virtually identical 29% increase in renal
perfusion with a smaller but still substantial increase
in glomerular filtration rate to both the All A,
saralasin, and the peptide converting enzyme inhibitor, SQ 20,881, when the agents were administered
to the dog in balance on a reduced sodium intake
(fig. 1). A striking increase in sodium excretion also
occurred. Neither agent influenced renal perfusion,
glomerular filtration rate, or sodium excretion in
animals ingesting a high sodium intake. Because there
was no difference in the vascular influence of the converting enzyme inhibitor and angiotensin analog, it
seems very likely that the renal vascular and function
response was due entirely to angiotensin II. Thus, in
the simplest and most gentle model of a volume
deficit, that induced by restriction of sodium intake, it
appears that the entire renal response can be accounted for on the basis of the direct action of
angiotensin II on the renal blood supply. Certainly the
results of all studies are in accord with that con-
VOL 2, No 4, JULY-AUGUST
1980
clusion,1*"17 although the experimental design of some
would not have allowed this sweeping a conclusion.
The fact that, in the unanesthetized dog on a
sodium-restricted intake, the entire response to a converting enzyme inhibitor can be accounted for on the
basis of prevention of angiotensin's action by no
means indicates that under all circumstances this interpretation will hold. It is quite clear in the
anesthetized dog that SQ 20,881, for example, will potentiate the local actions of bradykinin including an
increase in blood flow, an increase in urine flow, and
increased sodium excretion.* It may well be that this
additional action, under circumstances different from
those of Kimbrough et al.,16 becomes important.
What of larger volume deficits? Available studies in
animal models have documented an enhanced
response to pharmacologic interruption in a variety of
states, including partial occlusion of the thoracic inferior vena cava, hemorrhage, and congestive heart
failure,1*"10 but their experimental design will not
allow us to conclude that only formation of angiotensin II and the renal response to that hormone was
responsible for the renal response. In no case has a
parallel assessment of the two classes of agent been
reported. Because, in general, it appears that pharmacologic interruption has not entirely reversed the
renal response in these settings,1*"10 it seems likely that
under these circumstances an additional effector
system — perhaps a direct action of the sympathetic
nerves on the renal blood supply — was recruited.
The experimental protocol used by Kimbrough et
al.,1* in which the converting enzyme inhibitor was infused directly to the renal artery, raised interesting
questions concerning the locus of the converting enzyme being altered by the inhibitor. Because the
hfghest concentration and the largest total amount of
converting enzyme is found in the lung, it would have
been reasonable to assume that the converting enzyme
inhibitors operate at this level.81 Multiple observations
in the interim have suggested that angiotensin II formation within the kidney may be very important in the
renal response. First, while the total amount of converting enzyme in the kidney is small, it is sharply
localized to the juxtaglomerular apparatus where its
action on the afferent and efferent arteriole would be
maximal.23' ** Second, the concentration of angiotensin II of lymph draining the kidney is substantially
higher than in the arterial or renal venous plasma,
again suggesting local generation." Third, converting
enzyme inhibition with the nonapeptide, SQ 20,881,
blocked the action of angiotensin I on the canine renal
blood supply, suggesting that angiotensin I had to undergo hydrolysis to angiotensin II for activity, and
that conversion happened within the kidney.2"1 M More
recent evidence that at least part of the action of converting enzyme inhibitors on the renal blood supply is
due to enzyme within the kidney is presented below.
Two approaches have been used for localization of
the converting enzyme. Microdissection and assay
have revealed quantitatively important converting enzyme in the juxtaglomerular apparatus."1 ** As a second approach, fluorescent antibody has shown the
CONVERTING ENZYME INHIBITION AND THE KIDNEY/Meggs et al.
I
553
1 Control P.riod
Infufaon Period
, >os
p<.(H
•0
P< 05
O43166
SSti73
5J9 ± 6 0
431121
557*45
FIGURE 1. Influence of converting enzyme inhibition (SQ 20,881) and an angiotensin antagonist (P 113) on glomerular filtration rate
(GFR) studied in unaneslhetized dogs in
balance on a restricted sodium intake. Note the
parallel increase in GFR induced by the two
agents. Not shown is a similar increase in renal
blood flow and a brisk natriuresis. Reproduced
from Kimbrough et al. (ref. 15) by permission
of the author and publisher.
60
20
SHAM (n=5)
SQ2Ot81 ( n - t )
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highest concentration of the converting enzyme to lie
at the level of proximal tubule." Whether the enzyme,
a dipeptidyl peptide hydrolase, functions as "converting enzyme" at this site is, of course, not known. If it
does it would be reasonable to conclude that angiotensin formation had an important tubular action.
Considerably less is known about the renal blood
supply in man. Saralasin and SQ 20,881 both failed to
increase renal blood flow in normal subjects ingesting
sodium and potassium sufficient to depress the reninangiotensin system.28 Conversely, both classes of
agent increased renal blood flow (fig. 2) to a quantitatively similar extent, in normal subjects ingesting a
sodium-restricted intake, sufficient to induce a
documented activation of the renin-angiotensin
system.28 Moreover, the dose of converting enzyme inhibitor that induced a threshold increase in renal
blood flow was the same as that which induced a sharp
drop in plasma angiotensin II concentration; plasma
bradykinin concentration was not modified.2* Taken
in all, this evidence suggests that in normal man, as in
the dog, the entire renal vascular response to a modest
volume stimulus can be accounted for on the basis of a
direct action of angiotensin II on renal blood supply.
As mentioned above, restriction of sodium intake
results in a reduced vascular response to angiotensin
II in many systems, including that of the renal blood
supply. The development of converting enzyme inhibitors has made it possible to assess the role played
directly by angiotensin, as opposed to the other possible influences of sodium, on the blunted response.
Converting enzyme inhibition in the dog, in which a
reduction in the extracellular fluid volume had been
induced, resulted in a striking potentiation in the renal
vascular response to angiotensin II, but not norepinephrine, suggesting that occupation of receptors
by endogenous angiotensin II played a role.™ Recent
evidence that angiotensin may down-regulate receptors in other tissues*0- *l makes it possible that such a
phenomenon rather than receptor occupation played a
role, although the time involved in the experiments
M13 (n = 5)
with converting enzyme inhibition was much shorter
than usually associated with receptor down and up
regulation. Additional substances potentially relevant
as determinants of renal vascular reactivity to
angiotensin II include prostaglandins and other endogenous vasoactive substances, but a discussion of
these is beyond the scope of this review.1*1"
• Intro-arterial
p<0.005
o Intravenous
2.0
\
c
E
m
cr
5
.0
30
100
300
SQ 20881
FIGURE 2. Relationship between the dose of converting
enzyme inhibitor administered and the change in mean renal
blood flow f A MRBF) in normal human subjects studied
when in balance on a low-sodium intake. Note the doserelated increase in renal bloodflowwhen the agent was administered intravenously and the potentiation when the
agent was infused into the renal artery — suggesting a local,
intrarenal action. Reproduced by permission of the
publisher from Hollenberg et al. (ref. 28).
554
HYPERTENSION
Documentation of the renal vascular response to
SQ 20,881 infused intravenously in normal man on a
restricted sodium intake provided access to the solution of the problem raised above: Was any of the converting enzyme being inhibited by CEI within the
kidney? If all of the converting enzyme had been in
lung, one would have anticipated that infusion of the
peptide directly into the renal artery would have
resulted in either an identical response, as the agent
circulated through the kidney and reached the lung, or
a reduced response — to the extent that some of the
agent was lost or degraded in its prolonged transit. On
the other hand, a potentiated response would have indicated that, at least in part, the response was due to
enzyme within the kidney. The latter was found (fig.
2): an unequivocal potentiation of the renal vascular
response occurred to infusion directly into the renal
artery.28
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The Renal Circulation in Hypertensive Disease
The possibility that the renal blood supply participates not only in the pathogenesis of renovascular
hypertension, but also of essential hypertension, has
been the subject of continuing interest." Reduced
renal blood flow and glomerular filtration rate are certainly common in essential hypertension. The mechanisms responsible for these derangements are incompletely delineated, with possibilities including
fixed changes due to the organic influence of arteriolonephrosclerosis in the afferent arterioles and
glomeruli; a functional change in the reactivity of the
intrarenal vessels; or an increase in the intrarenal action of local vasoconstrictors such as angiotensin II.
Some years ago we reported a reciprocal relationship between renal blood flow and renin release from
the same kidney in patients with essential hypertension.*1 In brief, as renal bloodflowfell, renin secretion
calculated from renal blood flow and the renin activity
in arterial and renal venous plasma rose (fig. 3). At
that time it seemed reasonable to attribute both the
reduction in blood flow and the increasing renin
release to advancing arteriolonephrosclerosis. In view
of the evidence presented below, the alternative
possibility — that the reduction in renal blood flow
was a consequence of and not a cause of the increased
renin release — had to be considered.
A characteristic that would distinguish, at least in
part, the influence of an organic lesion from that due
to a functional abnormality is the reversibility of the
latter. Several lines of evidence now suggest that a
functional abnormality often makes a substantial contribution to the reduction in renal perfusion: the intrarenal infusion of vasodilators, such as acetylcholine and dopamine, resulted in a potentiated increase
in renal blood flow in about two-thirds of patients with
essential hypertension in association with normalization of the renal arteriogram." The renal response in
patients with advanced arteriolonephrosclerosis,
chronic pyelonephritis, and polycystic kidney disease,
all settings in which fixed organic lesions would be expected to contribute to abnormalities in renal perfu-
VOL 2, No 4, JULY-AUGUST 1980
• Meon flow
o Flow in rapid component
Renal
Blood Flow
450
i
300
(ml/iooq/mm )
I
I
I
I
150
I
m
n
75
Flow in Rapid
Component
(% of t o t a l )
50
2 5
0
25 •
Remn
Secretion Rate
20
15
(U/min/g)
Essentiol
Mild Severe Accelerated
Small Vessel Disease
FIGURE 3. Relationships between degree of small vessel
disease, evaluated from the arteriogram in patients with
essential hypertension, and both the character of renal perfusion and the rate of renin secretion. The original interpretation was that both the reduction in renal blood flow and
increased renal secretion rate reflected an influence of organic, fixed microvascular disease. The possibility that
angiotensin formation, due to increasing renal release,
resulted in the reduction in renal blood flow must now be
considered. Reproduced by permission of the publisherfrom
Hollenberg et al. (ref. 34).
sion, was markedly blunted.3* The reversible nature of
the reduction of renal blood flow in patients with essential hypertension represent a strong argument in
favor of a functional abnormality that may precede
the development of organic lesions.
The striking moment-to-moment variation in renal
perfusion documented in patients with essential
hypertension is also consistent with active vasomotion, and a functional abnormality that is responsible
CONVERTING ENZYME INHIBITION AND THE KIDKEY/Meggs et al.
— at least in part —for the reduction in renal perfusion.
Renal Response to Converting Enzyme Inhibition in
Essential Hypertension
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On the premise that angiotensin is a major intrarenal hormone, and that essential hypertension is a
process in which disordered volume control could lead
to excessive local formation of this hormone, we undertook a study of the renal responses to CEI.
Infusion of the nonapeptide, SQ 20,881, in patients
with essential hypertension led to an enhanced renal
vascular response,*7 with renal blood flow increasing
at lower doses of the pharmacologic agent and to a
greater extent than in normal subjects (fig. 4).
Moreover, as opposed to virtually every other antihypertensive agent studied to date, the peptide converting enzyme inhibitor, SQ 20,881, increased glomerular filtration rates in patients with essential
hypertension" with the increase in filtration rate being
most striking in the patients in whom an initial reduction in filtration rate was evident and in whom hypertension was most severe (fig. 5). To our knowledge, no
other antihypertensive agent has led to ah increase in
glomerular filtration rate as perfusion pressure fell.
The antihypertensive efficacy of CEI has often been
striking in patients with accelerated hypertension,"
but little has been reported on its renal action in this
setting — which is often characterized by important
abnormalities in renal perfusion and function. We
have had the opportunity to assess the renal response
to SQ 20,881 in one such patient who presented with a
brief history of severe hypertension (arterial blood
pressure as high as 240/150), hypertensive neuroretinopathy (hemorrhage, exudates, and papilledema),
early azotemia (recent rise in serum creatinine to 2.0
mg/dl), and reduced renal perfusion (fig. 6). Administration of SQ 20,881 in graded dosage led to a
large increase in renal perfusion at doses well below
those required to reverse the hypertension. Moreover,
when increasing SQ 20,881 dosage led to control of
200 -i
555
the hypertension, the increase in renal perfusion was
well-sustained. Control of hypertension with this
agent for several days was associated with gradual improvement of renal function. Could there be a functional component in the renal abnormality, at least
early in accelerated hypertension?
Before concluding that, by inference from the
studies of normal man, that the renal response
reflected a reduction in the influence of angiotensin II
on the renal blood supply in essential hypertension,
the caveat raised in the introduction must be
remembered: responses to these agents are complex.
In a series of studies from this laboratory, differences
in the endocrine response of normal subjects and
patients with essential hypertension have been
documented: plasma bradykinin, for example, rose in
the latter," and the rise in plasma bradykinin concentration was most striking in those in whom blood
pressure fell.*0 The reduction in plasma angiotensin II
concentration was also potentiated in the patients with
essential hypertension, suggesting that perhaps more
than one mechanism was operative. More recently, a
rise in PGE has been documented in response to CEI,
and the cyclo-oxygenase inhibitor, indomethacin, has
been shown to blunt the BP-lowering effect of CEI in
essential hypertension.10 In support of these studies,
Vinci et al.41 have recently reported that the vasodepressor response to converting enzyme inhibition in
patients with hypertension correlated more closely
with increased urinary kinins and plasma PGE than
changes in the plasma angiotensin II concentration.
Only preliminary information is available on the
renal response to the oral CEI, SQ 14,225. As was the
case for the peptide, SQ 20,881, the agent induces an
increase in renal perfusion in normal subjects when in
balance on a restricted sodium intake, and a potentiated response in patients with essential hypertension.
In nine normal subjects, a single 10 mg dose taken by
mouth led within 20 minutes to an increase of 0.83 ±
0.07 ml/g/min, whereas the increase was 1.28 ± 0.17
ml/g/min in four patients with essential hypertension.
There are differences already apparent, however, in
ESSENTIAL HYPERTENSION\
A RBF
Iml/IOOg/min)
100-
A BP
(mm Hg)
H0-
ESSENTIAL HYPERTENSION\
H3
SQ 20,881
(n mol/kg)
27
10
20
(minutes)
30
40
FIGURE 4. Changes in renal blood flow (A
RBF) and mean arterial blood pressure (A BP)
induced by graded doses of SQ 20,881 in normal subjects and patients with essential
hypertension, studied when in balance on a
restricted sodium intake. Note the enhanced
renal blood flow response in patients with essential hypertension despite the larger fall in
blood pressure. Reproduced by permission of
the publisher from Williams and Hollenberg
(ref 37).
556
HYPERTENSION
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the renal response to SQ 20,881 and SQ 14,225. SQ
20,881 never led to an increase in renal perfusion in
normal subjects in whom a liberal sodium intake suppressed the renin-angiotensin system.48 Preliminary
studies on SQ 14,225 in our laboratory have revealed
an increase in renal pcrfusion in seven normal subjects
despite a substantial sodium intake (0.41 ± 0.11
ml/g/min), and a potentiated renal vascular response
in patients with essential hypertension (1.4 ± 0.36
ml/g/min) despite suppression of the reninangiotensin system — at least as evidenced by low
plasma levels of renin and angiotensin. The possibility
that plasma and intrarenal concentrations of these
hormones do not parallel each other must be considered.
Perhaps germane to the problem of the renal
response to converting enzyme inhibition, Zusman
and Reiser" have shown that bradykinin increases
prostaglandin synthesis by renal medullary interstitial
cells, and Gimbrone and Alexander" have documented a similar phenomenon in cultured endothelial cells. Obika and Mills44 have shown that intrarenal PGE infusion resulted in an increase in
urinary kallikrenin activity. The possible role played
by the complex interaction of kinins, prostaglandins,
or other vasoactive hormones in the salutary renal
response to converting enzyme inhibition in patients
with essential hypertension requires assessment.
VOL 2, No 4, JULY-AUGUST
Conclusions
Taken in all, the available information suggests that
the renal vascular response to a modest but not
necessarily large volume stimulus is mediated entirely
by the direct action of angiotensin II on intrarenal
arterioles. On this basis, the renal response to converting enzyme inhibition probably reflects reversal of this
action. When the stimulus is larger, additional effector
mechanisms are probably recruited, and it may well be
that the renal response to converting enzyme inhibition reflects additional actions. In patients with essential hypertension, a potentiated response to converting enzyme inhibition may reflect an increased action
of angiotensin II on the renal blood supply, due either
to increased local formation or to an enhanced renal
response to a normal concentration, but the direct
evidence required to rule out other actions of the converting enzyme inhibitors on other systems is not yet
available. Evidence is appearing that the kidney plays
a role in the antihypertensive action of converting enzyme inhibition," and here, too, the mechanism of that
renal contribution is unclear.
The development of more specific antagonists to the
known prostaglandins, an effective antagonist to
bradykinin, and improved assays for these hormones
would help us to elucidate the mechanism of action of
_
160
CO~
CON2
O ro 120
OJ (<FIGURE 5. Influence of converting enzyme inhibition with
SQ 20,881 on creatinlne clearance, employed as an index of
glomerular filtration rate in patients with essential (denoted
by black circle) and renovascular (open circle) hypertension
studied when in balance on a restricted sodium intake. Note
the uniform increase in glomerular filtration rate in the
patients with essential hypertension in whom the control
value was less than the lower limit of normal, 90 ml/1.73
AP/min. Reproduced by permission of the publisher from
Hollenberg et al. (ref 38).
FIGURE 6. Influence of graded doses of SQ
20,881 on arterial blood pressure (BP) and
renal blood flow (xenon) in a patient with
accelerated hypertension. Mean renal blood
flow is indicated in the box next to each flow
determination. Note the increase in renal perfusion at an SQ 20,881 dose too small to influence
blood pressure, and the well-sustainedflowincrease despite the antihypertensive effect of the
largest dose employed.
1980
O <
CO |
8o
40
40
80
120
160
PRE-SQ 20,881
CONVERTING ENZYME INHIBITION AND THE KIDNEY/Meggs et al.
the converting enzyme inhibitors on the kidney in essential hypertension. If, indeed, the kidney plays a key
role in sustaining hypertension — as has been
suggested" — the answers to the questions raised here
may well be relevant to pathogenesis as well as for
effective therapy.
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Converting enzyme inhibition and the kidney.
L G Meggs and N K Hollenberg
Hypertension. 1980;2:551-557
doi: 10.1161/01.HYP.2.4.551
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