Cardiovascular Drugs

Angiotensin-Converting Enzyme Inhibitors

Nancy J. Brown, MD; Douglas E. Vaughan, MD

Abstract—ACE inhibitors have achieved widespread usage in the treatment of cardiovascular and renal disease. ACE
inhibitors alter the balance between the vasoconstrictive, salt-retentive, and hypertrophic properties of angiotensin II
(Ang II) and the vasodilatory and natriuretic properties of bradykinin and alter the metabolism of a number of other
vasoactive substances. ACE inhibitors differ in the chemical structure of their active moieties, in potency, in
bioavailability, in plasma half-life, in route of elimination, in their distribution and affinity for tissue-bound ACE, and
in whether they are administered as prodrugs. Thus, the side effects of ACE inhibitors can be divided into those that are
class specific and those that relate to specific agents. ACE inhibitors decrease systemic vascular resistance without
increasing heart rate and promote natriuresis. They have proved effective in the treatment of hypertension, they decrease
mortality in congestive heart failure and left ventricular dysfunction after myocardial infarction, and they delay the
progression of diabetic nephropathy. Ongoing studies will elucidate the effect of ACE inhibitors on cardiovascular
mortality in essential hypertension, the role of ACE inhibitors in patients without ventricular dysfunction after
myocardial infarction, and the role of ACE inhibitors compared with newly available angiotensin AT1 recep-
tor antagonists. (Circulation. 1998;97:1411-1420.)
Key Words: angiotensin n blood pressure n bradykinin n drugs n renin

muscle cells.7 In addition, Ang II interacts with the sympa-

A ngiotensin-converting enzyme inhibitors were devel-
oped as therapeutic agents targeted for the treatment of
hypertension. Since the initial application of these agents,
thetic nervous system both peripherally and centrally to
increase vascular tone.8 Ang II causes volume expansion
several additional clinical indications have been identified through sodium retention (via aldosterone9 and renal vaso-
and approved. This review summarizes the pharmacology of constriction) and fluid retention (via antidiuretic hormone).10
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ACE inhibitors and their current clinical indications.
Mechanism
ACE, or kininase II, is a bivalent dipeptidyl carboxyl metal-
lopeptidase present as a membrane-bound form in endothelial
cells, in epithelial or neuroepithelial cells, and in the brain
and as a soluble form in blood and numerous body fluids.1
ACE, or kininase II, cleaves the C-terminal dipeptide from
Ang I and bradykinin and a number of other small peptides
that lack a penultimate proline residue. Thus, ACE is strate-
gically poised to regulate the balance between the RAS and
the kallikrein-kinin system.
The RAS plays a pivotal role in blood pressure regulation
(Fig 1). Reduced sodium delivery at the macula densa,
decreased renal perfusion pressure, and sympathetic activa-
tion all stimulate secretion of renin by the juxtaglomerular
cell, the classic source of renin in the circulating RAS.2
Alternatively, renin may be produced locally in tissues.3,4
Renin cleaves the inactive decapeptide Ang I from the
prohormone angiotensinogen, a noninhibiting member of the
serpin superfamily of serine protease inhibitors.5 Ang II is
then cleaved from Ang I by the action of ACE.6 Ang II is a
potent vasoconstrictor, acting directly on vascular smooth
At the cellular level, Ang II promotes migration, prolifera-
tion, and hypertrophy.11–15 Most of these effects of Ang II
appear to be mediated through the AT1 receptor, although
recent studies are defining roles for the AT2 and AT4 subtype
receptors.16
As mentioned earlier, in addition to catalyzing the forma-
tion of Ang II, ACE (or kininase II) catalyzes the degradation
of bradykinin.6 In specific tissues or organs, bradykinin
causes smooth muscle contraction (eg, uterine and ileal),
increased vascular permeability, stimulation of peripheral and
C fibers, and augmentation of mucous secretion.17 More
importantly, however, bradykinin promotes vasodilation by
stimulating the production of arachidonic acid metabolites,
nitric oxide, and endothelium-derived hyperpolarizing factor
in vascular endothelium.18 In the kidney, bradykinin causes
natriuresis through direct tubular effects.19 Most of the phys-
iological effects of bradykinin appear to be mediated through
the B2 receptor.20
In summary, ACE regulates the balance between the
vasodilatory and natriuretic properties of bradykinin and the
vasoconstrictive and salt-retentive properties of Ang II. ACE
inhibitors alter this balance by decreasing the formation of
Ang II and the degradation of bradykinin (Fig 1). ACE

Received August 11, 1997; revision received January 28, 1998; accepted January 29, 1998.
From the Departments of Medicine and Pharmacology, Vanderbilt University Medical Center (N.J.B., D.E.V.), and the Veterans Administration
Medical Center (D.E.V.), Nashville, Tenn.
Correspondence to Nancy J. Brown, MD, 560 MRB-I, Vanderbilt University Medical Center, Nashville, TN 37232-6602.
E-mail nancy.brown@mcmail.vanderbilt.edu
© 1998 American Heart Association, Inc.

1411
 1412 ACE Inhibitors
Selected Abbreviations and Acronyms
Ang 5 angiotensin
MI 5 myocardial infarction
PRA 5 plasma renin activity
RAS 5 renin-angiotensin system
inhibitors also alter the formation and degradation of several
other vasoactive substances such as substance P,21 but the
contribution of these compounds to the therapeutic or adverse
effects of ACE inhibitors is uncertain.
Pharmacology
ACE inhibitors differ in the chemical structure of their active
moieties, in potency, in bioavailability, in plasma half-life, in
route of elimination, in their distribution and affinity for
tissue-bound ACE, and in whether they are administered as
prodrugs. ACE inhibitors may be classified into three groups
according to the chemical structure of their active moiety.
Captopril is the prototype of the sulfhydryl-containing ACE
inhibitors; others are fentiapril, pivalopril, zofenopril, and
alacepril. In vitro studies suggest that the presence of the
sulfhydryl group may confer properties other than ACE
inhibition to these drugs, such as free-radical scavenging and
effects on prostaglandins22,23; however, the clinical relevance
of these effects remains to be demonstrated. Fosinopril is the
only FDA-approved ACE inhibitor that contains a phosphinyl
group as its reactive moiety. The majority of the other ACE
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inhibitors contain a carboxyl moiety. The half-lives and
routes of elimination for selected ACE inhibitors appear in
Table 1. Captopril differs from other ACE inhibitors by its
short half-life. With the exception of fosinopril, trandolapril,
and spirapril, ACE inhibitors are cleared predominantly by
the kidney. For this reason, dose reductions are required in
the setting of impaired renal function. The majority of ACE
inhibitors are administered as prodrugs that remain inactive
until esterified in the liver. These prodrugs have enhanced
oral bioavailability compared with their active drugs. ACE is
present in plasma as well as in tissues, and there are
differences in the relative tissue affinity of ACE inhibitors.
For example, Fabris and coworkers24 examined the binding of
various ACE inhibitors to heart homogenates and found the
order of potency to be quinaprilat 5 benazaprilat . perindo-
prilat . lisinoprilat . fosinoprilat. Several investigators have
shown that the effects of ACE inhibitors on blood pressure
correlate better with tissue ACE levels than with circulating
Figure 1. Schematic of RAS and kallikrein-kinin system. ACE is
strategically poised to regulate the balance between Ang II and
bradykinin.
ACE,25,26 but the clinical significance of differences in tissue
binding has not been established.
Humoral Effects
The effects of ACE inhibitors on the RAS in humans is well
documented. ACE inhibitors block the pressor response to
intravenous Ang I but not Ang II.27 When ACE inhibitors are
given short-term, endogenous levels of Ang II and aldoste-
rone decrease, whereas PRA and Ang I increase,28,29 at least in
part because of loss of feedback inhibition.30 The resulting
increase in Ang I levels may result in degradation of Ang I to
Ang 1–7, a vasodilator,31 or in formation of Ang II via
non–ACE-mediated pathways,32–34 although the role of these
alternative degradation products in humans is controversial.
With chronic ACE inhibition, Ang II and aldosterone levels
tend to return toward pretreatment levels.35–37
The contribution of bradykinin to the hemodynamic effects
of ACE inhibitors in humans is uncertain. ACE inhibitors
potentiate the hypotensive effects of intravenous bradykinin
in humans.38,39 However, endogenous bradykinin is difficult
to measure because of its short half-life, and investigators
have reported that bradykinin levels are either increased40,41 or
unchanged42– 44 during ACE inhibition. Similarly, prostaglan-
din levels have been reported to be increased or unchanged in
patients treated with ACE inhibitors.40,45–51 The recent avail-
ability of specific bradykinin (B2) receptor antagonists52,53 has
begun to shed light on the contribution of bradykinin to the
actions of ACE inhibitors. In animal models, coadministra-
tion of a bradykinin antagonist attenuates the antihyperten-
sive effect of ACE inhibitors.54,55 Recent data suggest that B2
antagonism blunts the hypotensive effects56 and reduces the
endothelium-dependent vasodilator effects in humans as
well.57
Hemodynamic Effects
ACE inhibitors decrease systemic vascular resistance but
cause little change in heart rate.58 – 61 In normotensive and
hypertensive subjects with normal left ventricular function,
ACE inhibitors have little effect on cardiac output or pulmo-
nary capillary wedge pressure.62– 66 In the kidneys, ACE
inhibitors cause increased renal plasma flow and promote salt
excretion.67– 69 Glomerular filtration is usually unchanged;
thus, filtration fraction is decreased.
Clinical Indications
Hypertension
ACE inhibitors effectively lower the mean, systolic, and
diastolic pressures in hypertensive patients as well as in
salt-depleted normotensive subjects.70 –72 The acute change in
blood pressure correlates with pretreatment PRA and angio-
tensin levels, such that the greatest reductions in blood
pressure are seen in patients with the highest PRA.73–76
However, with long-term therapy, a greater percentage of
patients achieve a decrease in blood pressure, and the anti-
hypertensive effect no longer correlates with pretreatment
PRA.74 –76 The mechanism for this increased efficacy with
chronic administration is not clear but may involve the
kallikrein-kinin system or production of vasodilatory
prostaglandins.77
 Brown and Vaughan April 14, 1998 1413

TABLE 1. Pharmacology of ACE Inhibitors Approved in the United States

Captopril Enalapril Lisinopril Benazepril Quinapril Ramipril Trandolapril Moexipril Fosinopril
Zinc ligand Sulfhydryl Carboxyl Carboxyl Carboxyl Carboxyl Carboxyl Carboxyl Carboxyl Phosphinyl
Prodrug No Yes No Yes Yes Yes Yes Yes Yes
tmax active drug, h 0.7–0.9 2–8 6–8 1–2 2 3 4–10 1.5 3
t1/2 active drug, h 1.7 11 12 10–11 1.9–2.5, 25 Triphasic 4, 15–24 2–9 12
terminal 9–18, .50 terminal
Route of elimination Kidney Kidney Kidney Kidney Kidney Kidney Kidney, liver Kidney Liver, kidney
Dosage range, mg 6.25–300 2.5–40 5–40 5–80 5–80 1.25–20 1–8 7.5–30 10–80
F, %* 75–91 60 6–60 .37 .60 50–60 70 13 36
*F indicates bioavailability.

Although ACE inhibitors are generally effective in reduc-
ing blood pressure, they appear to be less potent in hyperten-
sive blacks than whites. In a Veterans Administration Coop-
erative Study Group trial, captopril reduced blood pressure
significantly more in white patients with mild to moderate
hypertension than in black patients at 7 weeks.78 Similarly,
ACE inhibitors and b-blockers were less effective than
calcium channel blockers in young and elderly black men.79
One possible explanation for these data is that hypertensive
blacks tend to have low renin levels more often than do
whites.80 – 82 In support of this, coadministration of drugs that
increase PRA, such as diuretics, abolishes the racial differ-
ences in response to ACE inhibitors.78 Weir et al83 suggested
that the mechanism through which ACE inhibitors lower
blood pressure differs in blacks and whites. This group
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Antihypertensive and Lipid Lowering Treatment to Prevent
Heart Attack Trial (ALLHAT).90 It should be emphasized that
existing data suggest that ACE inhibitors will have a favor-
able effect on cardiovascular mortality. ACE inhibitors lack
adverse metabolic effects,91 and they have been shown to
cause regression of left ventricular hypertrophy.60,92,93 Finally,
they have already been shown to reduce mortality in patients
with congestive heart failure94 –98 and diabetic nephropathy.99
Congestive Heart Failure and Left
Ventricular Dysfunction
ACE inhibitors favorably alter hemodynamics in patients
with systolic dysfunction. ACE inhibitors reduce afterload,
preload, and systolic wall stress100 –109 such that cardiac output
increases without an increase in heart rate. ACE inhibitors

observed a dissociation between the potency of ACE inhibi-
tors for decreasing plasma ACE activity and their antihyper-
tensive potency in blacks; however, in some dose groups,
baseline ACE activity was higher in the blacks than in the
whites studied. Nevertheless, this study underscores the need
to use higher doses of ACE inhibitors for blacks.
One of the hallmarks of ACE inhibitors is that they lower
peripheral vascular resistance without causing a compensa-
tory increase in heart rate.58 – 61 The lack of heart rate response
to ACE inhibitors contrasts with the effect of other vasodi-
lators, such as calcium channel blockers and direct-acting
vasodilators, on heart rate and may reflect an effect of ACE
inhibitors on baroreceptor sensitivity as well as inhibition of
the normal tonic influence of Ang II on the sympathetic
nervous system.84 – 86 During ACE inhibition, heart rate re-
sponses to postural changes and exercise are not impaired.87
The goal of antihypertensive therapy is not only to lower
blood pressure but, more importantly, to alter the risk of
end-organ damage and mortality. To date, trials of ACE
inhibitors in the treatment of essential hypertension have
focused on the end point of blood pressure reduction. For this
reason, the Joint National Committee for the Detection,
Evaluation, and Treatment of High Blood Pressure VI has not
recommended ACE inhibitors as first-line therapy for uncom-
plicated hypertension. ACE inhibitors are indicated for the
treatment of hypertension with coexistent conditions such as
congestive heart failure and diabetic nephropathy.88 Clinical
trials testing the effect of ACE inhibitors on cardiovascular
mortality in patients with essential hypertension are under
way. These include the Captopril Prevention Project89 and the
promote salt excretion by augmenting renal blood flow and
by reducing the production of aldosterone and antidiuretic
hormone. Since 1987, several large, prospective, randomized,
placebo-controlled trials have demonstrated that treatment
with ACE inhibitors results in a reduction in overall mortality
in patients with congestive heart failure due to systolic
dysfunction.94 –98 These trials are summarized in Table 2 and
have had a major impact on the management of congestive
heart failure. The reduction in mortality has been seen even in
patients with asymptomatic left ventricular dysfunction.110,111
This reduction in mortality results primarily from a reduction
in progression of congestive heart failure,94,96,97 although the
incidence of sudden death96 and MI110 may also decrease.
As mentioned earlier, it is not yet clear to what extent
bradykinin contributes to the beneficial therapeutic effects or
adverse effects of ACE inhibitors. Since the advent of
specific AT1 antagonists, a number of studies comparing ACE
inhibitors with AT1 antagonists are now under way. The first
of these, the Evaluation of Losartan in the Elderly (ELITE)
study, reported nearly equivalent effects of losartan and the
short-acting ACE inhibitor captopril on the progression of
congestive heart failure in elderly patients; however, there
was an unexpected reduction in the incidence of sudden death
in the losartan group.112 There was no difference between
captopril and losartan in the incidence of renal insufficiency.
Whether large-scale trials comparing AT1 receptor antago-
nists with longer-acting ACE inhibitors will confirm these
data remains to be seen.
Although ACE inhibitors improve outcome in patients with
systolic dysfunction, many patients with hypertension expe-
 1414 ACE Inhibitors

TABLE 2. Clinical Trials of ACE Inhibitors in Congestive Heart Failure and LV Dysfunction
Time of
Administration Treatment
Study Patient Population ACE Inhibitor After MI Duration Outcome Reference
Studies in LV dysfunction alone
CONSENSUS NYHA IV (n5253) Enalapril vs placebo 1 d–20 mo Decreased mortality; 94
decreased CHF
SOLVD-Treatment NYHA II and III (n52569) Enalapril vs placebo 22–55 mo Decreased mortality; 95
decreased CHF
V-HeFT II NYHA II and III (n5804) Enalapril vs hydralazine, 0.5–5.7 y Decreased mortality; 96
isosorbide decreased sudden
death
SOLVD-Prevention Asymptomatic LV dysfunction Enalapril vs placebo 14.6–62 mo Decreased mortality; 111
(n54228) decreased CHF
hospitalizations
Studies in LV dysfunction after MI*
SAVE MI, decreased LV function Captopril vs placebo 3–16 d 24–60 mo Decreased mortality 110
(n52231)
CONSENSUS II MI (n56090) Enalaprilat/enalapril vs 24 h 41–180 d No change in 118
placebo survival;
hypotension with
enalaprilat
AIRE MI and CHF (n52006) Ramipril vs placebo 3–10 d Minimum of Decreased mortality 97
6 months
ISIS-4 MI (n.50 000) Captopril vs placebo 24 h 28 d Decreased mortality 119
GISSI-3 MI (n519 394) Lisinopril vs control 24 h 6 wk Decreased mortality 121
TRACE MI, decreased LV function Trandolapril vs placebo 3–7 d 24–50 mo Decreased mortality 98
(n51749)
SMILE MI (n51556) Zofenopril vs placebo 24 h 6 wk Decreased mortality 120
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LV indicates left ventricular; CHF, congestive heart failure.

*Study involved patients with MI.

rience congestive heart failure due to diastolic dysfunction
related to left ventricular hypertrophy. In animal models,
ACE inhibitors have been shown to reverse ventricular
remodeling by blocking the trophic effects of Ang II on
cardiac myocytes.113,114 ACE inhibitors have been shown to
reverse left ventricular hypertrophy in patients with hyper-
tension.60,92,93 A meta-analysis of the effects of several anti-
hypertensive agents suggested that ACE inhibitors were the
most effective agent in reducing left ventricular hypertro-
phy.115 Studies examining mortality in patients with conges-
tive heart failure due to diastolic dysfunction are needed.
Left Ventricular Dysfunction After MI
On the basis of studies demonstrating that ACE inhibition
could reduce progressive enlargement after MI in experimen-
tal animals116 as well as in humans,117 it was hypothesized that
ACE inhibition might improve clinical outcome in patients
after MI. Several large, prospective, randomized trials have
now examined the effect of ACE inhibitors on mortality after
MI (Table 2).97,118 –121 The vast majority of these trials have
shown a decrease in cardiovascular mortality and a slowing
of the progression to congestive heart failure in patients
treated with ACE inhibitors. The optimal timing and dosage
of ACE inhibitor after MI are not known. In CONSENSUS II,
intravenous enalaprilat was administered within 24 hours of
MI.118 There was a significant increase in early hypotension in
the enalaprilat-treated group and, in contrast to other studies
with enalaprilat, there was no improvement in survival. On
the other hand, zofenopril, captopril, and lisinopril started
within 24 hours after MI in the SMILE,120 ISIS-4,119 and
GISSI-3 trials,121 respectively, did reduce mortality. In the
majority of trials, ACE inhibitor was administered 3 to 16
days after MI. It is likely that patients are more sensitive to
the hypotensive effects of ACE inhibitors in the immediate
post-MI period. An extensive discussion of the issues sur-
rounding the administration of ACE inhibitors after MI is
beyond the scope of the present review, but these issues were
recently reviewed by Pfeffer 122 and by Borghi and
Ambrosioni.123
Atherosclerotic Vascular Disease
Studies in patients with left ventricular dysfunction have
suggested the possibility that ACE inhibitors decrease the
frequency of ischemic events. For example, in the SAVE and
SOLVD trials, ACE inhibitors reduced the incidence of
recurrent MI and angina in patients with left ventricular
dysfunction or mild congestive heart failure by .20%.110,111
Nevertheless, it is not known whether ACE inhibitors will
prevent ischemic events in patients with normal ventricular
function. However, there is experimental evidence that ACE
inhibition can retard the development of atherosclerosis. In
animal models of atherosclerosis, including apolipoprotein E

knockout mice,124 Watanabe rabbits,125 and cholesterol-fed
monkeys,126 ACE inhibitors have been shown to reduce the
extent of vascular lesions. Furthermore, ACE inhibition has
been shown to reverse endothelial dysfunction in normoten-
sive patients with CAD, in hypertensive patients, and in
patients with non–insulin-dependent diabetes mellitus.127
ACE inhibition is thought to improve endothelial function by
attenuating the vasoconstrictive and superoxide radical– gen-
erating effects of Ang II while simultaneously enhancing the
bradykinin-dependent induction of endothelial nitric oxide
production. ACE inhibitors also promote ischemic precondi-
tioning, probably through a bradykinin-mediated mecha-
nism.128 Studies in vitro and in humans suggest that ACE
inhibitors favorably alter fibrinolytic balance, both by de-
creasing Ang II, a potent stimulus to plasminogen activator
inhibitor synthesis,129,130 and by increasing bradykinin, a
potent stimulus to tissue plasminogen activator secretion.131,132
Several ongoing clinical trials are designed to address the
hypothesis that ACE inhibitors prevent ischemic events in
high-risk patients without left ventricular dysfunction.133,134
Diabetic Nephropathy
The RAS and increased glomerular capillary pressure have
been implicated in the progression of renal dysfunction due to
a number of renal diseases, including diabetic nephropathy.135
ACE inhibitors decrease glomerular capillary pressure by
decreasing arterial pressure and by selectively dilating effer-
ent arterioles.136 In addition, Ang II causes mesangial cell
growth and matrix production.137,138 Numerous animal studies
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and small clinical trials have suggested that ACE inhibitors
significantly reduce the loss of kidney function in diabetic
nephropathy.139 ACE inhibitors prevent progression of mi-
croalbuminuria to overt proteinuria.140 A large, prospective,
placebo-controlled study has now shown that captopril slows
the progression of nephropathy in patients with insulin-
dependent diabetes mellitus, as measured by the rate of
decline in creatinine clearance and the combined end points
of dialysis, transplantation, and death.99 A second large-scale,
prospective, double-blind study extended these observations
by showing a protective effect of ACE inhibitors in patients
with a variety of renal diseases, including glomerulopathies,
interstitial nephritis, nephrosclerosis, and diabetic nephropa-
thy.141 The exception was polycystic kidney disease. Impor-
tantly, the protective effect of ACE inhibition was indepen-
dent of the severity of renal insufficiency.
Ongoing studies will determine whether ACE inhibitors
other than captopril are also effective in slowing progression
of nephropathy and will also clarify the value of ACE
inhibitors in slowing progression of renal disease in patients
with non–insulin-dependent diabetes mellitus. This is partic-
ularly relevant when one considers that, whereas 89% of the
patients in the captopril trial were white,99 non–insulin-
dependent diabetes mellitus is two times more prevalent
among blacks than whites.142 As mentioned above, blacks are
resistant to the antihypertensive effects of ACE inhibitors;
thus, it remains to be determined whether there are ethnic
differences in the renal protective effects of ACE inhibitors.
Other individual factors may determine the impact of ACE
inhibitors on the progression of renal insufficiency. In partic-
Brown and Vaughan April 14, 1998 1415
TABLE 3. Side Effects
Class effects
Hypotension
Cough
Hyperkalemia
Renal failure
Fetal anomalies
Angioedema
Dysgeusia
Sulfhydryl-related effects
Neutropenia
Rash
Nephrotic-range proteinuria
ular, Rigat et al143 described an insertion (I)/deletion (D)
polymorphism in the ACE gene that correlates with ACE
activity such that ACE levels are highest in patients who are
homozygous for the ACE D allele, lowest in patients ho-
mozygous for the ACE I allele, and intermediate in those who
are heterozygous. Yoshida et al144 reported a greater decrease
in proteinuria in response to ACE inhibition in patients with
IgA nephropathy who were homozygous for the DD allele. In
contrast, other investigators have reported a worse response
to therapy in patients who carry the ACE D allele.145 Obvi-
ously, large-scale studies are needed to define the impact of
genetic factors on the renal protective effects of ACE
inhibitors.
Adverse Effects
The adverse effects of ACE inhibitors (Table 3) can be
divided into those that are specific to the entire class and
those that are related to chemical structure (specifically,
related to the presence of a sulfhydryl group). Like all
antihypertensive agents, ACE inhibitors can cause hypoten-
sion. The frequency of hypotension is greater in renin-
dependent states, such as during low sodium intake and
diuretic use,146 and it is recommended that lower starting
doses be used under these conditions. ACE inhibitors can
cause hyperkalemia because of a decrease in aldosterone.147
This effect is usually not significant in patients with normal
renal function. However, in patients with impaired kidney
function or in patients who are taking potassium supplements
(including salt substitutes) or potassium-sparing diuretics,
hyperkalemia can occur.148,149
ACE inhibitors can cause a reversible decline in renal
function in the setting of decreased renal perfusion, whether
this is due to bilateral renal artery stenosis,150 severe conges-
tive heart failure,151 or volume depletion.152 The mechanism is
illustrated in Fig 2. When perfusion pressure or afferent
arteriolar pressure is decreased in the glomerulus, glomerular
filtration is maintained by efferent arteriolar vasoconstriction,
an effect of Ang II. Blocking the formation of Ang II,153 and
perhaps increasing the formation of bradykinin,154 causes
selective efferent arteriolar vasodilation and results in a
decrease in glomerular filtration in this setting.
 1416 ACE Inhibitors
Figure 2. Mechanism by which ACE inhibition can cause a
decrease in glomerular filtration in setting of hypoperfusion.
Decreased perfusion activates RAS. Whereas most vasocon-
strictors predominantly modify afferent tone, Ang II causes effer-
ent arteriolar and afferent vasoconstriction, increasing pressure
across glomerulus. Glomerular filtration is maintained. Thus,
during ACE inhibition, efferent arteriolar resistance decreas-
es153,154 and glomerular filtration declines.
Cough is a frequent side effect of ACE inhibitors. The
mechanism is not known but may involve increased levels of
bradykinin or substance P and stimulation of vagal C fibers.155
The frequency of cough varies among different patient
populations; the rate appears to be '10% in white popula-
tions but may be as high as 44% in Asian populations.156
Cough is more frequent among women than men.157,158 The
cough tends to be a dry, mildly annoying cough, but it often
requires cessation of therapy.
Angioedema is a rare but potentially life-threatening side
effect of ACE inhibitors. It is characterized by localized
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swelling of the lips, tongue, mouth, throat, nose, or other parts
of the face.155 The mechanism appears to involve bradykinin
or one of its metabolites.155 The rate of angioedema has been
reported to be 1 to 2 per 1000 in primarily white popula-
tions159 but appears to be increased in blacks.160 Although the
rate of angioedema is highest within the first month of ACE
inhibitor use, angioedema may occur years after the initiation
of therapy.160 Therefore, patients should be advised to recog-
nize early warning signs of localized edema and to discon-
tinue the drug should they occur.
If administered in the second or third trimester of preg-
nancy, ACE inhibitors can cause a number of fetal anomalies,
including oligohydramnios, fetal calvarial hypoplasia, fetal
pulmonary hypoplasia, fetal growth retardation, fetal death,
neonatal anuria, and neonatal death.161,162 For this reason,
ACE inhibitors should be used with caution in women of
child-bearing potential and must be stopped immediately in
any woman in whom pregnancy has been diagnosed.
Adverse effects that appear to be related to the presence of
a sulfhydryl group are neutropenia, nephrotic syndrome, and
skin rash.163 Neutropenia occurs in ,0.05% of patients.70 The
incidence is higher in patients who have renal insufficiency or
collagen vascular disease.164,165 Skin rash occurs in 1% of
patients166 and usually consists of a pruritic maculopapular
eruption; rarely, exfoliative dermatitis has been reported.167
The rash appears to be dose-related.77 Other ACE inhibitors
may cause a rash with a much lower frequency than capto-
pril,98 and there does not appear to be cross-reactivity among
ACE inhibitors.168,169
Drug Interactions
As mentioned above, concurrent administration of potassium
supplements, potassium-sparing diuretics, or salt substitutes
may precipitate hyperkalemia in ACE inhibitor–treated pa-
tients in whom aldosterone is suppressed. Patients taking
diuretics may be particularly sensitive to the hypotensive
effects of ACE inhibitors.146 Nonsteroidal anti-inflammatory
drugs may attenuate the antihypertensive effects of ACE
inhibitors.47,50,170,171 This effect appears to be more prominent
in patients with low renin levels.172
Cost
Captopril is the only ACE inhibitor currently available in a
generic form. The average wholesale price per 100 U ranges
from $3.41 for 12.5-mg tablets to $14.97 for 100-mg tablets.
At present, contract pricing makes the relative cost of the
other agents vary from institution to institution. In general,
these agents are priced such that the average wholesale price
per 100 U runs from $60 to $80. The limited selection of ACE
inhibitors available on many formularies today often precip-
itates patients being changed from one ACE inhibitor to
another. However, given the differing potencies, tissue affin-
ities, and bioavailabilities among ACE inhibitors, it is not
clear that all agents are equal. Rigorous studies comparing
potencies among ACE inhibitors are needed.
Future Directions
This review focuses on the pharmacology of ACE inhibitors
and on the broadening clinical applications of this class of
compounds. Clearly, the beneficial cardiovascular and renal
effects of ACE inhibitors go beyond the original, limited
indication for the treatment of hypertension. Although current
clinical efforts are directed at the emerging role of ACE
inhibitors in preventing cardiovascular events in normoten-
sive subjects, further work needs to be done to characterize
molecular and cellular mechanisms responsible for the clin-
ical effects of ACE inhibitors. In particular, the role of
bradykinin remains enigmatic. Although ACE inhibition after
MI appears to have an established role in clinical practice, the
ongoing controversy over the selective versus nonselective
use of ACE inhibitors after MI is unlikely to be resolved in
the near future. Clinical studies will compare the efficacy of
ACE inhibitors and specific AT1 receptor antagonists in the
treatment of cardiovascular and renal disease. Finally, studies
will determine to what extent individual characteristics such
as race and ACE genotype determine responses to ACE
inhibitors.
It is clear that ACE inhibitors represent one of the major
advances in cardiovascular therapeutics over the past 20
years. It is highly doubtful that even the most enthusiastic
advocate of these agents could have anticipated their broad
clinical applications. Furthermore, ACE inhibitors, in very
tangible terms, have catalyzed research into molecular and
cellular mechanisms of vascular disease that is paying large
dividends.
Acknowledgments
This work was supported by NIH grants R01-HL-51387 (Dr
Vaughan) and R29-HL-56963 (Dr Brown) and by a Clinical Inves-

tigator Award from the Veterans Affairs Research Administration
(Dr Vaughan).
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