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Differences between
angiotensin converting
enzyme inhibitors and receptor
blockers

Authors Section Editor Deputy Editor

Timothy W Smith, MD, George L Bakris, MD Alice M Sheridan,
PhD MD
James P Morgan, MD,
PhD

Last literature review version 16.3: September 2008 | This topic last
updated: July 25, 2008 (More)

INTRODUCTION — Angiotensin converting enzyme (ACE) inhibitors are widely

used in the treatment of hypertension. They have also been effective in a
number of other disorders, prolonging survival in patients with heart failure,
coronary heart disease, and acute myocardial infarction, and slowing the rate
of progression in chronic renal failure, particularly diabetic nephropathy. One
limiting side effect in a minority of patients is cough, a side effect that does not
appear to occur with increased frequency with the angiotensin receptor
blockers. The latter drugs are as effective as the ACE inhibitors in the
treatment of hypertension [ 1] . (See "Renin-angiotensin system inhibition in
the treatment of hypertension" ). It remains unclear, however, whether they
are ACE inhibitors without cough or whether they have some differences in
activity.

The evidence that there are clinically important differences between these two
classes of drugs will be reviewed here. There is also evidence that there may
be circumstances when combination therapy is beneficial.

MECHANISMS OF ACTION — Angiotensin II is an oligopeptide of eight amino

acids, formed from its precursor, angiotensinogen by a series of two enzymatic
cleavages. Angiotensinogen is released into the circulation by the liver. Renin,
produced by the kidney, in response to glomerular hypoperfusion, catalyzes
cleavage of angiotensinogen to angiotensin I, an inactive decapeptide.
Angiotensin I is in turn cleaved by angiotensin converting enzyme to produce
angiotensin II. Angiotensin II binds to its specific receptors and exert its
effects in the brain, kidney, adrenal, vascular wall, and the heart. ( See
"Chapter 2B: Renin-angiotensin system" ).
There are two well-described subtypes of angiotensin II receptors, designated
AT1 and AT2, both of which have a high affinity for angiotensin II [ 2,3] .

The AT1 subtype mediates the vasoconstrictor effect of angiotensin II

and is generally thought to mediate angiotensin II-induced growth in the
left ventricle and the arterial wall [ 4] .

The actions of the AT2 receptor are less well understood. AT2 receptors
are expressed in greater abundance in fetal tissues, followed by a
decline in expression after birth [ 5,6] . Their role in development has not
been elucidated [ 3,4] . In vivo data in a model of angiotensin II-induced
hypertension showed that exposure of a specific inhibitor of the AT2
receptor (PD123319) prevented angiotensin II-induced arterial
hypertrophy [ 7] . This and other observations suggest that the AT2
receptor plays a greater role in stimulating growth in the arterial wall.

Receptor activation — There are two major differences between the ACE
inhibitors and angiotensin II receptor antagonists: the receptors that are
affected; and the effect on kinins ( show figure 1 ). Angiotensin II can activate
both AT1 and AT2 receptors. As a result, inhibition of angiotensin II formation
with an ACE inhibitor will diminish the activity of both receptor subtypes. The
inhibition of angiotensin II production occurs both systemically and at tissue
sites of local renin-angiotensin systems. ( See "Actions of angiotensin II on the
heart" ).

In contrast, the angiotensin II receptor antagonists only diminish AT1 activity.

Thus, there is no change in AT2 receptor-mediated effects.

Effect on kinins — Converting enzyme is also a kininase. As a result, inhibiting

this enzyme with an ACE inhibitor may lead to increased kinin levels, an effect
not seen with the angiotensin II receptor antagonists. It is presumed that the
absence of kinin accumulation accounts for the lack of cough with the
angiotensin II receptor antagonists. ( See "Major side effects of angiotensin
converting enzyme inhibitors and angiotensin II receptor blockers" ). However,
kinin accumulation may also mediate some of the beneficial effects of ACE
inhibition.

Increased kinins may contribute to the hypotensive action of ACE

inhibitors by releasing nitric oxide from vascular endothelial cells. The
potential importance of kinins in this response was illustrated in a study
in humans who were treated with an ACE inhibitor (quinaprilat), or a
bradykinin B2-receptor antagonist (icatibant), or both [ 8] . ACE inhibition
increased flow-dependent vasodilation (as determined by ultrasound
and Doppler of the radial artery); this effect was abolished, and
flow-dependent vasodilation was actually reversed by the addition of
 the bradykinin B2 receptor antagonist. The effect of the combination was
similar to that seen with icatibant alone.

A significant role for bradykinin in the induction of hypotension with ACE

inhibitors was also found in a single-blinded, randomized study of 20
normotensive and 7 hypertensive individuals [ 9] . An ACE inhibitor alone (25
mg of captopril ), captopril plus a bradykinin B2-receptor antagonist (icatibant),
an angiotensin II subtype 1-receptor antagonist alone (75 mg of losartan ) and
placebo were randomly administered on four separate study days. Icatibant
significantly ameliorated the hypotensive response to captopril (10.5 versus
15.0 mmHg for combination therapy and captopril alone, respectively, p =
0.001); in addition, combination therapy resulted in the same degree of blood
pressure lowering as that observed with losartan alone (10.5 versus 11.0
mmHg). The elevation in plasma renin activity associated with ACE inhibition
was reversed with icatibant, suggesting that bradykinin was responsible for
this effect.

Increased kinins may contribute to another effect of ACE inhibitors, the

ability to improve insulin sensitivity which can lower the blood glucose in
patients with type 2 diabetes. ( See "Treatment of hypertension in
diabetes mellitus" , section on Choice of antihypertensive agents). In one
study in rats, the enhancement of insulin sensitivity by enalapril was
inhibited by a kinin antagonist whereas no change in insulin sensitivity
was seen with losartan [ 10] . The effect of kinins may be mediated in
part by increased blood flow to skeletal muscle, thereby promoting
insulin delivery and glucose uptake.

Rationale for combined therapy —There is reason to believe that combined

therapy with an ACE inhibitor and angiotensin receptor antagonist might have
an additive effect. With ACE inhibitors, the fall in angiotensin II leads to
increased renin release, which partially returns angiotensin II levels toward
baseline. In addition, ACE inhibitors only block the formation of angiotensin II
that is mediated by angiotensin converting enzyme. There is evidence that
alternative enzymatic pathways, particularly involving chymase, exist for the
production of angiotensin II within the myocardium [ 11-13] .

A similar effect may occur in the blood vessels. In a mouse model,

overexpression of vascular chymase leads to an elevation in blood pressure
[14] . It remains to be proven that this effect is mediated by increased local
production of angiotensin II.

CLINICAL IMPLICATIONS — Although initial studies in a variety of disease

states were performed with ACE inhibitors, it has been expected and in many
cases demonstrated that similar benefits could be achieved with ARBs. In
addition, combination therapy with both classes may be more effective that
monotherapy with either drug in heart failure and chronic renal failure.
The following is a summary of the clinical settings in which these drugs have
been used. The specific data are discussed in detail separately:

To slow the progression of proteinuric diabetic and nondiabetic chronic

renal failure. ( See "Antihypertensive therapy and progression of
nondiabetic chronic kidney disease" and see "Treatment and prevention
of diabetic nephropathy" ).

To improve hemodynamics and survival in patients with heart failure due

to systolic dysfunction. ( See "ACE inhibitors in heart failure due to
systolic dysfunction: Therapeutic use" and see "Angiotensin II receptor
blockers in heart failure due to systolic dysfunction: Therapeutic use" ).

To lower the blood pressure in patients with hypertension and also

allow more rapid regression of left ventricular hypertrophy. ( See
"Renin-angiotensin system inhibition in the treatment of hypertension"
and see "Renin-angiotensin system inhibition in the treatment of
hypertension" and see "Clinical implications and treatment of left
ventricular hypertrophy in hypertension" ).

It has also been suggested that ACE inhibitors and ARBs improve outcomes in
patients at high risk for a cardiovascular event. However, it is likely that this
beneficial effect is due to blood pressure reduction rather than a specific
consequence of blockade of the renin-angiotensin system. ( See "Choice of
antihypertensive drug and blood pressure goal in patients at increased risk for
a cardiovascular event" ).

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REFERENCES

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10. Tomiyama, H, Kushiro, T, Abeta, H, et al. Kinins contribute to the
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II-forming activity in a reconstructed ancestral chymase. Science 1996;
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12. Urata, H, Boehm, KD, Philip, A, et al. Cellular localization and regional
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GRAPHICS
 Comparison of the actions of angiotensin converting enzyme
inhibitors and angiotensin II receptor blockers

ACE: angiotensin converting enzyme; ACEI: angiotensin converting

enzyme inhibitor; ARB: angiotensin II receptor blocker.

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