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European Heart Journal Supplements (2003) 5 (Supplement A), A37–A41
Contribution of bradykinin to the cardioprotective
effects of ACE inhibitors
L. Murphey1, D. Vaughan2 and N. Brown1
1Division of Clinical Pharmacology, 2Division of Cardiovascular Medicine, Departments of Medicine and
Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA and 2Veterans Affairs Medical
Center, Nashville, Tennessee, USA
Bradykinin, through its B2 receptor, stimulates endothelial
release of a number of vasodilators, such as nitric oxide,
prostacyclin, and endothelium-derived hyperpolarizing factor
(EDHF). Angiotensin-converting enzyme (ACE) inhibitors
enhance the effects of local bradykinin by decreasing its
degradation and by increasing B2 receptor sensitivity. Clinical
and experimental studies demonstrate that blockade of the
B2 receptor attenuates the antihypertensive, antihypertrophic,
and antiatherosclerotic effects of ACE inhibitors. Thus, the
evidence strongly supports a role for bradykinin in mediating
the cardiovascular benefits of ACE inhibitors.
(Eur Heart J Supplements 2003; 5 (Suppl A): A37–A41)
© 2003 The European Society of Cardiology
Introduction
to release bradykinin, which acts in a paracrine manner via
bradykinin B2 receptors. Tissue kallikrein, a distinct enzyme
activated by different mechanisms, releases lysl-bradykinin
(kallidin), which also acts through the B2 receptor.
Bradykinin exerts a number of vascular effects (Fig. 2).
By stimulating synthesis and release of nitric oxide (NO),
prostacyclin, and endothelium-derived hyperpolarizing
factor (EDHF), bradykinin causes vasodilation and also
inhibits platelet adhesion and smooth muscle cell
proliferation[6]. Bradykinin is also one of the most potent
stimuli for endothelial release of tissue plasminogen
activator (tPA) in vivo[7].
Overview of the RAS and KKS
The major components and actions of the RAS and the KKS
are illustrated in Fig. 1. Both the RAS and KKS have been
localised to the vasculature[4,5], where the effects of
bradykinin oppose many of the actions of angiotensin II
(Ang II).
Bradykinin: Key component of the KKS
The KKS is activated on the surface of endothelial cells[5].
Plasma kallikrein cleaves high-molecular-weight kininogen,
Correspondence: Laine J. Murphey, MD, PhD, 556A Robinson
Research Building, Vanderbilt University Medical Center, Nashville,
TN 37232-6602 USA
1520-765X/03/0A0037 + 05 $35.00/0
Ang II: Key component of the RAS
ACE, a bivalent dipeptidyl carboxyl metallopeptidase, is
present in endothelial, epithelial or neuroepithelial cells as a
membrane-bound form, and as a soluble form in the brain,
blood and numerous body fluids[8]. ACE converts
angiotensin I (Ang I) to Ang II, the principal effector
molecule of the RAS. Four receptor subtypes have been
identified for Ang II[9]: the AT1 receptor mediates
vasoconstriction, vascular smooth muscle cell proliferation,
and production of superoxide ions; the AT2 receptor, which
is normally expressed at very low levels in adults, may be
upregulated during AT1 receptor blockade and counteracts
many AT1-mediated effects (see below)[10,11]; the role of the
AT3 receptor is not known at present; and AT4 influences
local blood flow[12] and stimulates synthesis of plasminogen
activator inhibitor 1 (PAI-1), the major physiological
inhibitor of fibrinolysis, in endothelial cells[13].
© 2003 The European Society of Cardiology
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Over 30 years ago, Ferreira et al.[1] isolated a bradykininpotentiating peptide from the venom of a Central American
viper. Shortly thereafter, Ondetti et al.[2] reported the
isolation of an angiotensin-converting enzyme (ACE)
inhibitor from the venom of the same snake. Erdös
subsequently demonstrated that ACE and kininase II, which
degrades bradykinin to inactive metabolites, are the same
enzyme[3], thus linking the renin-angiotensin system (RAS)
and the kallikrein-kinin system (KKS).
Key Words: ACE inhibitors, ramipril, bradykinin, endothelial
dysfunction, kallikrein-kinin system, renin-angiotensin system
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L. Murphey et al.
+
Figure 1 Components and major actions of the RAS
and KKS.
RAS / KKS linkages
Bradykinin and antihypertensive
effects of ACE inhibitors
The availability of a specific bradykinin B2 receptor
antagonist, icatibant acetate (HOE 140), has allowed
investigators to determine the contribution of bradykinin to
the effects of ACE inhibitors in vivo. Bradykinin receptor
blockade attenuates the hypotensive response to ACE
inhibition in rats and dogs[23–25]. In humans, ACE inhibition
enhances[26] whereas B2 receptor blockade decreases[7,27] the
vasodilator effects of exogenous bradykinin. Studies using
icatibant further indicate that endogenous bradykinin
contributes to the acute hemodynamic effects of ACE
inhibitors in humans. For example, bradykinin receptor
blockade decreases the potentiation of endotheliummediated, flow-dependent vasodilation by ACE inhibition in
Eur Heart J Supplements, Vol. 5 (Suppl A) January 2003
Figure 2 Vascular effects of bradykinin. Bradykinin
interacts with B2 receptors to stimulate production of
NO, PGI 2 and EDHF, which diffuse from the
endothelium to vascular smooth muscle cells. Through
differing mechanisms these mediators produce
vascular smooth cell relaxation. Antagonists and
inhibitors are indicated with boxes. BK=bradykinin;
EDHF=endothelium-derived hyperpolarizing factor;
L-NMMA=L-NG-monomethyl-L-arginine; NO=nitric
oxide; PGI2=prostacyclin; PLA2=phospholipase A2;
PLC=phospholipase C. (Adapted from Vanhoutte[49]).
healthy individuals[28]. Similarly, co-administration of
icatibant attenuates the acute hypotensive effects of oral
captopril in both normotensive and hypertensive subjects[29].
Bradykinin and antihypertrophic
effects of ACE inhibitors
ACE inhibitors decrease cardiac hypertrophy in patients
with hypertension[30]. Bradykinin receptor antagonism
decreases the antihypertrophic effect of ACE inhibitors in
hypertensive animals[23]. Conversely, genetic B2 receptor
deficiency is associated with the development of cardiac
hypertrophy[31]. In vitro, bradykinin prevents Ang IIinduced hypertrophy of cultured cardiomyocytes by
releasing nitric oxide (NO) from endothelial cells, thereby
increasing
cardiomyocyte
guanosine
3′5′-cyclic
monophosphate (cGMP)[32].
Bradykinin and anti-ischemic and
antiatherosclerotic effects of ACE
inhibitors
ACE inhibitors reduce the risk of myocardial infarction in
patients with decreased left ventricular function[33,34], as
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The RAS and KKS are linked at a number of levels. ACE
not only converts Ang I to Ang II but also bradykinin to
inactive metabolites[14]; hence, ACE inhibitors increase
circulating concentrations of bradykinin[15]. Recent
evidence suggests that ACE inhibitors also potentiate the
effects of bradykinin via direct effects at the bradykinin B2
receptor[16,17]. For example, Benzing et al.[18] demonstrated
that ramiprilat, a tissue-specific ACE inhibitor, inhibited the
desensitization of the B2 receptor via sequestration within
caveolae, lipid-rich pockets on the surface of endothelial
cells. Similarly, Marcic et al. demonstrated that ACE
inhibitors enhance the effect of bradykinin at its B2 receptor
by inducing ‘crosstalk’ between ACE and the receptor[19].
In vitro and animal studies suggest that the AT2 receptor
provides an additional connection between the RAS and the
KKS. During AT1 receptor blockade, unopposed activation
of the AT2 receptor leads to increased bradykinin, NO and
cyclic (c)GMP[11,20]. Although acute AT1 receptor blockade
does not potentiate the effects of exogenous bradykinin[21],
these data potentially implicate endogenous bradykinin in
the beneficial effects of chronic AT1 receptor blockade[22].
Likely mechanism of ramipril in coronary heart disease
well as in patients with normal left ventricular function who
are at risk for coronary artery disease[35]. Again, studies in
animals using icatibant implicate bradykinin in the
mechanism of the anti-ischemic effects of ACE inhibitors.
Thus ACE inhibition decreases infarct size following
coronary artery occlusion in dogs or rabbits and this effect
is abolished by either bradykinin receptor antagonism[36,37]
or nitric oxide synthase inhibition with NG-L-nitro-arginine
methyl ester (L-NAME)[38].
Kallikrein
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Angiotensinogen
Kininogen
Renin
Ang I
Bradykinin
ACE
Ang II
Inactive peptides
tPA
PAI-1
Ang IV
ALDO
Bradykinin, ACE inhibition, and
fibrinolytic balance
Figure 3 Relationship between the renin-angiotensin,
kallikrein-kinin,
and
fibrinolytic
systems.
Angiotensin-converting enzyme (ACE) can shift the
fibrinolytic balance in favor of PAI-1 by increasing the
formation of angiotensin II (Ang II) and the
catabolism of bradykinin. Ang I=angiotensin I; Ang
IV=angiotensin IV; PAI-1=plasminogen activator
inhibitor-1; tPA=tissue-type plasminogen activator.
(Adapted from Brown and Vaughan[39].)
hypertensive subjects, and patients post-MI. For example, in
the Healing and Early Afterload Reduction Therapy
(HEART) study[45], ACE inhibition decreased PAI-1 antigen
and activity in patients with acute anterior MI. Plasma tPA
levels were similar in both the ramipril and control groups.
The effect of ACE inhibition on PAI-1 antigen following
thrombolysis for acute MI has also been described[46]. ACE
inhibition was associated with a diminished rise in PAI-1
antigen following thrombolysis and an increased rate of
patency of the infarct-related artery.
The observation that chronic ACE inhibition but not AT1
receptor antagonism decreases circulating PAI-1 antigen
concentrations[47] raises the possibility that bradykinin not
only stimulates tPA release, but also contributes to the
regulation of PAI-1. Because NO suppresses PAI-1
expression after stimulation by Ang II in aortic smooth
muscle cells[48], it may be hypothesized that bradykinin
could moderate PAI-1 expression by releasing NO. Further
studies are needed to determine whether bradykinin opposes
the effects of Ang II on PAI-1 expression.
Conclusion
Bradykinin favorably alters fibrinolytic balance and
promotes release of vasoactive compounds that improve
endothelial function. ACE inhibitors potentiate bradykinin
by blocking (1) ACE-mediated breakdown of bradykinin,
and (2) B2 receptor desensitization. A substantial body of
evidence points to increased local bradykinin action as an
important contributing mechanism in the reduction of
cardiovascular events[35].
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One mechanism through which bradykinin may contribute
to the anti-ischemic effects of ACE inhibitors involves the
fibrinolytic system. The endogenous fibrinolytic system
serves as one of the major defense mechanisms against
intravascular thrombosis. Fibrinolytic activity is regulated
by the balance between tPA and PAI-1 (Fig. 3)[39,40].
Bradykinin stimulates endothelial release of tPA,[8,42]
whereas Ang II increases PAI-1 expression[13].
Brown et al.[7] have studied the mechanism of
bradykinin-induced tPA release from the human
vasculature. They demonstrated that bradykinin stimulates
vascular tPA release in a dose-dependent manner, that this
effect is independent of changes in flow, and that, like
vasodilation, this effect is mediated through the bradykinin
B2 receptor. However, following receptor activation,
bradykinin appears to cause vasodilation and stimulate tPA
release through distinct mechanisms. Thus, while
administration of the nitric oxide synthase (NOS) inhibitor
L-NG-monomethyl-L-arginine (L-NMMA) attenuates the
forearm vasodilator response to bradykinin, indicating that
NO contributes to bradykinin-induced vasodilation,
L-NMMA alone or in combination with the cyclooxygenase
inhibitor indomethacin did not affect the tPA response to
bradykinin, suggesting that tPA release is mediated through
a NOS- and cyclooxygenase-independent pathway.
ACE inhibitors improve endothelial function as measured
by the vasodilator response to endothelium-dependent
agonists[42]. ACE inhibition, but not AT1 receptor blockade,
potentiates the effect of exogenous bradykinin on tPA
release in the peripheral[41] and coronary vasculature[43]. A
recent study using icatibant indicates that ACE inhibition
increases constitutive vascular tPA release in subjects at risk
for coronary artery disease through effects on endogenous
bradykinin[44].
The findings that bradykinin induces tPA expression and
release while Ang II stimulates PAI-1 expression suggest
that ACE inhibitors reduce risk of MI, in part, through
effects on fibrinolytic balance. Indeed, activation of the
renin-angiotensin-aldosterone system by salt depletion or
diuretic use increases plasma PAI-1 concentrations, while
ACE inhibition significantly decreases plasma PAI-1
without consistently decreasing tPA concentrations[40].
Hence, ACE inhibitors improve the molar ratio of PAI-1 to
tPA. These effects have been observed in young
normotensive subjects, healthy postmenopausal women,
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L. Murphey et al.
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Eur Heart J Supplements, Vol. 5 (Suppl A) January 2003