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(Circulation. 2001;103:782.)
© 2001 American Heart Association, Inc.
Editorial |
Antioxidants and Myocardial Contractility
Illuminating the "Dark Side" of 
-Adrenergic Receptor Activation?
From the Cardiomyopathy Program and Cardiovascular Section, Boston University Medical Center, and Boston University School of Medicine, Boston, Mass.
Correspondence to Wilson S. Colucci, MD, Cardiovascular Section, Boston University Medical Center, 88 E. Newton Street, Boston, MA 02118. E-mail wilson.colucci{at}bmc.org
Key Words: Editorials • antioxidants • contractility • receptors, adrenergic, beta • myocardium
Oxidant
byproducts, such as superoxide anion
(O2–) and hydrogen
peroxide, are produced as a consequence of normal aerobic metabolism.
These molecules, which are highly reactive with other biological
molecules, are referred to as reactive oxygen species (ROS). Under
normal physiological conditions, ROS production is balanced by an
efficient system of antioxidants, molecules that are capable of
scavenging ROS and thereby preventing oxidant damage. At the cellular
level, naturally occurring enzymatic antioxidants such as superoxide
dismutase, glutathione peroxidase, and catalase play an important role
in the conversion of ROS to oxygen and water. Several nonenzymatic
antioxidants, including the lipid-soluble antioxidants vitamin E and
-carotene and the water-soluble antioxidants vitamin C and
glutathione, are also important in scavenging free radicals. Vitamin C
in particular protects plasma lipids from peroxidation, scavenges
O2–, and plays a
role in recycling vitamin E.
In pathological states, ROS may be present in relative excess. This shift of the balance in favor of oxidation, termed "oxidative stress," may have detrimental effects on cellular and tissue function. Oxidative stress is thought to contribute to the pathogenesis of a wide variety of disease states, including atherosclerosis1 and cancer, as well as to the normal process of aging. There is increasing evidence that myocardial oxidative stress may contribute to disease progression in heart failure.2 Although the effects of oxidative stress on the myocardium have been investigated in pathological states, very little is known about the role of ROS in the regulation of normal cardiac function. Recently, Ekelund et al3 tested the role of the pro-oxidant enzyme xanthine oxidase in regulating contractile function in normal dogs. Their finding that the xanthine oxidase inhibitor allopurinol exerted a positive inotropic effect suggested that ROS participate in the control of normal myocardial function. In this issue of Circulation, Mak and Newton4 provide the first direct evidence that ROS contribute to the regulation of normal contractile function in humans. In patients with normal left ventricular function undergoing cardiac catheterization for evaluation of a chest pain syndrome, the contractile response to intravenous dobutamine was assessed before and during the intracoronary infusion of vitamin C. The infusion rate of vitamin C was chosen to achieve an intracoronary concentration between 1 and 10 mmol/L, a level that improves endothelial function in vivo.5 Vitamin C had no effect on basal contractile function, but it potentiated the positive inotropic response to dobutamine by 22%. In a group of control patients, there were no differences in the inotropic responses to sequential dobutamine infusions, suggesting that the augmentation of the inotropic response to dobutamine was due to vitamin C rather than repetitive dobutamine infusions.
There are several possible mechanisms by which vitamin C may
have augmented the response to dobutamine. Vitamin C corrects coronary
vasomotor regulation and increases coronary blood flow in patients with
hypertension and vasospastic
angina.6 7 Although
the patients studied by Mak and
Newton4 had normal left
ventricular systolic function, the majority had coronary artery disease
and/or coronary risk factors (eg, hypertension and diabetes) that are
associated with oxidative
stress.1 Thus, it is possible
that vitamin C acted by improving the coronary blood flow response to
-adrenergic stimulation.
Another possibility is that myocardial ROS can directly
regulate the function of cardiac myocytes. It is now apparent that
nontoxic quantities of ROS can mediate biological processes in a
variety of cell types.8 For
example, Griendling and
colleagues9 showed that ROS
play a critical role in mediating angiotensin-stimulated growth in
vascular smooth muscle cells. The finding that vitamin C increases the
contractile response to an exogenous -adrenergic agonist raises the
possibility that ROS modulate -adrenergic signaling. Such an action
could occur at one or more points between the receptor and contractile
elements. Potential mechanisms include redox-dependent alterations in
the expression or function of -adrenergic receptors, related
G-proteins, adenylyl cyclase, cAMP metabolism, calcium handling
proteins, or proteins in the contractile apparatus. There is evidence
that ROS can regulate -adrenergic receptors, G-proteins, and
adenylyl cyclase function in rat
myocardium.10 Likewise, it
has been demonstrated that the function of several calcium handling
proteins, including the calcium-release channel, the voltage-dependent
calcium channel, and the sodium/calcium exchanger, undergo
redox-sensitive alterations in
activity.11 12 13
Understanding the molecular mechanism by which ROS regulate myocardial
contractile function may provide new insights regarding both normal
myocardial function and the potential role of deranged ROS in disease
states.
These data have other, somewhat less obvious implications.
The -adrenergic system plays an important role in determining the
myocardial responses to exercise and other short-term demands
for an increase in myocardial contractile function. At the same time,
it now seems likely that the -adrenergic system contributes to the
pathophysiology of myocardial
failure.14 When viewed in
this latter context, the finding that vitamin C increases the inotropic
response of normal human heart to dobutamine raises an interesting
conundrum. If blocking -adrenergic responses is beneficial in the
failing myocardium, then ROS should play a protective role by
attenuating this pathway. Because vitamin C increases -adrenergic
"throughput," it could be argued that antioxidants, although
improving short-term function, exert a deleterious effect on the
myocardium.
However, another hypothesis is also possible in which ROS
represent the "dark side" of long-term -adrenergic receptor
stimulation. According to this thesis, -adrenergic receptor
activation leads to increased production of ROS, perhaps as a necessary
consequence of increased myocardial oxygen
consumption.15 There might
be multiple consequences of a -adrenergically–mediated increase in
ROS formation. As already suggested, the data from Mak and
Newton4 provide evidence that
ROS production could act as a counter-regulatory mechanism to control
the intensity of -adrenergic responses. In vitro studies have also
shown that tonic exposure to ROS can exert deleterious effects on
myocardial structure and function. In isolated cardiac myocytes, we and
others found that ROS cause myocyte
apoptosis.16 17
Likewise, peroxynitrite, the product of
O2– and nitric
oxide, may mediate myocyte apoptosis in response to
interleukin-1.18 Evidence
that ROS are involved in pathological myocardial remodeling comes from
studies in which strategies to reduce ROS, including the use of
antioxidant vitamins, have exerted beneficial effects in animal models
of pressure overload or myocardial
infarction.19 20
Thus, although ROS might serve in the short-term to reduce
the intensity of -adrenergic signaling, in the long run, a
-adrenergically–mediated increase in ROS formation could be
detrimental to myocardial health. In this scenario, treatment with
antioxidants would not only augment the short-term inotropic response
to -adrenergic stimulation, but also prevent the direct ROS-mediated
adverse effects of long-term -adrenergic stimulation on the myocyte.
The findings of Mak and
Newton4 thus raise the
intriguing possibility that ROS contribute to the dark side of
long-term -adrenergic stimulation of the myocardium and offer a
mechanism by which interruption of -adrenergic signaling could exert
a beneficial effect on the myocardium.
Footnotes
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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