Carvedilol is a vasodilating beta-blocker currently marketed for the treatment of mild to moderate
hypertension and application is being filed to the FDA for treatment of
congestive heart failure.
Carvedilol reduces peripheral vascular resistance by blocking arterial alpha 1-adrenoceptors, thereby producing vasodilation, while preventing reflex
tachycardia by blocking cardiac beta 1- and beta 2-adrenoceptors. In addition to the safety and efficacy of
carvedilol as an
antihypertensive agent, experimental studies indicate that
carvedilol also provides significant cardioprotection in animal models of acute
myocardial infarction as well as protection against the vascular remodelling that occurs following injury of the vasculature. Recent pharmacological studies have uncovered several novel properties of
carvedilol which may function to protect the heart and vasculature from chronic
pathological processes, such as ischaemia,
atherosclerosis and the remodelling that occurs in the heart and blood vessels as a consequence of pressure overload, injury or shear stress. Specifically,
carvedilol, likely as a result of the carbazol moiety, is a potent
anti-oxidant. In physicochemical, biochemical and cellular assays
carvedilol and several of its metabolites inhibit lipid peroxidation, scavenge
oxygen free radicals, inhibit the formation of reactive
oxygen radicals and prevent the depletion of
endogenous antioxidants, such as
vitamin E and
glutathione. Moreover,
carvedilol blocks the oxidation of
low-density lipoproteins (
LDL), and thereby prevents the formation of
oxidized-LDL which is believed to stimulate foam cell formation and augment the development of
atherosclerotic plaque. The ability of
carvedilol to prevent the formation of
oxidized LDL, in addition to the general
anti-oxidant properties of the compound, results in the protection of the endothelium from
oxygen free radical injury, and thereby prevents the subsequent events triggered by endothelial damage. Recently,
carvedilol has also been shown to inhibit vascular smooth muscle cell proliferation and migration. Because
carvedilol can inhibit vascular smooth muscle cell proliferation induced by a wide variety of
mitogens (e.g.
growth factors,
angiotensin II,
endothelin,
thrombin), it is likely that the site of inhibition occurs at some point beyond the specific
mitogen receptors, possibly at a distal common pathway that affects the smooth muscle cell cycle. These unique activities of
carvedilol have also been confirmed in vivo in a rat model of neointimal formation following
vascular injury by balloon angioplasty, where vascular smooth muscle cell migration and proliferation are the key processes involved in the formation of
neointima leading to vascular
stenosis. In this model,
carvedilol suppressed neointimal growth to a remarkable extent ( > 85% inhibition of neointimal formation) at a dose that is similar to the
antihypertensive dose used clinically in hypertensive patients. Taken together, these unique multiple actions of
carvedilol provide not only for adequate control of elevated blood pressure, but may also provide for protection of the heart and vasculature from secondary damage due to
hypertension itself, as well as from other causes, such as ischaemia, pressure overload, shear stress,
vascular injury and
atherosclerosis.