Carvedilol is a widely used beta-blocker for the treatment of congestive heart failure (CHF). Large clinical trials have established that carvedilol reduces mortality and improves cardiac function for all CHF patients, particularly those with severe disease.

The effect of carvedilol may be due not only to beta blockade, but also to some other unknown mechanisms. One of the unique properties of this drug is potent antioxidant activity. Oxidative stress is an important contributor to contractile dysfunction.

Dr. Koitabashi and colleagues hypothesized that carvedilol may exert its beneficial effect by inhibiting reduction in transcription of a specific gene, sarco/endoplasmic reticulum Ca²⁺-ATPase isoform 2 (SERCA2). Investigators previously showed that the activity of SERCA2 correlates with cardiac performance parameters such as systolic and diastolic function. Furthermore, SERCA2 regulates intracellular Ca²⁺ handling in the failing myocardium.

Investigators wanted to know whether carvedilol attenuates the decrease of the SERCA2 gene under oxidative stress. If so, then the antioxidant activity of carvedilol may be an important mechanism in preventing heart failure.

They exposed cultured neonatal rat cardiomyocytes to hydrogen peroxide, causing oxidative stress. Then, they treated the cells with 3 drugs: carvedilol, a metabolite of carvedilol with no beta blocking activity, and the beta-1 selective blocker metoprolol.

Experiments showed that hydrogen peroxide decreased SERCA2 protein mRNA levels in the rat cardiomyocytes in a dose-dependent manner. Transient transfection assays showed that carvedilol decreased transcription of the SERCA2 gene promoter.

Treatment with carvedilol attenuated these decreases in SERCA2 protein levels and mRNA expression. This suggests carvedilol could protect impairment of cardiac function that hydrogen peroxide had induced.

Investigators found that the non-beta blocking metabolite of carvedilol also attenuated these hydrogen peroxide mediated decreases.

Metoprolol, a β₁ selective blocker, did not exert these effects on rat cardiomyocytes under oxidative stress. There was no increase in SERCA2 transcriptional activity.

These findings imply that carvedilol may be a very potent attenuator of oxidative stress from hydrogen peroxide or other conditions that impair cardiac function, such as volume or pressure overload.

Investigators believe that exposing rat cardiac myocytes to hydrogen peroxide yields a very good model of heart failure. Many conditions can induce oxidative stress within the cardiac myocyte, including hypertension and ischemia.

Although these data are from in vitro experiments, they strongly suggest that carvedilol has a strong antioxidant activity in addition to its beta blocking activity. The effectiveness of the drug in the clinical setting may be due at least in part to its antioxidant activity.