Peripheral benzodiazepine receptor ligand Ro5-4864 inhibits isoprenaline-induced cardiac hypertrophy in rats.

Oxidative stress plays a significant role in the pathogenesis of cardiac hypertrophy. Peripheral benzodiazepine receptors are ubiquitously expressed in various tissues, including the heart. Peripheral benzodiazepine receptors have been reported to be involved in the protection of cells against oxygen radical damage. The present study was designed to determine whether Ro5-4864 (a peripheral benzodiazepine receptor ligand) can inhibit isoprenaline-induced cardiac hypertrophy. Male Wistar rats (body weight 150-200g) were administered, isoprenaline (5mg/kg, body weight, subcutaneously) alone or along with Ro5-4864 (0.1 and 0.5mg/kg, body weight, intraperitoneally) once daily for 14days. Control rats received normal saline subcutaneously (1.0ml/kg). Isoprenaline-induced changes in heart weight to body weight ratio, left ventricular wall thickness (M-mode echocardiography and gross morphometry) and myocyte size were significantly prevented by both the doses of Ro5-4864. Ro5-4864 also attenuated isoprenaline-induced increase in interstitial fibrosis, lipid peroxidation and changes in endogenous antioxidants (glutathione, superoxide dismutase and catalase). Isoprenaline-induced cardiac hypertrophy was associated with increased expression of beta myosin heavy chain, which was also prevented by Ro5-4864. This is the first study to demonstrate a salutary effect of Ro5-4864 in experimental cardiac hypertrophy.

Catecholamine-induced myocardial fibrosis and oxidative stress is attenuated by Terminalia arjuna (Roxb.).

OBJECTIVES: Myocardial fibrosis and oxidative stress accompany a number of cardiac disorders such as hypertrophic cardiomyopathy, hypertensive heart disease and cardiac failure. Stem bark of Terminalia arjuna has been advocated for cardiac ailments. The present study evaluated the effects of T. arjuna bark extract on myocardial fibrosis and oxidative stress induced by chronic beta-adrenoceptor stimulation. METHODS: Aqueous extract of T. arjuna bark was evaluated at 63, 125 and 250 mg/kg given orally for antifibrotic and antioxidant effects in rats given the selective beta-adrenoceptor agonist isoprenaline (5 mg/kg s.c.) for 28 days. Captopril (50 mg/kg per day, given orally), an inhibitor of angiotensin-converting enzyme used as a standard cardioprotective drug, was used as a positive control. KEY FINDINGS: Isoprenaline caused fibrosis, increased oxidative stress and cardiac hypertrophy (increased heart weight : body weight ratio and cardiomyocyte diameter). The T. arjuna bark extract and captopril significantly prevented the isoprenaline-induced increase in oxidative stress and decline in endogenous antioxidant level. Both also prevented fibrosis but not the increase in heart weight : body weight ratio. CONCLUSIONS: T. arjuna protects against myocardial changes induced by chronic beta-adrenoceptor stimulation.

Chronic beta-adrenergic activation-induced left ventricular systolic dysfunction is associated with systemic release of TNF-alpha and IL-1-beta in rats.

The relationship between systemic cytokine release and chronic beta-adrenergic activation-induced left ventricular dysfunction (LVSD) has not been widely reported in the literature. In the present study,we examined changes in the serum levels of inflammatory cytokines (IL-1-beta, IL-6 and TNF-alpha) following chronic beta-adrenergic activation-induced LVSD. Male Wistar rats were administered isoproterenol (ISO, 5 mg/kg, sc, once daily) for 4 weeks (ISO 4) or 12 weeks (ISO 12). Echocardiography was done and serum levels of IL-1-beta, IL-6 and TNF-alpha were estimated at the end of each protocol. In the ISO 4 group, there was a significant increase in relative wall thickness (p < 0.01) and heart weight: body weight ratio (p < 0.001) without any significant changes in fractional shortening (FS) or serum cytokine levels. However, in the ISO 12 group, there was a 32% decrease in FS along with increased serum levels of IL-1-beta and TNF-alpha. The present findings indicate that LVSD induced by chronic beta-adrenergic activation in rats is accompanied by increased serum cytokine levels.