Metformin prevents progression of heart failure in dogs: role of AMP-activated protein kinase.

BACKGROUND: Some studies have shown that metformin activates AMP-activated protein kinase (AMPK) and has a potent cardioprotective effect against ischemia/reperfusion injury. Because AMPK also is activated in animal models of heart failure, we investigated whether metformin decreases cardiomyocyte apoptosis and attenuates the progression of heart failure in dogs. METHODS AND RESULTS: Treatment with metformin (10 micromol/L) protected cultured cardiomyocytes from cell death during exposure to H2O2 (50 micromol/L) via AMPK activation, as shown by the MTT assay, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining, and flow cytometry. Continuous rapid ventricular pacing (230 bpm for 4 weeks) caused typical heart failure in dogs. Both left ventricular fractional shortening and left ventricular end-diastolic pressure were significantly improved in dogs treated with oral metformin at 100 mg x kg(-1) x d(-1) (n=8) (18.6+/-1.8% and 11.8+/-1.1 mm Hg, respectively) compared with dogs receiving vehicle (n=8) (9.6+/-0.7% and 22+/-0.9 mm Hg, respectively). Metformin also promoted phosphorylation of both AMPK and endothelial nitric oxide synthase, increased plasma nitric oxide levels, and improved insulin resistance. As a result of these effects, metformin decreased apoptosis and improved cardiac function in failing canine hearts. Interestingly, another AMPK activator (AICAR) had effects equivalent to those of metformin, suggesting the primary role of AMPK activation in reducing apoptosis and preventing heart failure. CONCLUSIONS: Metformin attenuated oxidative stress-induced cardiomyocyte apoptosis and prevented the progression of heart failure in dogs, along with activation of AMPK. Therefore, metformin may be a potential new therapy for heart failure.

Celiprolol, a vasodilatory beta-blocker, inhibits pressure overload-induced cardiac hypertrophy and prevents the transition to heart failure via nitric oxide-dependent mechanisms in mice.

BACKGROUND: The blockade of beta-adrenergic receptors reduces both mortality and morbidity in patients with chronic heart failure, but the cellular mechanism remains unclear. Celiprolol, a selective beta(1)-blocker, was reported to stimulate the expression of endothelial NO synthase (eNOS) in the heart, and NO levels have been demonstrated to be related to myocardial hypertrophy and heart failure. Thus, we aimed to clarify whether celiprolol attenuates both myocardial hypertrophy and heart failure via the NO-signal pathway. METHODS AND RESULTS: In rat neonatal cardiac myocytes, celiprolol inhibited protein synthesis stimulated by either isoproterenol or phenylephrine, which was partially suppressed by N(G)-nitro-L-arginine methyl ester (L-NAME). Four weeks after transverse aortic constriction (TAC) in C57BL/6 male mice, the ratio of heart weight to body weight (mg/g) (8.70+/-0.42 in TAC, 6.61+/-0.44 with celiprolol 100 mg x kg(-1) x d(-1) PO, P<0.01) and the ratio of lung weight to body weight (mg/g) (10.27+/-1.08 in TAC, 7.11+/-0.70 with celiprolol 100 mg x kg(-1) x d(-1) PO, P<0.05) were lower and LV fractional shortening was higher in the celiprolol-treated groups than in the TAC group. All of these improvements were blunted by L-NAME. Celiprolol treatment significantly increased myocardial eNOS and activated phosphorylation of eNOS. Myocardial mRNA levels of natriuretic peptide precursor type B and protein inhibitor of NO synthase, which were increased in the TAC mice, were decreased in the celiprolol-treated mice. CONCLUSIONS: These findings indicated that celiprolol attenuates cardiac myocyte hypertrophy both in vitro and in vivo and halts the process leading from hypertrophy to heart failure. These effects are mediated by a selective beta1-adrenergic receptor blockade and NO-dependent pathway.