Mechanisms of Combined Treatment With Celiprolol and Candesartan for Ventricular Remodeling in Experimental Heart Failure

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Abstract
Background Both β-adrenergic blockers and angiotensin-II receptor blockers were reported to improve the prognosis of patients with heart failure, but the efficacy of combination therapy with these agents has not been fully elucidated. Also the efficacy of celiprolol, a β1-selective adrenoceptor antagonist with partial β2-agonist properties, for heart failure treatment is still controversial. We examined the cardioprotective effects and mechanisms of the therapy with celiprolol or candesartan, an angiotensin-II receptor blockers and their combination in heart failure induced by isoproterenol (ISO). Methods and Results ISO 300 mg/kg was injected in rats to produce heart failure. Two months after the injection, the ISO-injected rats were divided into 4 groups (8 rats each) and treated for 4 weeks as follows: (a) vehicle; (b) celiprolol 10 mg/kg per day (BB); (c) candesartan 0.2 mg/kg per day (ARB); and (d) their combination BB + ARB. ISO significantly elevated left ventricular (LV) end-diastolic pressure, decreased peak-negative dP/dt and LV ejection fraction. BB and ARB similarly ameliorated cardiac dysfunction due to ISO, but BB + ARB were more potent than the individual therapies. Separately, ARB preserved the histological structure in LV myocardium. In contrast, BB ameliorated calcium handling, as shown by the increased ratio of SERCA2 to phospholamban protein, despite having little effect on the histology. Conclusion Both celiprolol and candesartan showed cardioprotective effects in this heart failure model. The potential use of the combination treatment in heart failure might result in a synergistic effect through the different cardioprotective mechanisms of celiprolol and candesartan. (Circ J 2005; 69: 596 - 602)