Abstract 211: Azelnidipine, a Long-Acting Dihydropyridine Calcium Channel Blocker, Suppresses the Development of Cardiac Hypertrophy and Fibrosis in Adrenomedullin Knock Out Mice.
Background: Azelnidipine is a newly developed long-acting dihydropyridine calcium channel blocker that was recently reported to exert strong inhibitory effects on reactive oxygen species (ROS) generation. There is growing interest in whether azelnidipine would be an effective agent with which to treat cardiac remodeling, acting via both anti-oxidative and blood pressure-lowering effects. Our aim in this study was to use knockout mice of adrenomedullin (AM), a vasodilating peptide and strong endogenous antioxidant, to examine the effects of azelnidipine on the cardiac remodeling induced by chronic infusion of angitensin (Ang) II.
Methods and Results: AM+/− mice, which showed about a 50% reduction in AM levels, and their wild-type littermates were continuously administered Ang II (3.2 mg/kg/day) for 2 weeks using osmotic pumps. In each group, vehicle, azelnidipine (3 mg/kg/day) or hydralazine (5 mg/kg/day) was orally administered for 3 weeks, starting 1 week before the Ang II infusion. The cardiovascular stress caused by Ang II led to increases in left ventricular wall thickness, heart weight/body weight ratios, cardiomyocyte size and perivascular fibrosis, which were all significantly more pronounced in AM+/− than wild-type mice. Correspondingly, the expression of angiotensin converting enzyme (ACE), angiotensinogen (ATG), and transforming growth factor (TGF)-β was more upregulated in AM+/− than wild-type mice, while expression of sarcoplasmic/endoplasmic reticulum Ca2+ ATPase (SERCA)-2 was downregulated. Azelnidipine-treatment attenuated all of the effects of Ang II in both AM+/− and wild-type mice and offset the difference between the two strains. By contrast, hydralazine had no effect on cardiac remodeling or function, though it reduced blood pressure to the same extent as azelnidipine. Finally, expression of p67-phox, a cytosolic component of NAD(P)H oxidase and a marker of oxidative stress, was attenuated by treatment with azelnidipine.
Conclusions: Our findings indicate that azelnidipine exerts a protective effect against Ang II-induced cardiac stress, which may reflect, in part, its antioxidant properties.