Enhancement of cardiac oxidative stress by tachycardia and its critical role in cardiac hypertrophy and fibrosis

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Abstract
Objective To examine the mechanism and significance of tachycardia-induced cardiac damage, using azelnidipine, a relatively new dihydropyridine calcium channel blocker which does not increase heart rate. Methods Comparing azelnidipine and amlodipine, we examined the cardiac effects and the direct effects on a sinus node/atrial preparation in stroke-prone spontaneously hypertensive rats (spSHRs). By pacing the right atrium, we examined the effect of tachycardia per se on cardiac oxidative stress. Using apocynin, a reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor, we investigated the role of oxidative stress in cardiac remodelling. Results Azelnidipine suppressed cardiac hypertrophy, fibrosis, NADPH oxidase and superoxide in spSHRs more potently than amlodipine, and was associated with lower heart rates than amlodipine. Azelnidipine caused a greater reduction than amlodipine in the beat rate of the sinus node/atrial preparation of spSHRs. A 10 or 20% increase in heart rate, independent of blood pressure or sympathetic nerve activity, significantly enhanced cardiac NADPH oxidase activity, superoxide and activated mitogen-activated protein kinases. Reduction of cardiac oxidative stress by apocynin led to the suppression of cardiac hypertrophy, inflammation and fibrosis in spSHRs, beyond its hypotensive effect. Conclusions Our work provided evidence that the increase in heart rate per se, independent of sympathetic nerve activity, enhances cardiac oxidative stress and activates mitogen-activated protein kinases, which seem to be responsible for cardiac remodelling. Azelnidipine, without causing an increase in heart rate, has the potential to be useful for the treatment of cardiac remodelling.