Yamamoto Eiichiro, Lai Zhong-Fang, Yamashita Takuro, Tanaka Tomoko, Kataoka Keiichiro, Tokutomi Yoshiko, Ito Takaaki, Ogawa Hisao, Kim-Mitsuyama Shokei
Department of Pharmacology and Molecular Therapeutics, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan.
J Hypertens. 2006 Oct;24(10):2057-69. doi: 10.1097/01.hjh.0000244956.47114.c1.
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.
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.
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.
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.
使用阿折地平（一种相对较新的不增加心率的二氢吡啶类钙通道阻滞剂）研究心动过速诱导的心脏损伤的机制及意义。
比较阿折地平和氨氯地平，我们研究了在易卒中型自发性高血压大鼠（spSHRs）中二者对心脏的影响以及对窦房结/心房标本的直接作用。通过刺激右心房，我们研究了心动过速本身对心脏氧化应激的影响。使用阿朴吗啡（一种还原型烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶抑制剂），我们研究了氧化应激在心脏重塑中的作用。
在spSHRs中，阿折地平比氨氯地平更有效地抑制心脏肥大、纤维化、NADPH氧化酶和超氧化物，并且与比氨氯地平更低的心率相关。阿折地平比氨氯地平更显著地降低了spSHRs窦房结/心房标本的搏动率。心率增加10%或20%，独立于血压或交感神经活动，显著增强心脏NADPH氧化酶活性、超氧化物并激活丝裂原活化蛋白激酶。阿朴吗啡减轻心脏氧化应激导致spSHRs心脏肥大、炎症和纤维化受到抑制，这超出了其降压作用。
我们的研究提供了证据，即独立于交感神经活动的心率增加本身会增强心脏氧化应激并激活丝裂原活化蛋白激酶，这似乎是心脏重塑的原因。阿折地平不会引起心率增加，具有治疗心脏重塑的潜力。
