Department of Pharmacology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi, Japan.
Br J Pharmacol. 2009 Nov;158(5):1366-74. doi: 10.1111/j.1476-5381.2009.00407.x. Epub 2009 Sep 28.
The heart of the canine model of chronic atrioventricular block is known to have a ventricular electrical remodelling, which mimics the pathophysiology of long QT syndrome. Using this model, we explored a new pharmacological therapeutic strategy for the prevention of cardiac sudden death.
The L-type Ca(2+) channel blocker amlodipine (2.5 mg.day(-1)), L/N-type Ca(2+) channel blocker cilnidipine (5 mg.day(-1)), or the angiotensin II receptor blocker candesartan (12 mg.day(-1)) was administered orally to the dogs with chronic atrioventricular block for 4 weeks. Electropharmacological assessments with the monophasic action potential (MAP) recordings and blood sample analyses were performed before and 4 weeks after the start of drug administration.
Amlodipine and cilnidipine decreased the blood pressure, while candesartan hardly affected it. The QT interval, MAP duration and beat-to-beat variability of the ventricular repolarization period were shortened only in the cilnidipine group, but such effects were not observed in the amlodipine or candesartan group. Plasma concentrations of adrenaline, angiotensin II and aldosterone decreased in the cilnidipine group. In contrast, plasma concentrations of angiotensin II and aldosterone were elevated in the amlodipine group, whereas in the candesartan group an increase in plasma levels of angiotensin II and a decrease in noradrenaline and adrenaline concentrations were observed.
Long-term blockade of L/N-type Ca(2+) channels ameliorated the ventricular electrical remodelling in the hypertrophied heart which causes the prolongation of the QT interval. This could provide a novel therapeutic strategy for the treatment of cardiovascular diseases.
犬慢性房室传导阻滞模型的心脏已知存在心室电重构，模拟长 QT 综合征的病理生理学。使用该模型，我们探索了一种预防心脏性猝死的新的药物治疗策略。
将 L 型钙通道阻滞剂氨氯地平（2.5mg·天-1）、L/N 型钙通道阻滞剂西尼地平（5mg·天-1）或血管紧张素 II 受体阻滞剂坎地沙坦（12mg·天-1）口服给予慢性房室传导阻滞犬，连续给药 4 周。在药物治疗开始前和 4 周后进行单相动作电位（MAP）记录和血液样本分析的电药理学评估。
氨氯地平和西尼地平降低了血压，而坎地沙坦几乎没有影响。只有在西尼地平组中，QT 间期、MAP 持续时间和心室复极期的心率变异性缩短，但在氨氯地平和坎地沙坦组中未观察到这种作用。西尼地平组血浆肾上腺素、血管紧张素 II 和醛固酮浓度降低。相反，氨氯地平组的血管紧张素 II 和醛固酮浓度升高，而坎地沙坦组则观察到血管紧张素 II 血浆水平升高和去甲肾上腺素和肾上腺素浓度降低。
长期阻断 L/N 型钙通道改善了导致 QT 间期延长的肥厚心脏的心室电重构。这可能为心血管疾病的治疗提供一种新的治疗策略。
