Differential efficacy of L- and T-type calcium channel blockers in preventing tachycardia-induced atrial remodeling in dogs
Differential efficacy of L- and T-type calcium channel blockers in preventing tachycardia-induced atrial remodeling in dogs
复制标题
DOI：
10.1016/s0008-6363(00)00288-1
复制
发表时间：
2001-03-01
影响因子：
10.8
通讯作者：
Nattel, S
中科院分区：
文献类型：
--
作者：
Fareh, S;Bénardeau, A;Nattel, S
背景：心动过速诱导的重构可能在房颤（AF）的维持和转复后的复发中起重要作用，Ca2+超载可能是一个重要的介质。本研究旨在评估选择性t型（米贝弗拉迪）和l型（地尔硫卓）Ca2+通道阻滞剂在预防心动过速引起的心房重构中的相对疗效。方法：以盲法给狗每天服用米贝弗拉迪（100毫克）、地尔硫卓（240毫克）或安慰剂，从4天前开始，持续7天，心房起搏速度为每分钟400次。然后进行电生理研究以评估难治性、难治性异质性和房颤持续时间的变化。结果：在安慰剂组（567 +/- 203秒）和地尔氮卓组（963 +/- 280秒，P = NS）中，突发起搏引起的房颤的平均持续时间相似，但在米贝弗拉地尔组（3.6 +/- 0.9秒，P < 0.002）和非起搏对照组（66.6 +/- 2.7秒）中要短得多。与米贝拉迪相比，地尔硫卓没有改变心动过速引起的难治性、缩短或异质性。为了排除剂量不足对地尔硫卓无效的解释，我们研究了另一组用720毫克/天地尔硫卓治疗的狗，再次发现没有保护作用。对照犬急性静脉给予地尔硫卓不能改变心房难治性或房颤持续时间，不包括通过抵消药物的促纤作用来掩盖重构抑制。结论：选择性t型Ca2+通道阻滞剂米贝替拉对7天房性心动过速引起的心房重构有保护作用，而选择性l型阻滞剂地尔硫卓则没有作用。这些发现对于理解临床相关心房心动过速诱导的重构的机制和预防具有潜在的重要意义。(C) 2001 Elsevier Science B.V.版权所有
Background: Tachycardia-induced remodeling likely plays an important role in atrial fibrillation (AF) maintenance and recurrence after cardioversion, and Ca2+ overload may be an important mediator. This study was designed to evaluate the relative efficacies of selective T-type (mibefradil) and L-type (diltiazem) Ca2+-channel blockers in preventing tachycardia-induced atrial remodeling. Methods: Dogs were given daily doses of mibefradil (100 mg), diltiazem (240 mg) or placebo in a blinded fashion, beginning 4 days before and continuing through a 7-day period of atrial pacing at 400 bpm. An electrophysiological study was then performed to assess changes in refractoriness, refractoriness heterogeneity and AF duration. Results: Mean duration of burst-pacing induced AF was similar in placebo (567 +/- 203 s) and diltiazem-treated (963 +/- 280 s, P = NS) animals, but was much less in mibefradil-treated dogs (3.6 +/- 0.9 s, P < 0.002) and non-paced controls (66.6 +/- 2.7 s). In contrast to mibefradil, diltiazem did not alter tachycardia-induced refractoriness abbreviation or heterogeneity. To exclude inadequate dosing as an explanation for diltiazem's inefficacy, we studied an additional group of dogs treated with 720 mg/day of diltiazem, and again noted no protective effect. Acute intravenous administration of diltiazem to control dogs failed to alter atrial refractoriness or AF duration, excluding a masking of remodeling suppression by offsetting profibrillatory effects of the drug. Conclusions: Whereas the selective T-type Ca2+-channel blocker mibefradil protects against atrial remodeling caused by 7-day atrial tachycardia, the selective L-type blocker diltiazem is without effect. These findings are potentially important for understanding the mechanisms and prevention of clinically-relevant atrial-tachycardia-induced remodeling. (C) 2001 Elsevier Science B.V. All rights reserved.