Effects of mefloquine on cardiac contractility and electrical activity in vivo, in isolated cardiac preparations, and in single ventricular myocytes
Effects of mefloquine on cardiac contractility and electrical activity in vivo, in isolated cardiac preparations, and in single ventricular myocytes
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DOI：
10.1038/sj.bjp.0703060
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发表时间：
2000-01-01
影响因子：
7.3
通讯作者：
Eisner, DA
中科院分区：
文献类型：
--
作者：
Coker, SJ;Batey, AJ;Eisner, DA
[1]为了检测抗疟药甲氟喹可能的心脏毒性，给麻醉的豚鼠静脉注射递增剂量（0.3-30 mg/kg）。甲氟喹对ECG间期无明显改变，但逐渐升高收缩压（3 mg kg（-1）），然后有降压作用（10 mg kg（-1））。10 mg/kg（-1）（2/6）或30 mg/kg（-1）（4/6）甲氟喹给药后，可能因心脏收缩衰竭或房室传导阻滞引起的严重低血压导致死亡。2在离体心脏标本中，甲氟喹（3-100 μ M）不改变有效不应期，但在较高浓度下，静息张力增加。100 μ M甲氟喹可降低左心房的张力（从5.8 +/- 1.7到2.2 +/- 0.4 mN），而在乳头肌中，尽管30 μ M甲氟喹降低了发达的张力（从2.6 +/- 0.5到1.1 +/- 0.1 mN）随后加入100 μ M引起显著的，但不是持续的，正性肌力作用（从1.2 +/- 0.1到3.8 +/- 0.8 mN）。3在单个心室肌细胞中，甲氟喹（10 μ M）缩短动作电位时程（例如APD（90）从285 +/- 29至141 +/- 12 ms），并降低收缩期Ca 2+瞬变的幅度。这些作用伴随着L型Ca 2+电流的降低。4这些结果表明，甲氟喹对心脏的主要不良作用是负性肌力作用。这一作用可以通过阻断L-型Ca 2+通道来解释。
1 To examine the possible cardiotoxicity of the antimalarial drug mefloquine, increasing doses (0.3-30 mg kg(-1)) were given i.v. to anaesthetized guinea-pigs. Mefloquine did not alter ECG intervals significantly but gradually increased systolic blood pressure (at 3 mg kg(-1)) then had a depressor effect (at 10 mg kg(-1)). Death due to profound hypotension, probably resulting from cardiac contractile failure or AV block, occurred after either 10 mg kg(-1) (2/6) or 30 mg kg(-1) (4/6) mefloquine.2 In isolated cardiac preparations mefloquine (3-100 mu M) did not alter the effective refractory period but at the higher concentrations resting tension increased. Developed tension was reduced by 100 mu M mefloquine in left atria (from 5.8 +/- 1.7 to 2.2 +/- 0.4 mN) whereas in papillary muscles although 30 mu M mefloquine reduced developed tension (from 2.6 +/- 0.5 to 1.1 +/- 0.1 mN) subsequent addition of 100 mu M caused a marked, but not sustained, positive inotropic effect (from 1.2 +/- 0.1 to 3.8 +/- 0.8 mN).3 In single ventricular myocytes, mefloquine (10 mu M) shortened action potential duration (e.g. APD(90) from 285 +/- 29 to 141 +/- 12 ms) and reduced the amplitude of the systolic Ca2+ transient. These effects were accompanied by a decrease in the L-type Ca2+ current.4 These results indicate that the main adverse effect of mefloquine on the heart is a negative inotropic action. This action can be explained by blockade of L-type Ca2+ channels.