Sandmann S, Spitznagel H, Chung O, Xia Q G, Illner S, Jänichen G, Rossius B, Daemen M J, Unger T
Institute of Pharmacology, Christian-Albrechts-University of Kiel, Germany.
Cardiovasc Res. 1998 Aug;39(2):339-50. doi: 10.1016/s0008-6363(98)00087-x.
Calcium channel antagonists (CCA) have been proposed for the prevention of cardiac events after myocardial infarction (MI). Mibefradil is a CCA featuring a selective blockade of T-type Ca2(+)-channels. The aim of the study was to characterize the effects of mibefradil on haemodynamic and morphological parameters in a model of postMI chronic heart failure and to establish the "therapeutic window" for the start of therapy.
MI was induced by permanent ligation of the left coronary artery in male normotensive Wistar rats. Animals were assigned to placebo- or mibefradil-treated (10 mg/kg/day p.o.) groups as follows: (1) sham operation; (2) MI placebo treatment; (3) 7 days preMI start of treatment; (4) 3 h postMI start of treatment; (5) 24 h postMI start of treatment; (6) 3 days postMI start of treatment; (7) 7 days postMI start of treatment. Treatment was continued for 6 weeks postMI. At this time point, mean arterial blood pressure (MAP), heart rate, left ventricular enddiastolic pressure (LVEDP) and contraction force (dP/dtmax) were measured in conscious rats at baseline and after methoxamine (MEX; 0.5-1.0 mg/h i.v.) stimulation to increase afterload. The hearts were subjected to histological determination of infarct size (IS), infarct length (IL), noninfarcted length (NL), left ventricular circumference (LVC), inner LV-diameter (LVD) and septal thickness (ST).
Six weeks after MI, MAP was lowered, LVEDP increased and dP/dtmax reduced. Mibefradil treatment increased basal MAP in groups 3-5 compared to the placebo-treated MI group. Under mibefradil, LVEDP was reduced at baseline in groups 3-6 and, after MEX, in all groups. dP/dtmax was increased in groups 3-4 at baseline and after MEX. In the placebo-treated MI group, the infarcted area was 39% of the LV and heart weight, LVD and LVC were increased. Heart weights of mibefradil-treated rats (groups 3-6) did not differ from those of the placebo-treated group. Early onset of treatment with mibefradil reduced IS and IL and increased NL in groups 3-4. LVD and LVC were decreased in group 3 only. ST was increased in groups 3-5.
Chronic treatment with mibefradil exerts beneficial actions on cardiac structure and performance in postMI cardiac failure in rats, especially when the onset of treatment is either prior to or within hours after the acute ischemic event.
钙通道拮抗剂（CCA）已被提议用于预防心肌梗死（MI）后的心脏事件。米贝拉地尔是一种选择性阻断T型Ca2+通道的CCA。本研究的目的是在MI后慢性心力衰竭模型中表征米贝拉地尔对血流动力学和形态学参数的影响，并确定治疗开始的“治疗窗”。
通过永久性结扎雄性正常血压Wistar大鼠的左冠状动脉诱导MI。将动物分为安慰剂组或米贝拉地尔治疗组（10mg/kg/天，口服），如下：（1）假手术；（2）MI安慰剂治疗；（3）MI前7天开始治疗；（4）MI后3小时开始治疗；（5）MI后24小时开始治疗；（6）MI后3天开始治疗；（7）MI后7天开始治疗。MI后继续治疗6周。在这个时间点，在清醒大鼠的基线以及甲氧明（MEX；0.5 - 1.0mg/h，静脉注射）刺激以增加后负荷后，测量平均动脉血压（MAP）、心率、左心室舒张末期压力（LVEDP）和收缩力（dP/dtmax）。对心脏进行组织学测定梗死面积（IS）、梗死长度（IL）、非梗死长度（NL）、左心室周长（LVC）、左心室内径（LVD）和室间隔厚度（ST）。
MI后6周，MAP降低，LVEDP升高，dP/dtmax降低。与安慰剂治疗的MI组相比，米贝拉地尔治疗使3 - 5组的基础MAP升高。在米贝拉地尔治疗下，3 - 6组在基线时LVEDP降低，在MEX后，所有组均降低。3 - 4组在基线和MEX后dP/dtmax升高。在安慰剂治疗的MI组中，梗死面积为左心室和心脏重量的39%，LVD和LVC增加。米贝拉地尔治疗的大鼠（3 - 6组）的心脏重量与安慰剂治疗组无差异。米贝拉地尔早期治疗可降低3 - 4组的IS和IL，并增加NL。仅3组的LVD和LVC降低。3 - 5组的ST增加。
米贝拉地尔慢性治疗对大鼠MI后心力衰竭的心脏结构和功能具有有益作用，特别是当治疗在急性缺血事件之前或数小时内开始时。
