Dhein S, Krusemann K, Engelmann F, Gottwald M
Institute of Pharmacology, University of Cologne, Germany.
Naunyn Schmiedebergs Arch Pharmacol. 1998 Jun;357(6):662-70. doi: 10.1007/pl00005222.
Ischemia leads to intracellular acidification which can be counteracted by the Na+/H+-exchange mechanism. A blockade of this exchanger has been hypothesized to cause stronger intracellular acidification in the course of ischemia thereby protecting the heart from ischemic damage. The aim of our study was to find out (1) whether in the course of ischemia areas become electrically silent, (2) whether this is enhanced by the Na+/H+-exchange inhibitor cariporide (4-Isopropyl-3-methylsulfonylbenzoyl-guanidine; Hoe 642) and whether cariporide has protective effects. Therefore, we submitted isolated rabbit hearts, perfused according to the Langendorff technique to regional ischemia (LAD occlusion) for 30 min followed by 30 min reperfusion with (n=7) or without (n=7) pre-treatment with 1 microM cariporide. Under these conditions 256-channel epicardial potential mapping was carried out. Under non-ischemic conditions cariporide did not alter any of the parameters under observation. We found that ischemia led to marked alterations of the activation pattern, to action potential shortening and a marked increase in the dispersion of refractoriness. In the ischemic region there was a significant ST deviation from the isoelectrical line (control 32+/-10; 30 min ischemia: 290+/-35 arbitrary units [a.u.]). This was markedly reduced by cariporide (control 39+/-10; 30 min ischemia: 170+/-25 a.u.). The increase in dispersion by ischemia (by 50+/-5 ms) was significantly counteracted by cariporide (increased dispersion by 20+/-4 ms). In a similar way the alteration of the activation pattern was antagonized. Under the influence of cariporide we found a lower increase in the left ventricular enddiastolic pressure, and a significantly slower recovery of the action potential duration. After 30 min of ischemia 24+/-5 (control series) 24.5+/-5 mm2 (cariporide) became electrically silent. In a second series of experiments the incidence of arrhythmia was assessed: we found ventricular fibrillation in 6/7 untreated control hearts and in 4/7 cariporide treated hearts. In a third series of experiments we determined the intracellular [ATP] after 30 min of LAD occlusion using a histochemical method. We observed a decrease in [ATP] in the ischemic region as compared to the non-ischemic right ventricular wall, which was less pronounced in cariporide-treated hearts. Thus, we conclude that (1) cariporide protects the heart from ischemic damage and (2) at least under these conditions an enlargement of the electrically silent area did not occur.
缺血会导致细胞内酸化，而钠氢交换机制可抵消这种酸化。据推测，阻断这种交换体可在缺血过程中导致更强的细胞内酸化，从而保护心脏免受缺血损伤。我们研究的目的是弄清楚：（1）在缺血过程中，是否存在电静止区域；（2）钠氢交换抑制剂卡里波罗（4-异丙基-3-甲基磺酰基苯甲酰胍；Hoe 642）是否会增强这种情况，以及卡里波罗是否具有保护作用。因此，我们将按照Langendorff技术灌注的离体兔心脏进行局部缺血（结扎左前降支）30分钟，然后在有（n = 7）或无（n = 7）1 microM卡里波罗预处理的情况下再灌注30分钟。在这些条件下进行256通道心外膜电位标测。在非缺血条件下，卡里波罗未改变任何观察参数。我们发现，缺血导致激活模式明显改变、动作电位缩短以及不应期离散度显著增加。在缺血区域，ST段与等电线有明显偏差（对照组32±10；缺血30分钟：290±35任意单位[a.u.]）。卡里波罗可使其显著降低（对照组39±10；缺血30分钟：170±25 a.u.）。缺血导致的离散度增加（50±5毫秒）被卡里波罗显著抵消（离散度增加20±4毫秒）。同样，激活模式的改变也被拮抗。在卡里波罗的影响下，我们发现左心室舒张末期压力升高幅度较小，动作电位持续时间的恢复明显较慢。缺血30分钟后，24±5（对照组）、24.5±5平方毫米（卡里波罗组）区域变为电静止。在第二组实验中评估心律失常的发生率：我们发现在7个未治疗的对照心脏中有6个发生室颤，在7个用卡里波罗治疗的心脏中有4个发生室颤。在第三组实验中，我们使用组织化学方法测定结扎左前降支30分钟后的细胞内[ATP]。我们观察到，与非缺血的右心室壁相比，缺血区域的[ATP]降低，但在卡里波罗治疗的心脏中这种降低不太明显。因此，我们得出结论：（1）卡里波罗可保护心脏免受缺血损伤；（2）至少在这些条件下，电静止区域没有扩大。
