Scholz W, Albus U, Counillon L, Gögelein H, Lang H J, Linz W, Weichert A, Schölkens B A
Hoechst AG, Cardiovascular Research H 821, Frankfurt/Main, Germany.
Cardiovasc Res. 1995 Feb;29(2):260-8.
The aim was to characterise the new compound HOE642 as a selective and cardioprotective Na+/H+ exchange inhibitor in various models.
The effect of HOE642 was tested in the osmotically activated Na+/H+ exchange of rabbit erythrocytes and in propionate induced swelling of human thrombocytes. Recovery of pH after an NH4Cl prepulse and effects on other ion transport systems by patch clamp technique were investigated in rat cardiomyocytes. NHE subtype specifity of the compound was determined by 22Na+ uptake inhibition in a fibroblast cell line separately expressing subtype isoforms 1-3. Protective effects of HOE642 in cardiac ischaemia and reperfusion by ligation of coronary artery were investigated in isolated working rat hearts and in anaesthetised rats.
HOE642 concentration dependently inhibited the amiloride sensitive sodium influx in rabbit erythrocytes, reduced the swelling of human platelets induced by intracellular acidification, and delayed pH recovery in rat cardiomyocytes. In the isolated working rat heart subjected to ischaemia and reperfusion HOE642 dose dependently reduced the incidence and the duration of reperfusion arrhythmias. It also reduced the the release of lactate dehydrogenase and creatine kinase, and preserved the tissue content of glycogen, ATP, and creatine phosphate. In anaesthetised rats undergoing coronary artery ligation intravenous and oral pretreatment with HOE642 caused a dose dependent reduction or a complete prevention of ventricular premature beats, ventricular tachycardia, and ventricular fibrillation. The compound was well tolerated and neutral to circulatory variables. Other cardiovascular agents tested in this model were not, or were only partly, effective at doses showing marked cardiodepressive effects.
HOE642 is a very selective NHE subtype 1 inhibitor showing cardioprotective and antiarrhythmic effects in ischaemic and reperfused hearts. Further development of well tolerated compounds like HOE642 could lead to a new therapeutic approach in clinical indications related to cardiac ischaemia and reperfusion.
旨在将新型化合物HOE642表征为各种模型中具有选择性和心脏保护作用的钠氢交换抑制剂。
在兔红细胞的渗透激活钠氢交换以及丙酸盐诱导的人血小板肿胀中测试HOE642的作用。在大鼠心肌细胞中研究氯化铵预脉冲后的pH恢复情况以及通过膜片钳技术对其他离子转运系统的影响。通过在分别表达亚型同工型1-3的成纤维细胞系中抑制22Na+摄取来确定该化合物的NHE亚型特异性。在离体工作大鼠心脏和麻醉大鼠中，通过结扎冠状动脉研究HOE642在心脏缺血和再灌注中的保护作用。
HOE642浓度依赖性地抑制兔红细胞中amiloride敏感的钠内流，减少细胞内酸化诱导的人血小板肿胀，并延迟大鼠心肌细胞中的pH恢复。在经受缺血和再灌注的离体工作大鼠心脏中，HOE642剂量依赖性地降低再灌注心律失常的发生率和持续时间。它还减少了乳酸脱氢酶和肌酸激酶的释放，并保留了糖原、ATP和磷酸肌酸的组织含量。在接受冠状动脉结扎的麻醉大鼠中，静脉内和口服HOE642预处理导致剂量依赖性减少或完全预防室性早搏、室性心动过速和心室颤动。该化合物耐受性良好，对循环变量无影响。在该模型中测试的其他心血管药物在显示明显心脏抑制作用的剂量下无效或仅部分有效。
HOE642是一种非常选择性的NHE亚型1抑制剂，在缺血和再灌注心脏中显示出心脏保护和抗心律失常作用。进一步开发像HOE642这样耐受性良好的化合物可能会为与心脏缺血和再灌注相关的临床适应症带来新的治疗方法。
