HOE-694, A NEW NA+/H+ EXCHANGE INHIBITOR AND ITS EFFECTS IN CARDIAC ISCHEMIA

被引:194
作者
SCHOLZ, W
ALBUS, U
LANG, HJ
LINZ, W
MARTORANA, PA
ENGLERT, HC
SCHOLKENS, BA
机构
[1] Hoechst AG, Frankfurt, 6230
关键词
HOE-694; NA+/H+; EXCHANGE; ISCHEMIA; ARRHYTHMIA; CARDIAC PROTECTION;
D O I
10.1111/j.1476-5381.1993.tb13607.x
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
1 The benzoylguanidine derivative Hoe 694 ((3-methylsulphonyl-4-piperidino-benzoyl) guanidine methanesulphonate) was characterized as an inhibitor of Na+/H+ exchange in rabbit erythrocytes, rat platelets and bovine endothelial cells. The potency of the compound was slightly lower or comparable to ethylisopropyl amiloride (EIPA). 2 To investigate a possible cardioprotective role of the Na+/H+ exchange inhibitor Hoe 694, rat isolated working hearts were subjected to ischaemia and reperfusion. In these experiments all untreated hearts suffered ventricular fibrillation on reperfusion. Addition of 10(-7) M Hoe 694 to the perfusate almost abolished reperfusion arrhythmias in the rat isolated working hearts. 3 Hoe 694 reduced the release of lactate dehydrogenase (LDH) and creatine kinase (CK), which are indicators of cellular damage during ischaemia, into the venous effluent of the hearts by 60% and 54%, respectively. 4 The tissue content of glycogen at the end of the experiments was increased by 60% and the high energy phosphates ATP and creatine phosphate were increased by 240% and 270% respectively in the treated hearts as compared to control hearts.. 5 Antiischaemic effects of the Na+/H+ exchange inhibitor, Hoe 694, were investigated in a second experiment in anaesthetized rats undergoing coronary artery ligation. In these animals, pretreatment with Hoe 694 caused a dose-dependent reduction of ventricular premature beats and ventricular tachycardia as well as a complete suppression of ventricular fibrillation down to doses of 0.1 mg kg-1, i.v. Blood pressure and heart rate remained unchanged. 6 We conclude that the new Na+/H+ exchange inhibitor, Hoe 694, shows cardioprotective and antiarrhythmic effects in ischaemia and reperfusion in rat isolated hearts and in anaesthetized rats. In view of the role which Na+/H+ exchange seems to play in the pathophysiology of cardiac ischaemia these effects could probably be attributed to Na+/H+ exchange inhibition.
引用
收藏
页码:562 / 568
页数:7
相关论文
共 33 条
[1]   INVESTIGATION OF IONIC MECHANISM OF INTRACELLULAR PH REGULATION IN MOUSE SOLEUS MUSCLE-FIBERS [J].
AICKIN, CC ;
THOMAS, RC .
JOURNAL OF PHYSIOLOGY-LONDON, 1977, 273 (01) :295-316
[2]   KINETIC-PROPERTIES OF THE PLASMA-MEMBRANE NA+-H+ EXCHANGER [J].
ARONSON, PS .
ANNUAL REVIEW OF PHYSIOLOGY, 1985, 47 :545-560
[3]   THE TIME OF ONSET AND SEVERITY OF ACIDOSIS IN MYOCARDIAL ISCHEMIA [J].
COBBE, SM ;
POOLEWILSON, PA .
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY, 1980, 12 (08) :745-760
[4]  
FANTL P, 1968, J PHYSIOL-LONDON, V198, P1
[5]   THE REGULATION OF THE INTRACELLULAR PH IN CELLS FROM VERTEBRATES [J].
FRELIN, C ;
VIGNE, P ;
LADOUX, A ;
LAZDUNSKI, M .
EUROPEAN JOURNAL OF BIOCHEMISTRY, 1988, 174 (01) :3-14
[6]   THE ROLE OF THE NA+/H+ EXCHANGE SYSTEM IN THE REGULATION OF THE INTERNAL PH IN CULTURED CARDIAC-CELLS [J].
FRELIN, C ;
VIGNE, P ;
LAZDUNSKI, M .
EUROPEAN JOURNAL OF BIOCHEMISTRY, 1985, 149 (01) :1-4
[7]  
FRELIN C, 1984, J BIOL CHEM, V259, P8880
[8]  
HEINZ F, 1985, METHOD ENZYMAT AN, V8, P507
[9]   THE SODIUM HYDROGEN-EXCHANGE SYSTEM IN CARDIAC-CELLS - ITS BIOCHEMICAL AND PHARMACOLOGICAL PROPERTIES AND ITS ROLE IN REGULATING INTERNAL CONCENTRATIONS OF SODIUM AND INTERNAL PH [J].
LAZDUNSKI, M ;
FRELIN, C ;
VIGNE, P .
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY, 1985, 17 (11) :1029-1042
[10]   SODIUM-CALCIUM EXCHANGE IN EXCITABLE CELLS - FUZZY SPACE [J].
LEDERER, WJ ;
NIGGLI, E ;
HADLEY, RW .
SCIENCE, 1990, 248 (4953) :283-283