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

1 The benzoylguanidine derivative Hoe 694 ((3-methylsulphonyl-4-piperi dino-benzoyl) guanidine methanesulphonate) was characterized as an inh ibitor of Na+/H+ exchange in rabbit erythrocytes, rat platelets and bo vine 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 69 4, rat isolated working hearts were subjected to ischaemia and reperfu sion. In these experiments all untreated hearts suffered ventricular f ibrillation on reperfusion. Addition of 10(-7) M Hoe 694 to the perfus ate almost abolished reperfusion arrhythmias in the rat isolated worki ng hearts. 3 Hoe 694 reduced the release of lactate dehydrogenase (LDH ) and creatine kinase (CK), which are indicators of cellular damage du ring ischaemia, into the venous effluent of the hearts by 60% and 54%, respectively. 4 The tissue content of glycogen at the end of the expe riments was increased by 60% and the high energy phosphates ATP and cr eatine phosphate were increased by 240% and 270% respectively in the t reated hearts as compared to control hearts.. 5 Antiischaemic effects of the Na+/H+ exchange inhibitor, Hoe 694, were investigated in a seco nd experiment in anaesthetized rats undergoing coronary artery ligatio n. 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 unch anged. 6 We conclude that the new Na+/H+ exchange inhibitor, Hoe 694, shows cardioprotective and antiarrhythmic effects in ischaemia and rep erfusion 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.