PROTECTIVE EFFECTS OF HOE642, A SELECTIVE SODIUM-HYDROGEN EXCHANGE SUBTYPE-1 INHIBITOR, ON CARDIAC ISCHEMIA AND REPERFUSION

Objective: The aim was to characterise the new compound HOE642 as a se lective and cardioprotective Na+/H+ exchange inhibitor in various mode ls. Methods: The effect of HOE642 was tested in the osmotically activa ted Na+/H+ exchange of rabbit erythrocytes and in propionate induced s welling of human thrombocytes. Recovery of pH after an NH4Cl prepulse and effects on other ion transport systems by patch clamp technique we re investigated in rat cardiomyocytes. NHE subtype specifity of the co mpound was determined by Na-22(+) uptake inhibition in a fibroblast ce ll line separately expressing subtype isoforms 1-3, Protective effects of HOE642 in cardiac ischaemia and reperfusion by ligation of coronar y artery were investigated in isolated working rat hearts and in anaes thetised rats. Results: HOE642 concentration dependently inhibited the amiloride sensitive sodium influx in rabbit erythrocytes, reduced the swelling of human platelets induced by intracellular acidification, a nd delayed pH recovery in rat cardiomyocytes. In the isolated working rat heart subjected to ischaemia and reperfusion HOE642 dose dependent ly reduced the the incidence and the duration of reperfusion arrhythmi as. It also reduced the the release of lactate dehydrogenase and creat ine kinase, and preserved the tissue content of glycogen, ATP, and cre atine phosphate. In anaesthetised rats undergoing coronary artery liga tion intravenous and oral pretreatment with HOE642 caused a dose depen dent 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 cardiov ascular agents tested in this model were not, or were only partly, eff ective at doses showing marked cardiodepressive effects. Conclusions: HOE642 is a very selective NHE subtype 1 inhibitor showing cardioprote ctive and antiarrhythmic effects in ischaemic and reperfused hearts. F urther development of well tolerated compounds like HOE642 could lead to a new therapeutic approach in clinical indications related to cardi ac ischaemia and reperfusion.