Combined therapy with dimethylthiourea, diltiazem and amiloride/dimethylamiloride in the ischemic/reperfused heart.
OBJECTIVE
The relative contribution of oxygen free radicals, disturbances in calcium homeostasis and Na+/H+ exchange in the development of injury in the ischemic/reperfused heart was investigated. The study was designed to assess whether these factors initiate independent mechanisms of injury or, alternatively, they share a common mechanism of toxicity.


METHODS
Isolated working rat hearts were subjected to different periods (30-55 min) of global ischemia and then were reperfused for 30 min. We compared the effects of oxygen radical scavengers (10 mM dimethylthiourea, DMTU and 0.6 mM desferrioxamine), inhibitors of Na+/H+ exchange (0.15 mM amiloride and 15 microM dimethylamiloride, DMA) and of 0.1 microM diltiazem, which was used to limit calcium overload, given alone or in combination, on the rate of myocardial injury development (recovery of hemodynamic function, LDH release, incidence of severe arrhythmias and structural integrity of cardiomyocytes were estimated at reperfusion following different periods of ischemia).


RESULTS
All interventions studied, when given alone, provided nearly equivalent cardioprotection. DMTU or desferrioxamine when applied in combination with diltiazem provided additive cardioprotection, relatively limited, however, as compared to the remarkable cardioprotection achieved by DMTU or desferrioxamine in combination with amiloride.


CONCLUSIONS
All mechanisms studied may contribute in an equal manner to the rate of injury development in the ischemic/reperfused heart. The oxygen free radicals-induced myocardial injury may be partially attributed to some disturbance in intracellular calcium homeostasis, possibly calcium overload, whereas the damaging effect of the Na+/H+ exchange activated upon reperfusion is probably largely related to some other mechanism.
Karwatowska-Prokopczuk
E
E
Department of Clinical Physiology, Medical Centre of Postgraduate Education, Warszawa, Poland.
Czarnowska
E
E
Prokopczuk
A
A
D000584:Amiloride / Q000031:analogs & derivatives / Q000627:therapeutic use*; D000818:Animals; D004110:Diltiazem / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D004699:Endocardium / Q000473:pathology; D066298:In Vitro Techniques; D008297:Male; D017202:Myocardial Ischemia / Q000188:drug therapy; D015428:Myocardial Reperfusion Injury / Q000473:pathology / Q000517:prevention & control*; D051381:Rats; D017208:Rats, Wistar; D013890:Thiourea / Q000031:analogs & derivatives* / Q000627:therapeutic use
C039465:5-dimethylamiloride; D000584:Amiloride; C038983:1,3-dimethylthiourea; D004110:Diltiazem; D013890:Thiourea