Very low dose of the Na+/Ca2+ exchange inhibitor, KB-R7943, protects ischemic reperfused aged Fischer 344 rat hearts: considerable strain difference in the sensitivity to KB-R7943

Abstract

Decreased ischemic tolerance in the aged myocardium is associated with accelerated intracellular Ca(2+) overload. However, few drugs have been shown to attenuate reperfusion injury in aged hearts. Because the Na(+)/Ca(2+) exchanger (NCX1) has been reported to play an important role in Ca(2+) overload during reperfusion, we investigated whether KB-R7943 (KB-R), a novel inhibitor of the reverse mode of Na(+)/Ca(2+) exchange, can protect aged rat hearts against reperfusion injury. In the pilot study, isolated hearts from young Sprague-Dawley (SD) rats (12 weeks old), and young (12 weeks old) and aged (78 weeks old) Fischer 344 (F) rats were subjected to 25 min of global ischemia followed by 10 min of reperfusion with various concentrations of KB-R (0, 1 nM, 0.1 microM, 10 microM) and additional 20 min of reperfusion without agent. In subsequent studies with the same protocol in aged F rats, we added a protective dose of KB-R (1 nM) during the initial 10 min of reperfusion. In addition, we compared the amount of NCX1 and the sensitivity of the reverse mode of Na(+)/Ca(2+) exchange to KB-R under extracellular Na(+)-free condition in F rats with young SD rats. In the pilot study, protective effects were elicited with 1 nM of KB-R in both young and aged F rats, while 10 microM KB-R was needed for SD rats. In subsequent studies using aged F rats, there was better recovery of LV systolic function and high-energy phosphates with reduced creatine kinase release and the duration of reperfusion arrhythmias. 45Ca(2+) uptake via the reverse mode of Na(+)/Ca(2+) exchange was also inhibited with 1 nM of KB-R in young F rats, but not in young SD rats. Although the amount of NCX1 was not different among young SD, young F, and aged F rat hearts. These results demonstrated that KB-R could protect aged F rat hearts as well as young hearts of both strains against ischemia-reperfusion injury. Moreover, the sensitivity to KB-R is very different between these strains, suggesting serious caution when the agent is applied to human beings.