Equal reduction in infarct size by ethylisopropyl-amiloride pretreatment and ischemic preconditioning in the in situ rabbit heart

Role of the Na+–H+exchanger (NHE1) in heart muscle function during transient acidosis. A study in papillary muscles from rat and guinea pig hearts

“…The hypothesis was that a selective blocker of a cardiac-specific NHE isoform (NHE1) will prevent myocardial damage associated with ischemia and reperfusion. Experimental evidence in several species and models has demonstrated a marked protection against ischemic injury by Na + -H + -inhibition (Bugge et al 1996;Bugge and Ytrehus 1995;Munch-Ellingsen et al 1998). Sardet et al (1991) have shown that phorbol esters (protein kinase C (PKC) activators) stimulated phosphorylation of NHE1 with a time course similar to that of the rise in intracellular pH.…”

In vitro and in vivo pharmacology of a structurally novel Na+‐H+ exchange inhibitor, T‐162559

“…The amino acid sequence of NHE-1 has been demonstrated to be highly homologous in humans, rats and rabbits (495%, NoeÈ l & Pouysse gur, 1995), and for this reason T-162559 is thought to be capable of inhibiting rabbit NHE-1 and conferring on the rabbit heart tolerance against ischaemia and reperfusion. Cariporide and other NHE-1 inhibitors exert a similar cardioprotective eect in rabbits (Hendrikx et al, 1994;Miura et al, 1997;Munch-Ellingsen et al, 1998). In the rabbit model, T-162559 did not show a dose dependency between the two doses.…”

Protection of the Myocardium During Ischemia and Reperfusion

“…In these studies, ischemic preconditioning was shown to afford marked protection against ischemia-andreperfusion-induced injury, which was manifest as an attenuation of contractile dysfunction and creatine kinase leakage 12 or a limitation of infarct size. 5,[15][16][17] The earlier studies 12,15-17 all showed that Na ϩ /H ϩ exchange inhibition is equally as effective as ischemic preconditioning in protecting the myocardium during ischemia and reperfusion. The current findings of Gumina and colleagues 5 similarly demonstrate comparable efficacies with both interventions in dog hearts subjected to 60 minutes of index ischemia, but they suggest that Na ϩ /H ϩ exchange inhibition may afford superior protection when this is extended to 90 minutes.…”

“…A number of studies have addressed this issue, again by using pharmacological inhibitors to suppress Na ϩ /H ϩ exchanger activity at various times during the experimental protocol: during the cycles of triggering ischemia, 12,13 during index ischemia, 9,12,14 -16 or during both periods. 17 Although contradictory findings have also been reported, 13,14 the majority of these studies 9,12,[15][16][17] have shown that the cardioprotective benefit of ischemic preconditioning is not attenuated by Na ϩ /H ϩ exchange inhibition, indicating that an active exchanger is not necessary to achieve such benefit. To the contrary, in some studies, 12,17 the combination of Na ϩ /H ϩ exchange inhibition with ischemic preconditioning has been shown to provide an additive benefit, with the limitation of infarct size 17 or the improvement in the recovery of contractile function 12 appearing to be significantly greater with the combined intervention relative to either intervention alone.…”

“…15,16 At first consideration, this might appear to indicate species-specific responses, with Na ϩ /H ϩ exchange inhibition and ischemic preconditioning possessing distinct mechanisms of action in the rat but sharing a common mechanism of action in the rabbit. This scenario is unlikely, however, because in the rabbit heart, interventions that abolish the cardioprotective benefit of ischemic preconditioning (such as protein kinase C inhibition and ATP-sensitive K ϩ channel blockade) do not seem to affect the cardioprotective efficacy of Na ϩ /H ϩ exchange inhibition.…”