Inhibition of Na⁺/H⁺ Exchanger With EMD 87580 does not Confer Greater Cardioprotection Beyond Preconditioning on...

Postischemic accumulation of intracellular Na⁺ promotes calcium overload and contributes to cellular necrosis. Cardioprotection afforded by pharmacologic blockade of the sodium-hydrogen exchanger subtype 1 (NHE1) is thought to be more remarkable than that obtained by ischemic conditioning (IC). The window of protection provided by IC pretreatment is maintained even when performed up to 48 hours before ischemia. In addition, the perception exists that combined NHE1 inhibition plus IC produces greater than additive protection against ischemic injury. The current study compared the efficacy of NHE1 blockade by N-[2-methyl-4,5-bis(methylsulfonyl)-benzoyl]-guanidine (EMD 87580 5 mg/kg) combined with first- or second-window IC on ischemic tolerance in dogs subject to 90-minute acute ischemia and 180-minute reperfusion. Infarct size (tetrazolium staining), vascular responses, and myocardial perfusion (microspheres) were assessed. EMD 87580 given before ischemia or before reperfusion did not reduce infarct size (compared to vehicle-treated group). Significant protection against tissue necrosis was obtained by both first- and second-window IC, but additive cardioprotection (ie, greater than that afforded by IC) was not observed by treatment with EMD 87580. Vascular reactivity in the infarct-related artery was not preserved after ischemia-reperfusion in any of the experimental groups. Likewise, either the pharmacologic or the nonpharmacologic interventions did not modify myocardial perfusion. These data demonstrate that EMD 87580 did not protect against ischemia-reperfusion injury regardless of the time of drug administration. Combined EMD 87580 and IC did not antagonize protection that was achieved by either first- or second-window IC alone; no additive protection beyond preconditioning was obtained. Further study is necessary to assess the value of NHE1 blockers as protective agents against myocardial injury.