NMR measurements of Na+ and cellular energy in ischemic rat heart: role of Na(+)-H+ exchange

Abstract

Interleaved 23Na- and 31P-nuclear magnetic resonance (NMR) spectra were continuously collected on perfused rat hearts subjected to low-flow ischemia (30 min, 10% flow) or zero-flow ischemia (21 min) followed by reperfusion. During untreated low-flow and zero-flow ischemia, intracellular Na+ (Nai+) increased by 53 +/- 11 (+/- SE) and 78 +/- 8%, respectively, and remained elevated for zero-flow hearts. However, during both low- and zero-flow ischemia, Nai+ did not increase in hearts treated with the Na(+)-H+ exchange inhibitor, 5-(N-ethyl-N-isopropyl)amiloride (EIPA). The pH decreases during ischemia were unchanged. EIPA treatment reduced ATP depletion during ischemia. During reperfusion from zero-flow ischemia, EIPA-treated hearts displayed more rapid and extensive recoveries of phosphocreatine and ATP. Recovery of left ventricular developed pressure was improved for zero-flow hearts treated with EIPA during the ischemic period exclusively (104 +/- 13%) compared with untreated hearts (36 +/- 21%). These data indicate that Na(+)-H+ exchange is an important mechanism for Nai+ accumulation, but not for pH regulation, during myocardial ischemia. Additionally, Nai+ homeostasis plays an important role in the postischemic recovery of cellular energy and ventricular function.

Acute effects of 17β-estradiol on myocardial pH, Na+, and Ca2+ and ischemia-reperfusion injury

“…However, investigators at our laboratory (31) and others (42) have shown that NHE1 inhibitors either have no effect on or limit the fall in pH i during ischemia. Furthermore, inhibiting ischemia-induced Na ϩ uptake via other pathways also limits ischemia-induced acidification (9,24,34).…”

Protective Effect of HOE642, a Selective Blocker of Na+‐H+ Exchange, Against the Development of Rigor Contracture in Rat Ventricular Myocytes

“…Although moderate intracellular acidosis has been found to protect hypoxic myocytes by slowing down ATP depletion (Koop & Piper, 1992), and could modify actin-myosin interaction (Stienen & Elzinga, 1990), several studies have failed to detect any effect of NHE blockade on cytosolic acidification (Pike et al 1993;Hendrikx et al 1994;Russ et al 1996) or ATP depletion (Sack et al 1994;Sch afer et al 1995) during ischaemia. In the present study, however, a moderate although significant acidification of the intracellular milieu was consistently observed in isolated myocytes when the NHE blocker was present during energy deprivation, even in the absence of an acidotic extracellular pH.…”

“…Although the protective effect of NHE inhibition during ischaemia has been clearly demonstrated, the mechanisms responsible for this effect remain largely unknown. NHE inhibitors could theoretically enhance intracellular acidosis, limit Na¤ gain (Pike et al 1993), and limit Ca¥ overload by reducing Na¤-Ca¥ exchange (Murphy et al 1991), but none of these actions has been convincingly related to the anti-ischaemic effect of these substances. The development of rigor contracture is a key event in the genesis of cell injury during energy deprivation.…”

Preconditioning rabbit cardiomyocytes: role of pH, vacuolar proton ATPase, and apoptosis.

“…The protective effect is thought to be mediated by inhibiting Na ϩ entry, thus limiting Ca ϩϩ entry by Na ϩ /Ca ϩϩ exchange (23,25,26). A mechanism of preconditioning whereby activation of NHE-1 would reduce acid accumulation and protect myocytes seems unlikely because ( a ) enhanced Na ϩ and Ca ϩϩ accumulation would be detrimental and ( b ) inhibition of this channel has little effect on pH during ischemia (33)(34)(35)(36)(37)(38).…”