(Circulation. 1997;96:3617-3625.)
© 1997 American Heart Association, Inc.
Articles |
Na+/H+ Exchanger Activity Does Not Contribute to Protection by Ischemic Preconditioning in the Isolated Rat Heart
From Cardiovascular Research, The Rayne Institute, St Thomas' Hospital, and the Cardiothoracic Department, St Bartholomew's Hospital (S.J.E.), London, UK.
Correspondence to Dr Metin Avkiran, Cardiovascular Research, The Rayne Institute, St Thomas' Hospital, Lambeth Palace Rd, London SE1 7EH, UK. E-mail m.avkiran{at}umds.ac.uk
Background Despite evidence that pharmacological inhibition of the Na+/H+ exchanger (NHE) is cardioprotective, activation of NHE has been proposed as a protective mechanism of ischemic preconditioning (PC).
Methods and Results In isolated rat ventricular myocytes (n=8 to 11 per group) loaded with the fluorescent pH indicator C-SNARF-1, we showed that HOE-642 (HOE) was a potent inhibitor of the sarcolemmal NHE (80% inhibition at 1 µmol/L); such inhibition was readily reversible by washout of the drug. We confirmed that 1 µmol/L HOE produces significant and reversible inhibition of NHE activity in isolated rat hearts as well (n=4), and in this model, we tested (n=8 per group) whether the presence of the drug during (1) the prolonged period of ischemia (40 or 60 minutes) or (2) the preceding brief periods of PC ischemia (3 minutes plus 5 minutes) modulates the protective efficacy of PC. In protocol 1, HOE was infused for 5 minutes immediately before the prolonged ischemic period. With 40 minutes of prolonged ischemia, the postischemic recovery of left ventricular developed pressure (LVDP) was 15±2% in controls and was improved to 45±7% with HOE (P<.05), 55±5% with PC (P<.05), and 68±2% with PC+HOE (P<.05 versus all groups). When the prolonged ischemic period was extended to 60 minutes, an additive effect of PC and HOE was readily apparent and LVDP recovery with PC+HOE (66±2%) was almost double that observed with HOE (37±4%) or PC (34±5%) alone (P<.05). In protocol 2, HOE was infused for 3 minutes immediately before each episode of PC ischemia and was subsequently washed out before a 40-minute prolonged ischemic period (HOE+PC). LVDP recovery was 34±4% in controls and was improved to 57±2% with PC (P<.05) and 55±3% with HOE+PC (P<.05). Improved recovery of LVDP was matched by reduced creatine kinase leakage in all cases.
Conclusions Because coadministration of HOE (at a concentration sufficient to inhibit NHE activity) did not reduce the efficacy of PC in either protocol, we conclude that NHE activity does not contribute to the cardioprotective actions of PC. On the contrary, NHE inhibition during the prolonged ischemic period may enhance the protection afforded by PC.
Key Words: ischemia • sodium • myocytes
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