NA+ H+ EXCHANGER ACTIVITY DOES NOT CONTRIBUTE TO PROTECTION BY ISCHEMIC PRECONDITIONING IN THE ISOLATED RAT-HEART/

Background Despite evidence that pharmacological inhibition of the Na/H+ exchanger (NHE) is cardioprotective, activation of NHE has been pr oposed as a protective mechanism of ischemic preconditioning (PC). Met hods and Results In isolated rat ventricular myocytes (n=8 to 11 per g roup) loaded with the fluorescent pH indicator C-SNARF-1, we showed th at HOE-642 (I-ICE) was a potent inhibitor of the sarcolemmal NHE (80% inhibition al 1 mu mol/L); such inhibition was readily reversible by w ashout of the drug. We confirmed that 1 mu mol/L HOE produces signific ant and reversible inhibition of NHE activity in isolated rat hearts a s 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 mi nutes plus 5 minutes) modulates the protective efficacy of PC. In prot ocol 1, HOE was infused for 5 minutes immediately before the prolonged ischemic period. With 40 minutes of prolonged ischemia, the postische mic 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 a dditive effect of PC and HOE was readily apparent and LVDP recovery wi th 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 f or 3 minutes immediately before each episode of PC ischemia and was su bsequently washed out before a 40-minute prolonged ischemic period (HO E+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 rec overy of LVDP was matched by reduced creatine kinase leakage in all ca ses. Conclusions Because coadministration of HOE (at a concentration s ufficient to inhibit NHE activity) did not reduce the efficacy of PC i n either protocol, we conclude that NHE activity does not contribute t o the cardioprotective actions of PC. On the contrary, NHE inhibition during the prolonged ischemic period may enhance the protection afford ed by PC.