Na-H exchange inhibition with cariporide limits functional impairment caused by repetitive ischemia

Intracellular calcium ([Ca]i) overload on reperfusion may be one of the mec hanisms responsible for ischemia-induced regional myocardial dysfunction. B ecause inhibiting the Na-H exchanger (NHE) limits intracellular sodium ([Na ]i) and subsequent [Ca]i accumulation, we hypothesized that NHE inhibition would attenuate regional dysfunction in response to 25 cycles of ischemia ( I, 2-min) and reperfusion (R, 8-min) of the left circumflex coronary artery (LCx) in conscious swine. Six animals were instrumented to measure arteria l pressure, regional myocardial blood flow (colored microspheres), systolic wall thickening (WTh) in the normally perfused (left anterior descending, LAD) and LCx regions (sonomicrometry), LCx blood flow velocity (Doppler), a nd to reversibly occlude the LCx (hydraulic occluder). Each animal complete d three protocols separated by 7 days: ISC, 25 I/R cycles; CAR, 25 I/R cycl es + NHE inhibition (cariporide); and VEH, vehicle administration for 4.2 h . Regional myocardial blood flow was measured during LCx occlusion in the f irst protocol and 10 min after I/R 25 in all protocols. Systemic hemodynami cs were similar among and within each protocol. Blood flow measured during LCx occlusion confirmed that perfusion was reduced (p < 0.05) to this compa red with the LAD region. During ISC, LCx WTh was reduced (p < 0.05) after f ive I/R cycles, and a stable reduction (approximate to 55% of baseline; p < 0.05) was present after 20 I/R cycles. During CAR, LCx systolic WTh was re duced (p < 0.05) only after 15 and 25 I/R cycles (approximate to 80 and 72% , respectively). The decrease in LCx WTh was greater in ISC than in CAR (p < 0.05). LCx WTh was not altered during VEH, while LAD WTh was similar with in and among all protocols. Regional blood flow measured after 25 I/R cycle s was not different among protocols. Our results indicate that NHE inhibiti on delays the onset and limits the degree of regional dysfunction in respon se to repeated bouts of ischemia and reperfusion.