Long-term myocardial preservation - Beneficial and additive effects of polarized arrest (Na+-channel blockade), Na+/H+-exchange inhibition, and Na+K+/2Cl(-)-cotransport inhibition combined with calcium desensitization

Background Polarized arrest, induced by tetrodoxin (TTX) at an optimal conc entration of 22 mu mol/L, has been shown to reduce ionic imbalance and impr ove myocardial preservation compared with hyperkalemic (depolarized) arrest , Additional pharmacologic manipulation of ionic changes (involving inhibit ion of Na+ influx by the Na+/H+ exchanger [HOE694] and Na+/K+/2Cl(-) cotran sporter [furosemide], and calcium desensitization [BDM]) may further improv e long-term preservation, In this study, we (i) established optimal concent rations of each drug (ii) determined additive effects of optimal concentrat ions of each drug and (iii) compared our optimal preservation solution to a n established depolarizing cardioplegia (St Thomas' Hospital solution No 2: STH2) used during long-term hypothermic storage for clinical transplantati on. Methods. The isolated working rat heart, perfused with Krebs Henseleit (HH) buffer was used; cardiac function was measured after 20 min aerobic workin g mode perfusion, The hearts (n=6/group) were arrested with a 2 mi infusion (for 30 sec) of the polarizing (control) solution (22 mu mol/L TTX in KH) or control + drug and subjected to 5 hr or 8 hr of storage at 7.5 degrees C in the arresting solution. Postischemic function during reperfusion was me asured (expressed as percentage of preischemic function). Results. Dose-response studies established optimal concentrations of HOE694 (10 mu mol/L), Rzrosemide (1.0 mu mol/L) and PHM (30 mol/L) in the polariz ing (control) solution. Sequential addition to the control solution (Group I) of optimal concentrations of HOE694 (Group II), furosemide (Group III), and BDM (Group IV) were compared with STH2 (Group V); postischemic recovery of aortic flow was 29+/-7%, 49+/-6%*, 56+/-2%*, 76+/-3%*, and 25+/-6%, res pectively (*P<0.05 vs. I and V). Creatinte kinase leakage was lowest, and m yocardial ATP content was highest in Group IV. Conclusions, A polarizing preservation solution (KH+TTX) containing HOE694, furosemide, and BDM significantly enhanced long-term preservation compared with an optimized depolarizing, solution (STH2) used clinically for long-t erm donor heart preservation.