RSR13, a synthetic allosteric modifier of hemoglobin, improves myocardial recovery following hypothermic cardiopulmonary bypass

Background - During hypothermic blood cardioplegia, oxygen delivery to myoc ytes is minimal with ineffective anaerobic metabolism predominating. RSR 13 , 2-[4][(3,5-dimethylanilino) carbonyl]methyl]phenoxyl-2-methylpropionic ac id, a synthetic allosteric modifier of hemoglobin (Hb), increases release o f oxygen from Hb, increasing oxygen availability to hypoxic tissues, and re verses the hypothermia-dependent increase in Hb oxygen affinity. We studied recovery of myocardial mechanical and metabolic function and examined myoc ardial morphology after cardioplegia, comparing RSR13 (1.75 mmol/L)-supplem ented blood (RSR13-BC) to standard blood cardioplegia (BC). Methods and Results - Twelve dogs underwent 15 minutes of 37 degrees C glob al ischemia on cardiopulmonary bypass, followed by 75 minutes of hypothermi c cardioplegia (13 degrees C) with either BC (n = 6) or RSR13-BC (n 6). The re were no differences in baseline function between groups. Cardiac functio n was assessed after 30 minutes of 37 degrees C reperfusion (BC versus RSR1 3-BC, respectively) by measuring: % return to normal sinus rhythm (0/100%), % of baseline + dP/dt (33.7 +/- 1.7 / 76.3 +/- 1.9), % of baseline-dP/dt ( 26.6 +/- 2.0 / 81.1 +/- 1.6), stroke volume (3.5 +/- 0.5 / 7.1 +/- 0.9 mL), cardiac output (340 +/- 20 / 880 +/- 40.3 mL/min). and LVEDP (11.3 +/- 2.2 / 0.3 +/- 2.9 mm Hg). Postischemic oxidative and metabolic parameters incl uding myocardial lactate, pyruvate, ATP content, and percent water content also were determined. Histological analysis demonstrated preservation of en dothelial and myocyte morphology in hearts receiving RSR13-BC compared with BC. Conclusions - These results indicate that in the setting of hypothermic car diopulmonary bypass, RSR13 improves recovery of myocardial mechanical and m etabolic function compared with standard hypothermic BC. Findings from this study suggest that RSR13-BC, by decreasing hemoglobin oxygen affinity, imp roves oxidative metabolism and preserves cellular morphology, resulting in significantly improved contractile recovery on reperfusion.