Orotic acid improves recovery of left ventricular function days after heterotopic transplantation
Orotic acid (OA) accelerates compensatory myocardial hypertrophy after regional ischemia and improves left ventricular (LV) function acutely after global ischemia. Here, the effect of OA on LV function was investigated 4 days after global ischemia (75 minutes, 21°C) using heterotopically transplanted rabbit hearts (n = 18). Experimental animals received daily intraperitoneal OA (100 mg/kg/d starting 1 day before transplantation), with a threefold increase in serum OA level by 4 days. After 1 hour of reperfuslon, developed pressure (DP) was equally depressed in control and experimental groups; however, 4 days later control animals dropped their DP by 3 ± 3 mmHg (vs. DP at 1 hour), whereas experimental animals significantly increased their DP by 25 ± 8. Heterotopically transplanted hearts manifest diminished systolic function (from ischemia and unloading) as well as decreased expression of adult myosin. Since OA increases protein synthesis in other models, we investigated whether the improvement in systolic function resulted from an OA-mediated augmentation (or preservation) of normal adult myosin expression. Both OA-treated and untreated hearts manifested decreased expression of the β myosin heavy chain (β-MHC) protein and steady-state mRNA levels. Since function improved with decreased β-MHC expression, an alternative mechanism underlying OA-mediated improvement in function is implicated. Nevertheless, OA may be a therapeutic agent facilitating chronic recovery from global ischemia.
Yeh T., J; Rebeyka, IM; Jakoi, ER; Johnson, DE; Dignan, RJ; Dyke, CM; Wechsler, AS
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