OROTIC-ACID IMPROVES LEFT-VENTRICULAR RECOVERY 4 DAYS AFTER HETEROTOPIC TRANSPLANTATION

Orotic acid accelerates compensatory myocardial hypertrophy after regi onal ischemia and improves left ventricular function acutely after glo bal ischemia. In this study, the effect of erotic acid on left ventric ular function was investigated 4 days after global ischemia (75 minute s, 21 degrees C) using heterotopically transplanted rabbit hearts (n = 18). Experimental animals received daily 100-mg/kg doses of intraperi toneally administered erotic acid, starting 1 day before transplantati on, and showed a threefold increase in the serum level of erotic acid by 4 days. After 1 hour of reperfusion, the developed pressure was equ ally depressed in both the control and experimental groups; however, 4 days later, the developed pressure in control animals was decreased b y 3 +/- 3 mm Hg (versus the developed pressure measured at 1 hour) whi le the developed pressure in experimental animals was significantly in creased by 25 +/- 8 mm Hg. Heterotopically transplanted hearts manifes ted diminished systolic function (stemming from ischemia and unloading ) as well as decreased expression of adult myosin. Because erotic acid has been observed to produce an increase in protein synthesis in othe r models, we investigated whether this improvement in systolic functio n resulted from an erotic acid-mediated augmentation (or preservation) of normal adult myosin expression. Both erotic acid-treated and untre ated hearts manifested decreased expression of the beta-myosin heavy c hain protein and steady-state messenger RNA levels. Because function i mproved with decreased beta-myosin heavy chain expression, an alternat e mechanism underlying erotic acid-mediated improvement in function is implicated. Nevertheless, erotic acid may be a therapeutic agent faci litating long-term recovery from global ischemia.