l-Arginine, a nitric oxide precursor, attenuates ischemia-reperfusion injury by inhibiting inositol-1,4,5-triphosphate

Abstract

Objective: We evaluated the effect of pretreatment with nitric oxide precursor before ischemia on recovery with reperfusion in rat hearts. Methods: Isolated rat hearts were perfused with Krebs-Henseleit buffer without (C group) or with 3 mmol/L l-arginine (A group) before 30 minutes of ischemia. The left ventricular function, including heart rate, developed pressure, maximal dp/dt, and coronary flow, were measured before pretreatment and after 10 and 30 minutes of reperfusion. Cyclic guanosine monophosphate (by radioimmunoassay), calcium (by absorption spectrophotometry), and inositol 1,4,5-triphosphate synthesized from tritiated myo-inositol (by ion-exchange chromatography preceding counting) were measured at the same times and immediately after ischemia. Results: Recovery of ventricular function was significantly greater in the A group than in the C group. Pretreatment increased postischemic cyclic guanosine monophosphate content compared with the preischemic level (from 1.06 ± 0.12 to 1.94 ± 0.09 pmol/mg protein, p < 0.05). No change in cyclic guanosine monophosphate was evident in the C group. In the C group, inositol triphosphate content increased after 10 minutes of reperfusion beyond the preischemic level (from 0.53 ± 0.023 to 1.15 ± 0.045 cpm × 10^-3/gm, p < 0.05) as did calcium at 30 minutes (from 4.12 ± 0.164 to 6.86 ± 0.544 mmol/gm dry weight). In the A group, both of these increases were significantly attenuated. Conclusion: These data suggest that l-arginine pretreatment may reduce calcium overload by increasing cyclic guanosine monophosphate production, which in turn downregulates inositol triphosphate synthesis during reperfusion. (J Thorac Cardiovasc Surg 1998;115:931-6)