In vivo31P nuclear magnetic resonance findings on heterotopically allografted hearts in rats treated with a novel immunosuppressant, FK 506

Abstract

Administration of FK506 for 15 days at daily doses of 3.2 mg/kg p.o., 10 mg/kg p.o., 0.32 mg/kg i.m., or 1 mg/kg i.m. to heart-allografted rats resulted in a significant prolongation of graft survival time. The best graft acceptance was obtained in the 1 mg/kg i.m. group: all six grafts survived longer than 50 days, and two of them, indefinitely. The³¹P nuclear magnetic resonance (NMR) technique was utilized to investigate in vivo the energy metabolism of grafts. The ratios of inorganic phosphate (P_i)/phosphocreatine (PCr) and PCr/ATP were useful parameters for monitoring cardiac insufficiency after transplantation. The mean ratios of P_i/PCr and PCr/ATP in syngeneic grafts were 0.38±0.11 and 1.88±0.42, respectively. In the control allografts, a rapid increase in the P_i/PCr ratio and a decrease in the PCr/ATP ratio were found from day 5. During the period of FK 506 administration, increased P_i/PCr and decreased PCr/ATP ratios were also observed in all groups. The changes in these ratios were related with FK506 dosage. The results suggest that FK506 has a side-effect on graft metabolism. The metabolism tended to improve upon cessation of the drug in all grafts, but it worsened again in 3–3 1/2 weeks in the rats treated with 3.2 mg/kg p.o., 10 mg/kg p.o., or 0.32 mg/kg i.m. This seemed to be due to graft rejection. In the 1 mg/kg i.m. group, lowering of the P_i/PCr ratio and elevation of the PCr/ATP ratio were observed after the withdrawal of FK506, and these ratios remained stable until the end of the observation period. In conclusion, FK506 was found to be a potent immunosuppressant with a significant side-effect on graft metabolism.