C018 Mycophenolate mofetil prevents cyclosporine induced endothelial dysfunction in rat allograft aortic model

Systemic endothelial dysfunction and increased arterial sensitivity to vasoconstrictor agents are commonly observed after renal transplantation and appear partly related to the vascular toxicity of calcineurin inhibitors, that promote oxidative stress and decrease nitric oxide (NO) availability. We tested whether the inhibitor of inosine monophosphate deshydrogenase mycophenolate mofetil (MMF), an immunosuppressive agent with antioxidant properties, prevents the deleterious endothelial effects of cyclosporine A (CsA) in a rat allograft aortic model. Four groups of Lewis rats (n=7 per group), grafted with an aortic abdominal allograft from a Brown Norway donor, were fed for two weeks with either vehicle (control), CsA (5mg/kg/day), MMF (40mg/kg/day), or CsA+MMF. Arterial pressure was measured by tail cuff plethysmography. At day 15 after transplantation, endothelium-dependent (acetylcholine: Ach) and independent relaxations (sodium nitroprusside: SNP) were assessed in native thoracic aortic segments. Thoracic aortas were incubated with the NO-synthase inhibitor LNNA (10-5mol/L) to assess the contribution of NO in acetylcholine-induced relaxation. Moreover, the concentration of phenylephrine (Phe) providing the half-maximum vasoconstriction (EC50) was determined and 8-isoprostane plasma levels were measured (ELISA, n=3-5 per group). CsA impaired the relaxation to Ach compared with control and MMF alone. Combined treatment with MMF+CsA restored these relaxing responses (Figure 1). The relaxations to Ach were abolished by LNNA in all groups. There was no difference between groups for arterial pressure and the relaxation to SNP. Both MMF treated and control groups displayed similar dose response curves to Phe (Figure 2) whereas CsA treated group revealed significant decrease of EC50 (CsA : 1.0 0.1; control: 3.2 1.0; MMF: 2.7 1.3 and MMF+CsA: 2.9 1.0 10-7mol/L). 8-isoprostane levels were higher in CsA treated rats compared with other groups. Thus, our results demonstrate that MMF treatment combined with CsA prevents the native conduit artery endothelial dysfunction and suppresses the greater sensitivity to phenylephrine observed after CsA alone. These effects could result from the antioxidant properties of MMF and the related increase in NO availability