Abstract 2581: Tacrolimus Preserves Endothelial-Dependent Vasomotor Function And Decreases Sensitivity To Vasospasm By Increasing Endothelin(B) Receptor Expression
Objective: Immunosuppressants essential to graft survival post-transplant are associated with endothelial dysfunction, a major contributor to cardiac allograft vasculopathy. Our previous studies have demonstrated that cyclosporine (CsA) results in vascular dysfunction characterized by impairment of endothelial-dependent (Edep) vasorelaxation and enhanced sensitivity to endothelin-1 (ET)-induced vasospasm. This study examined the effect of an alternative agent, tacrolimus (Tac), on vasomotor function.
Methods: Lewis rats were injected with Tac (0.5, 1.5, or 3.0mg/kg), or saline control (Con) IP daily for 2 weeks. Segments of thoracic aorta (TAo) were assessed for Edep and endothelial-independent (Eind) vasorelaxation following exposure to acetylcholine and sodium nitroprusside, respectively. Groups were compared by deriving the %max relaxation (Emax) from baseline. Vessel sensitivity to ET-induced vasoconstriction was assessed by deriving %max contraction (Cmax). Expression of endothelial and inducible nitric oxide synthase (eNOS, iNOS), ET(A) and ET(B) receptor (Rc) proteins was determined in TAo.
Results: Tac exposure did not impair Edep vasorelaxation compared to Con (Emax: Con, 45±3%; Tac low, 43±3%; Tac med, 52±3%; Tac high 48±2%, P=0.26). Impairment of Eind vasorelaxation was noted with all doses compared to Con (Emax: Con, 31±2%; Tac low, 40±3%; Tac med, 48±3%; Tac high, 46±2%; P=0.0001). Compared with Con, all treatment groups showed decreased sensitivity to ET (Cmax: Con, 219±20%; Tac low, 160±15%; Tac med, 178±16%; Tac high, 163±13%; P<<med>0.05). Tac did not alter eNOS, iNOS, or ET(A) Rc expression compared to Con, while an increase in ET(B) Rc expression was noted with all Tac doses (P=0.007).
Conclusions: Tac treatment does not impair Edep vasorelaxation and decreases sensitivity to vasospasm, but results in impairment of Eind relaxation. Our previous findings suggest that CsA-induced vasomotor dysfunction is a result of alterations in nitric oxide (NO) and ET regulation. The current study suggests that Tac has beneficial effects with respect to NO/ET homeostasis, as demonstrated by preserved Edep vasomotor function, decreased ET sensitivity, and increased ET(B) Rc expression to elicit Edep vasodilation.