Tacrolimus preserves vasomotor function and maintains vascular homeostasis.

BACKGROUND: Post-transplant immunosuppression is associated with endothelial dysfunction that may lead to vasculopathy. We have previously demonstrated that cyclosporine causes vascular dysfunction. In this we study examined the effect of tacrolimus (Tac) in an identical model. METHODS: Lewis rats (n = 8 per group) were injected with Tac (low, medium or high dose) or saline (Con) daily for 2 weeks. Segments of thoracic aorta (TAo) were assessed for endothelium-dependent (Edep) and -independent (Eind) vasorelaxation (E(max)) and sensitivity to endothelin (ET)-induced vasoconstriction (C(max)). ET(A) and ET(B) receptor (Rc) expression levels were determined in TAo. Tumor necrosis factor-alpha (TNF-α) and transforming growth factor-beta (TGF-ß) expression were determined in myocardial (LV) tissue. Plasma ET levels and tissue oxidative injury were quantified by enzyme-linked immunoassay. RESULTS: Tac did not impair Edep relaxation when compared with Con (p = 0.69). Impairment of sodium nitroprusside-mediated Eind vasorelaxation was noted with Tac (E(max): Con 69 ± 2%, Tac high 54 ± 2%; p = 0.0001), whereas no such impairment was seen with diltiazem-mediated Eind vasorelaxation (p = 0.06). Tac decreased sensitivity to ET (C(max): Con 222 ± 19%, Tac high 162 ± 11%; p = 0.0002) and ET levels (Con 0.8 ± 0.1 fmol/ml, Tac 0.4 ± 0.1 fmol/ml; p = 0.02). Tac did not alter ET(A) Rc expression (p = 0.28), but increased ET(B) Rc levels (p = 0.02). Oxidative injury was similar in both LV (p = 0.43) and Ao (p = 0.73) tissue. Similarly, TNF-α expression (p = 0.16) was not different between groups, whereas expression of TGF-ß demonstrated a significant decrease with Tac treatment (p = 0.02). CONCLUSION: Our findings suggests that tacrolimus has beneficial effects with respect to endothelial function.

Donor pretreatment with hypertonic saline attenuates primary allograft dysfunction: a pilot study in a porcine model.

BACKGROUND: Hypertonic saline (HTS) has been previously demonstrated to have immune modulatory and vascular protective effects. We assessed the effect of donor pretreatment with HTS on allograft preservation in a porcine model of orthotopic heart transplantation. METHODS AND RESULTS: Orthotopic transplants were performed after 6 hours of cold static allograft storage. Donor pigs were randomly assigned to pretreatment with (n=7) or without (n=6) HTS (4.5 mL/kg of 7.5% NaCl) administered 1 hour before donor heart arrest. Administration of HTS increased serum sodium level from 138+/-2 mmol/L to 154+/-4 mmol/L, which normalized to 144+/-3 mmol/L 1 hour after infusion. Successful weaning from cardiopulmonary bypass was significantly greater in HTS-treated hearts (6/7 vs 1/6; P=0.029). Preload recruitable stroke work after transplantation was improved compared to control (88+/-21% vs 35+/-8% of baseline; P=0.0001). Similarly, end-systolic elastance was improved compared to control (85+/-17% vs 42+/-12% of baseline; P=0.0002). Posttransplantation systolic blood pressure was significantly higher in the donor HTS group (60+/-9 mm Hg vs 35+/-6 mm Hg; P=0.04). Donor HTS treatment improved coronary artery endothelial-dependent vasorelaxation compared with control (Emax: HTS, 59+/-4%; control, 47+/-3%; P=0.04). HTS also resulted in improved endothelial-independent vasorelaxation compared with control (Emax: HTS, 71+/-3%; control, 59+/-4%; P=0.03; ED-50: HTS, 0.56x10 to 6+/-0.23 mol/L; control, 2.5x10 to 6+/-1.0 mol/L; P=0.04). Sensitivity to endothelin-1-induced vasospasm was reduced with HTS pretreatment (% maximum contraction [Cmax]: HTS, 338+/-15%; control, 419+/-40%; P=0.01). CONCLUSIONS: Donor HTS pretreatment attenuates posttransplantation cardiac allograft myocardial dysfunction, improves posttransplantation systemic hemodynamic function, and preserves posttransplantation cardiac allograft vascular function. HTS may be a novel organ donor intervention to prevent primary graft dysfunction.