Prevention of early islet graft failure by selective inducible nitric oxide synthase inhibitors after pig to nude rat intraportal islet transplantation

Background. Clinical and experimental data indicate that early failure of intraportally grafted islets is caused by inflammation including secretion of cytokines and nitric oxide. Direct inducible nitric oxide synthase suppression may avoid detrimental effects associated with steroid administration. We compared the efficiency of selective and unselective inducible nitric oxide synthase inhibitors with dexamethasone to suppress nitric oxide generation after intraportal islet xenotransplantation into nude rats. Methods, Nonfasting serum glucose levels were daily evaluated after intraportal transplantation of 4000 freshly isolated pig islets into diabetic nude rats (85 mg/kg streptozotocin) either sham-treated with saline (n=21) or continuously infused for 7 days with L-N-G-monomethyl-arginine (n=7), S-methyl-isothiourea (n=15), or S-(2-aminoethyl)-isothiourea (n=19) in a dosage of 240, 100, or 50 mg/kg/day, respectively. Dexamethasone was injected i.p. twice as a daily bolus of 20 mg/kg (n=10) starting 1 day pretransplant. The nitrate/nitrite serum level was quantified colorimetrically 0, 24, and 48 hr posttransplant. Results, Saline treatment partially resulted in graft function (4/21) throughout the observation period (21 days). L-N-G-monomethyl arginine treated rats showed sustained hyperglycemia (0/7) not different from diabetic controls. Normoglycemia was observed after treatment with dexamethasone (6/10, P<0.05 versus saline and L-N-G-monomethyl-arginine), S-methyl-isothiourea (10/15, P<0.01), or S-(2-aminoethyl)-isothiourea (15/19, P<0.001). Graft function was associated with complete suppression of nitric oxide generation after S-methyl-isothiourea and S-(2-aminoethyl)-isothiourea treatment (P<0.001 versus saline) and partial suppression after dexamethasone treatment (P<0.05). Conclusions. Our observation of long-term function of xenogeneic islets in an inflammatory environment without interference of reactive T cells revealed the potency of highly selective isothioureas to completely suppress inducible nitric oxide synthase making reduction of islet-toxic immunosuppression feasible.