THE AZASPIRANE SKF-105685 AMELIORATES RENAL-ALLOGRAFT REJECTION IN RATS

The azaspirane SKF 105685 (N,N-dimethyl-8, 8-dipropyl-2-azaspiro (4.5) decane-2-propanamine dihydrochloride) has been shown to attenuate or reverse the course of immunologic disease in several animal models, po ssibly through the induction of nonspecific suppressor activity. To in vestigate its effects on immune-mediated rend disease, SKF 105685 was administered by gavage to rats with kidney allografts. Six days after transplantation, GFR (inulin clearance, 1.46 +/- 0.27 versus 0.41 +/- 0.15 mL/min per kg; P < 0.005) and RPF (p-aminohippurate clearance, 5. 48 +/- 0.98 versus 1.99 +/- 0.72 mL/min per kg; P < 0.01) were signifi cantly higher in SKF 105685-treated rats compared with vehicle-treated control rats. In addition, mononuclear inflammatory cell infiltrates were significantly reduced in SKF 105685-treated animals compared with controls. Treatment also reduced renal production of thromboxane B2 ( 81 +/- 22 versus 424 +/- 76 pg/min per mg of protein; P < 0.0005), pro staglandin E2 (612 +/- 165 versus 2,059 +/- 351 pg/min per mg of prote in; P < 0.005), and 6-keto prostaglandin F1alpha (217 +/- 56 versus 94 3 +/- 186 pg/min per mg of protein; P < 0.005), but interleukin-1beta mRNA levels within kidney ollografts were not affected by treatment. T hus, the azaspirane SKF 105685 is a novel immunosuppressive agent that substantially ameliorates renal allograft rejection in the rat. Altho ugh the mechanism of action is unknown, the beneficial effects of SKF 105685 in rejection may relate to its ability to induce suppressor act ivity and/or its effects on eicosanoid production.