Fiore C E, Pennisi P, Cutuli V M, Prato A, Messina R, Clementi G
Department of Internal Medicine, University of Catania O.V.E., Via Plebiscito 628, 95124, Catania, Italy.
Eur J Pharmacol. 2000 Nov 24;408(3):323-6. doi: 10.1016/s0014-2999(00)00800-1.
Cyclosporin A is implicated in the pathogenesis of post-transplantation bone disease. Because of recent evidence that cyclosporin A may cause renal and cardiovascular toxicity by inhibiting nitric oxide (NO) activity, and that NO slows bone remodeling and bone loss in animal and human studies, we investigated a possible link between NO production and beneficial effects on bone health in cyclosporin A-treated rats. Thirty-six 10-week-old male rats were assigned to six groups of six animals each, and treated for 4 weeks with: vehicle; cyclosporin A; L-arginine; N(G)-nitro-L-arginine methylester (L-NAME, a general inhibitor of NO synthase activity); a combination of cyclosporin A+L-arginine; and a combination of cyclosporin A+L-NAME. Whole body and regional (spine and pelvis) bone mineral content of rats were measured under basal conditions and at the end of the treatment period by dual-energy X-ray absorptiometry (DXA) scanning. Femur weights and serum concentrations of pyridinoline, a reliable marker of bone resorption, were measured at the end of the study period. Cyclosporin A-, L-NAME-, and cyclosporin A+L-NAME-treated rats had significantly lower bone mineral content and femur weights, and significantly higher pyridinoline levels than did control animals. The administration of L-arginine appeared to prevent bone loss caused by cyclosporin A, suggesting that this amino acid, which can be converted to produce NO, might prove useful in preventing disturbed bone modeling and inhibition of bone growth associated with cyclosporin A therapy.
环孢素A与移植后骨病的发病机制有关。由于最近有证据表明，环孢素A可能通过抑制一氧化氮（NO）活性而导致肾脏和心血管毒性，并且在动物和人体研究中NO可减缓骨重塑和骨质流失，因此我们研究了在环孢素A处理的大鼠中，NO生成与对骨骼健康有益作用之间的可能联系。将36只10周龄雄性大鼠分为6组，每组6只动物，分别用以下药物处理4周：赋形剂；环孢素A；L-精氨酸；N（G）-硝基-L-精氨酸甲酯（L-NAME，一种一氧化氮合酶活性的通用抑制剂）；环孢素A + L-精氨酸组合；环孢素A + L-NAME组合。在基础条件下以及治疗期结束时，通过双能X线吸收法（DXA）扫描测量大鼠的全身和局部（脊柱和骨盆）骨矿物质含量。在研究期结束时测量股骨重量和吡啶啉的血清浓度，吡啶啉是骨吸收的可靠标志物。与对照动物相比，环孢素A、L-NAME和环孢素A + L-NAME处理的大鼠骨矿物质含量和股骨重量显著降低，吡啶啉水平显著升高。给予L-精氨酸似乎可以预防环孢素A引起的骨质流失，这表明这种可以转化生成NO的氨基酸可能对预防与环孢素A治疗相关的骨建模紊乱和骨生长抑制有用。
