| Abstract: | 移植是現今器官衰竭治療的趨勢，但手術後服用免疫抑制劑隨之而來的副作用則是極待克服的問題。例如臨床上已有許多文獻指出現今最常使用的兩種免疫抑制劑Tacrolimus (FK 506) 及Cyclosporine在長期服用後，會伴隨有神經毒性及腎毒性之副作用 ，但至目前為止並沒有文獻明確指出 FK 506及Cyclosporine 對於下泌尿道系統是否亦有影響。本篇實驗探討 FK 506及Cyclosporine 是否會影響正常膀胱排尿收縮之功能。
本實驗在大鼠脊髓腔內注射FK 506及Cyclosporine，經由所記錄到的膀胱壓 (intravesicular pressur；IVP)、尿道外括約肌肌電圖 (external urethral sphincter-electromyogram；EUS-EMG)，來評估膀胱的排尿收縮功能。實驗結果顯示，在脊髓腔內注射FK 506及Cyclosporine處理後，發現引發排尿收縮所需的壓力閾值、排尿後壓力、儲尿期、排尿量以及肌電圖積分都有顯著的增加。另外在脊髓腔內分別給予glutamatergic agonist (L-glutamate、NMDA) 以及glutamatergic antagonist (NBQX、APV) 來更進一步探討FK 506及Cyclosporine影響正常膀胱排尿收縮可能透過的途徑。由實驗結果顯示，L-glutamate及NMDA可緩解FK 506及Cyclosporine所引發增加之作用，另外在 APV之後追加 FK 506 (APV+FK 506) 或NBQX之後追加Cyclosporine (NBQX+Cyclosporine) 均會加強 FK 506 及 Cyclosporine 對膀胱的影響。
基於上述的實驗結果推測，FK 506可能藉由調控了AMPA receptor而Cyclosporine可能藉由調控了NMDA receptor來影響正常膀胱排尿收縮的功能。
The effects of immunosupressants, tacrolimus (FK 506) and Cyclosporine on the micturition reflex were examined in anesthetized rats. Both FK 506 (i.t., 100μM, 5ul) and Cyclosporine produced increase in voiding threshold (VT, 178.14±20.19% and 151.93±18.86%, respectively, p<0.05, n=9) and holding duration (HD, 341.28±28.28% and 326.84±23.98%, respectively, p<0.05, n=9) and voiding volume (VV, 145.66±7.40% and 145.06±7.26%, respectively, p< 0.05, n=9). Pretreatment of glutamate (i.t., 100μM, 5 ul ; VT=102.39±2.82% and 104.94±3.89%, HD= 100.58 ± 6.37 % and 90.59±7.54%, VV=96.66±8.28% and 102.26±10.62%, p<0.05, n=9), and N-methyl-D-aspartic acid (NMDA, i.t., 100μM, 5 ul; VT= 101.07±2.08% and 103.15±4.43%, HD=104.35±8.04% and 87.96±8.55%, VV=92.20±5.08% and 94.86±10.49% in FK 506 and Cyclosporine, respectively, p<0.05, n=9), ameliorate the effect on voiding reflex elicited by intrathecal FK 506 and Cyclosporine. In addition, APV (i.t., 100μM, 1-5μl ) pretreatment exaggerated the effects elicited by FK 506 (HD= 698.78±98.34 % , VV=266.66±31.06%, p< 0.05, n=9), while no significant effect was elicited by NBQX pretreatment. On the contrary, NBQX (i.t., 20μM, 1-5μl) pretreatment exaggerated the effects elicited by Cyclosporine (HD=737.98±94.55% , VV=274.33±14.30%, p< 0.05, n=9), while no significant effect was elicited by APV pretreatment. indicating a glutamatergic neurotransmission was affected by FK 506. All these results demonstrate that FK 506 and Cyclosporine may induce a distinct modulation in bladder functions mediated by their effects on glutamatergic transmission.
Key words: FK 506,Cyclosporine, glutamate, NMDA, voiding reflex, urinary bladder |
