多柔比星对大鼠离体胸主动脉和颈总动脉血管环的舒张作用及其机制

Vasodilating effect of doxorubicin on isolated thoracic aorta and carotid artery of rats and its mechnisms

目的研究多柔比星(DOX)对大鼠离体胸主动脉和颈总动脉血管环的作用及其机制。方法采用离体血管环恒温灌流系统,通过累积加药法每10 min加入DOX依次使其终浓度递增为1,3,10,30和100μmol·L-1,观察其对基础状态、去氧肾上腺素(PE,1μmol·L-1)和氯化钾(KCl,60 mmol·L-1)预收缩的胸主动脉及颈总动脉血管环的作用,并采用左旋硝基精氨酸甲酯(L-NAME)、4-氨基吡啶(4-AP)、溴化四乙铵(TEA)、氯化钡(BaCl2)、格列苯脲(Gli)、吲哚美辛(Indo)和普萘洛尔预处理探讨其对血管作用的可能机制。结果 DOX对基础状态下及KCl预收缩的胸主动脉和颈总动脉血管环张力无明显影响;DOX可浓度依赖性地舒张PE预收缩的内皮完整胸主动脉和颈总动脉环(P<0.05),且其对去内皮胸主动脉血管环也有舒张作用,但舒张程度弱于内皮完整组(P<0.05);一氧化氮合酶抑制剂L-NAME 0.1 mmol·L-1、电压依赖性钾通道(KV)抑制剂4-AP 1 mmol·L-1、钙敏感性钾通道(KCa)抑制剂TEA 1 mmol·L-1和内向整流型钾通道(KIR)抑制剂BaCl21 mmol·L-1均可明显抑制DOX的舒血管作用(P<0.05),环氧化酶抑制剂Indo 0.01 mmol·L-1、ATP敏感性钾通道抑制剂Gli 0.01 mmol·L-1和β肾上腺素能受体阻滞剂普萘洛尔0.01 mmol·L-1对DOX舒血管作用无明显影响;DOX 1,10和100μmol·L-1可浓度依赖性减弱无钙液中PE诱发的血管收缩,并可使氯化钙量效曲线右移。结论 DOX对大鼠离体胸主动脉和颈总动脉血管环有浓度依赖性舒张作用,其舒血管机制可能与血管内皮细胞一氧化氮/cGMP途径、KV、KCa、KIR、血管平滑肌细胞内钙释放和外钙内流有关。

OBJECTIVE To investigate the effect and mechanisms of doxorubicin(DOX)on isolated thoracic aorta and carotid artery of rats.METHODS The cumulative dosing method was used to add DOX every 10 min to reach the final concentrations of 1,3,10,30 and 100μmol·L-1,and the tension of isolated thoracic aorta and carotid artery in basal tension,precontracted by phenylephrine(PE)1μmol·L-1and KCl 60 mmol·L-1,was respectively recorded in vitro vascular ring perfusion apparatus.Furthermore,NG-nitro-L-arginine methyl ester(L-NAME),tetraethylammonium(TEA),4-aminopyridine(4-AP),BaCl2,glibenclamide(Gli),indometacin(Indo)and proparanolol were used to explore the mechnisms of the vasodilating effect of DOX.RESULTS DOX had no effect on the thoracic aorta and carotid artery in basal tension and precontracted by KCl.However,DOX induced concentration-dependent relaxation in both the thoracic aorta and carotid artery precontracted by PE(P<0.05),and it had stronger vasodilating effect on the endothelium-intact thoracic aorta than on the endothelium-denuded thoracic aorta(P<0.05).After the treatment with nitric oxidase inhibitor,L-NAME 0.1 mmol·L-1,calcium activated potassium channel(KCa)inhibitor,TEA 1 mmol·L-1,voltage-dependent potassium channel(KV)inhibitor,4-AP 1 mmol·L-1and inward rectifier potassium channel(KIR)inhibitor,BaCl21 mmol·L-1,the vasodilating effect of DOX was obviously decreased(P<0.05),but the application of Indo 0.01 mmol·L-1,Gli 0.01 mmol·L-1andβ-adrenregic receptor blocker propranolol 0.01 mmol·L-1had no effect on the vasodilating effect of DOX.Additional y,DOX 1,10 and 100μmol·L-1significantly reduced PE-induced contraction of the thoracic aorta in Ca2+-free solution,and the concentration-effect curve of CaCl2could be shifted to the right in the presence of DOX(P<0.05).CONCLUSION These results have demonstrated that DOX vasodilating effects on the thoracic aorta and carotid artery are concentration-dependent.The mechanisms are likely to be related to nitric oxide/cGMP pathway,KV,KCa,KIR,intracellular calcium release and extracellular calcium influx.