Tozer G M, Prise V E, Motterlini R, Poole B A, Wilson J, Chaplin D J
Tumour Microcirculation Group, Gray Laboratory Cancer Research Trust, Mount Vernon Hospital, Northwood, Middlesex, UK.
Int J Radiat Oncol Biol Phys. 1998 Nov 1;42(4):849-53. doi: 10.1016/s0360-3016(98)00303-4.
To determine the relative effects of inhibiting nitric oxide synthase (NOS) and haemoxygenase (HO) on blood flow to the rat P22 carcinosarcoma.
HO is the enzyme responsible for in vivo production of carbon monoxide (CO). The vascular effects of zinc protoporphyrin IX (ZnPP), a competitive inhibitor of HO, were compared with those of copper protoporphyrin IX (CuPP), a poor inhibitor of HO, in isolated ex vivo perfusions of the P22 tumour and in intact tumour-bearing rats. In ex vivo perfusions, tumour vascular resistance was calculated from measurements of perfusion pressure at a known flow rate. In intact animals, blood flow to tumour and normal tissues was calculated using a radiotracer uptake method. The effects of ZnPP were compared with those of the NOS inhibitor, N(omega)-nitro-L-arginine (L-NNA), and the combination of the two drugs.
HO activity in the P22 tumour was reduced by 50% following administration of either ZnPP or CuPP directly to ex vivo perfused tumours, suggesting an indirect effect on the enzyme. Enzyme inhibition was not associated with any significant vasoactive effect. Neither ZnPP nor CuPP, at a dose of 45 micromol x kg(-1) administered i.p., inhibited tumour HO in vivo. However, they did significantly decrease tumour blood flow to 60-70% of control, with similar effects in skin and brain. Skeletal muscle blood flow was increased to 150% of control. L-NNA decreased both tumour and skeletal muscle blood flow to around 40% of control. These differences suggest that the nonspecific effects of ZnPP and CuPP were not mediated by NOS inhibition. The combination of ZnPP and L-NNA improved the selective reduction in tumour blood flow achieved with either agent alone.
This suggests that the HO/CO pathway does not play a major vasodilatory role in this tumour. However, ZnPP and CuPP could be useful for inducing a relatively selective decrease in tumour blood flow via mechanisms unrelated to HO inhibition, especially when combined with NOS inhibition.
确定抑制一氧化氮合酶（NOS）和血红素加氧酶（HO）对大鼠P22癌肉瘤血流的相对影响。
HO是负责体内一氧化碳（CO）生成的酶。在P22肿瘤的离体灌注实验以及完整的荷瘤大鼠中，比较了HO的竞争性抑制剂原卟啉锌IX（ZnPP）和HO的低效抑制剂原卟啉铜IX（CuPP）的血管效应。在离体灌注实验中，根据已知流速下的灌注压力测量值计算肿瘤血管阻力。在完整动物中，使用放射性示踪剂摄取法计算肿瘤和正常组织的血流。将ZnPP的效应与NOS抑制剂N（ω）-硝基-L-精氨酸（L-NNA）以及两种药物联合使用的效应进行比较。
将ZnPP或CuPP直接应用于离体灌注的肿瘤后，P22肿瘤中的HO活性降低了50%，提示对该酶有间接影响。酶抑制与任何显著的血管活性效应无关。腹腔注射剂量为45 μmol·kg⁻¹的ZnPP或CuPP在体内均未抑制肿瘤HO。然而，它们确实使肿瘤血流显著降低至对照的60 - 70%，对皮肤和脑有类似作用。骨骼肌血流增加至对照的150%。L-NNA使肿瘤和骨骼肌血流均降低至对照的约40%。这些差异表明ZnPP和CuPP的非特异性效应不是由NOS抑制介导的。ZnPP和L-NNA联合使用改善了单独使用任何一种药物时实现的肿瘤血流选择性降低。
这表明HO/CO途径在该肿瘤中不发挥主要的血管舒张作用。然而，ZnPP和CuPP可通过与HO抑制无关的机制诱导肿瘤血流相对选择性降低，特别是与NOS抑制联合使用时。
