Fujimura A, Ebihara A
Department of Clinical Pharmacology, Medical College of Oita, Japan.
Life Sci. 1990;46(12):827-31. doi: 10.1016/0024-3205(90)90111-4.
Our previous indirect evidences suggested that the adrenergic nervous system is involved in the mechanisms responsible for the time-dependent changes in the effects of furosemide in Wistar rats. In the present study, the role of this system was examined more directly by means of 6-hydroxydopamine-induced sympathectomy. Thirty mg/kg of 6-hydroxydopamine hydrobromide (6-OH-DA) (n = 9) or its vehicle alone (n = 9) was injected intra-arterially (i.a.) twice in Wistar rats. Furosemide (5 mg/kg) was administered i.a. at 1000 hrs (03HALO*) or at 2200 hrs (15HALO). Urine was collected for 60 min after the drug and urinary excretion of sodium and furosemide were determined respectively. Urine volume and urinary excretion of sodium and furosemide were significantly greater at 1000 hrs (03HALO) than at 2200 hrs (15HALO) in the vehicle-injected rats as observed in the previous study. However these administration-time-dependent changes in the effects of furosemide disappeared in the rats with 6-OH-DA. Thus, the present study provides more direct evidence and supports our original hypothesis concerning the mechanisms of this chronopharmacological phenomenon of the agent. Since 6-OH-DA does not penetrate the central nervous system from the blood stream, the present data also indicate that the peripheral adrenergic system is involved in this event.
我们之前的间接证据表明，肾上腺素能神经系统参与了呋塞米对Wistar大鼠作用的时间依赖性变化的机制。在本研究中，通过6-羟基多巴胺诱导的交感神经切除术更直接地研究了该系统的作用。给Wistar大鼠动脉内（i.a.）注射30mg/kg氢溴酸6-羟基多巴胺（6-OH-DA）（n = 9）或单独注射其溶媒（n = 9），共两次。在1000小时（03HALO*）或2200小时（15HALO）动脉内注射呋塞米（5mg/kg）。给药后收集60分钟尿液，分别测定钠和呋塞米的尿排泄量。如先前研究所观察到的，在注射溶媒的大鼠中，1000小时（03HALO）时的尿量、钠和呋塞米的尿排泄量显著高于2200小时（15HALO）时。然而，在6-OH-DA处理的大鼠中，呋塞米作用的这些给药时间依赖性变化消失了。因此，本研究提供了更直接的证据，并支持了我们关于该药物这种时辰药理学现象机制的原始假设。由于6-OH-DA不能从血流穿透进入中枢神经系统，目前的数据还表明外周肾上腺素能系统参与了这一事件。
