Grobecker H, Roizen M F, Jacobowitz D M, Kopin I J
Eur J Pharmacol. 1977 Nov 15;46(2):125-33. doi: 10.1016/0014-2999(77)90248-5.
The effects of repeated high doses of the adrenergic neuron blocking drug guanethidine or a hexahydropyrazinoindole compound (2-guanyl-1,2,3,10,10a, hexahydro-1,2,a-pyrazinoindole, EMD 21192) (30 mg/kg i.p., 21.5 mg/kg i.p. respectively, equimolar doses) on sympathoadrenal activity were investigated in normotensive adult rats. During treatment for 5 weeks with either guanethidine or EMD 21192 the systemic blood pressure fell steadily. Noradrenaline content in the heart and vas deferens were decreased markedly by guanethidine and to a much less degree by EMD 21192. EMD 21192 markedly lowers the catecholamine content of the adrenal medulla, presumably as a result of inhibition of dopamine-beta-hydroxylase. The plasma catecholamine concentrations reflected the different sites of action of the drugs in the sympathoadrenal system, i.e. guanethidine mainly reduced circulating norepinephrine and dopamine-beta-hydroxylase by more than 50%, whereas EMD 21192 decreased considerably by the total catecholamines (mainly epinephrine) without altering significantly in the plasma norepinephrine. Disappearance or reduction of fluorescent nerve endings in the iris and the heart and a decrease of the intensity of fluorescence in chromaffin cells of the adrenal gland caused by the drugs were consistent with the biochemical alteration. Whereas the repeated doses of guanethidine caused degeneration of sympathetic nerves, destruction of adrenergic neurons was not found after prolonged treatment with EMD 21192.
在正常血压的成年大鼠中，研究了重复高剂量的肾上腺素能神经元阻断药物胍乙啶或一种六氢吡嗪吲哚化合物（2-胍基-1,2,3,10,10a-六氢-1,2,a-吡嗪吲哚，EMD 21192）（分别为腹腔注射30mg/kg、21.5mg/kg，等摩尔剂量）对交感肾上腺系统活性的影响。在用胍乙啶或EMD 21192治疗5周期间，全身血压稳步下降。胍乙啶可使心脏和输精管中的去甲肾上腺素含量显著降低，而EMD 21192的降低程度则小得多。EMD 21192可显著降低肾上腺髓质的儿茶酚胺含量，这可能是由于抑制了多巴胺-β-羟化酶。血浆儿茶酚胺浓度反映了药物在交感肾上腺系统中的不同作用部位，即胍乙啶主要使循环中的去甲肾上腺素和多巴胺-β-羟化酶降低50%以上，而EMD 21192可使总儿茶酚胺（主要是肾上腺素）显著降低，而血浆去甲肾上腺素无明显变化。药物引起的虹膜和心脏中荧光神经末梢的消失或减少以及肾上腺嗜铬细胞中荧光强度的降低与生化改变一致。重复剂量的胍乙啶可导致交感神经变性，而长期用EMD 21192治疗后未发现肾上腺素能神经元被破坏。
