Cardiovascular dopamine receptor stimulation antagonized by metoclopramide
Cardiovascular dopamine receptor stimulation antagonized by metoclopramide
复制标题
甲氧氯普胺拮抗心血管多巴胺受体刺激
DOI：
10.1111/j.2042-7158.1975.tb10699.x
复制
发表时间：
1975
影响因子：
3.3
通讯作者：
P. Blower
中科院分区：
文献类型：
--
作者：
M. D. Day;P. Blower
甲氧氯普胺（N-（二乙基氨基乙基）-2-甲氧基-4-氨基-5-氯苯甲酰胺）抑制实验动物（Justin-BesanGon & Laville，1964）和人（汉德利，1967）的呕吐。放射学研究表明，在人类中，它能够刺激胃排空和肠运动（James & Hume，1968）;最近的证据表明，在治疗偏头痛方面可能具有临床疗效（Matts，1974）。甲氧氯普胺与止吐的丁酰苯酮衍生物氟哌啶醇一样，在动物中拮抗阿扑吗啡诱导的刻板反应（Hackman，Pentikainen & others，1973），表明中枢多巴胺能通路可能参与了该反应。此外，氟哌啶醇在麻醉犬中拮抗多巴胺的抑制作用（Sampson，Scroop & Louis，1974），因此认为研究甲氧氯普胺对多巴胺的心血管反应的影响是相关的。14只Wistar大鼠，雌雄不限，用戊巴比妥钠（60 mg kg-1，i. p.）用了平均血压为105 mm Hg。反应测量为平均血压的变化（平均血压计算为舒张压+ 1 /3脉压）。在未治疗的动物中，0.3至3 pg kg-1的多巴胺剂量产生短暂的降压反应，而更高剂量（3至100 pg kg-1）产生与剂量相关的平均血压升高。用酚妥拉明（3 mg·kg ~（-1），iv.）和普萘洛尔（1 mg kg-1，i. v.）。在这样处理的大鼠中，对多巴胺的升压反应转化为剂量相关的降压反应。静脉注射甲氧氯普胺（0.1-10 mg kg-1）可引起对多巴胺（0.0241 mg kg-1，i. v.）的降压反应剂量相关性降低。在服用1 mg kg-1或更高剂量的甲氧氯普胺后，对多巴胺的反应发生了变化，降压反应降低，出现了升压成分（图1）。降压反应多巴胺（0.1毫克千克-1）进行性减少剂量的甲氧氯普胺。总剂量为4.4 mg kg-1的甲氧氯普胺后，多巴胺的降压反应被取消，取而代之的是一个小的升压反应。静脉注射甲氧氯普胺（10 - 30 mg kg-1）可使平均血压出现短暂的福尔斯下降，而氟哌啶醇（10 mg kg-1）对此无影响。在6只大鼠中的进一步研究表明，剂量低于10 mg/kg的甲氧氯普胺不抑制对去甲肾上腺素或异丙肾上腺素的血压反应，表明特异性多巴胺受体拮抗作用。
Metoclopramide (N-(diethylaminoethyl)-2-methoxy-4-amino-5-chlorobenzamide) inhibits emesis in both laboratory animals (Justin-BesanGon & Laville, 1964) and man (Handley, 1967). Radiological studies have shown that in man it is capable of stimulating gastric emptying and intestinal motility (James & Hume, 1968); recent evidence suggests a possible clinical effectiveness in the treatment of migraine (Matts, 1974). Metoclopramide, like the anti-emetic butyrophenone derivative haloperidol, antagonizes apomorphine-induced stereotypy in animals (Hackman, Pentikainen & others, 1973) indicating possible involvement of central dopaminergic pathways in this response. In addition, haloperidol antagonizes the hypotensive action of dopamine in the anaesthetized dog (Sampson, Scroop & Louis, 1974) and it was therefore thought pertinent to study the effect of metoclopramide on the cardiovascular responses to dopamine. 14 Wistar rats of either sex, anaesthetized with sodium pentobarbitone (60 mg kg-l, i.p.) were used. The average mean blood pressure was 105mm Hg. Responses were measured as changes in mean blood pressure (mean blood pressure was calculated as diastolic pressure + 1 /3 pulse pressure). In untreated animals doses of dopamine in the range 0.3 to 3 pg kg-l produced transient depressor responses whereas higher doses (3 to 100 pg kg-' produced dose-related increases in mean blood pressure. Blood pressure responses to noradrenaline and isoprenaline were abolished by pretreatment with a combination of phentolamine (3 mg kg-l, i.v.) and propranolol (1 mg kg-l, i.v.). In rats so treated the pressor responses to dopamine were converted to dose-related depressor responses. Intravenous metoclopramide (0.1-10 mg kg-l) caused dose-related reductions in the depressor responses to dopamine (0.0241 mg kg-l, i.v.). After doses of 1 mg kg-l or more of metoclopramide the response to dopamine were changed such that the depressor response was reduced and a pressor component appeared (Fig. 1). The depressor responses to dopamine (0.1 mg kg-l) were progressively reduced by increasing doses of metoclopramide. After a total dose of 4.4 mg kg-1 of metoclopramide the depressor response to dopamine was abolished and was replaced by a small pressor response. Intravenous doses of metoclopramide (10 to 30 mg kg-l) produced short-lived falls in mean blood pressure which were unaffected by haloperidol (10 mg kg-l). Further studies in 6 rats indicated that metoclopramide at doses below 10 mg kg-' did not depress blood pressure responses to either noradrenaline or isoprenaline indicating a specific dopamine receptor antagonism.