Massingham R, Dubocovich M L, Langer S Z
Naunyn Schmiedebergs Arch Pharmacol. 1980 Oct;314(1):17-28. doi: 10.1007/BF00498427.
Intravenous administration of N,N-di-n-propyldopamine (DPDA: 50 and 200 micrograms/kg/min, i.v.) produces hypotensive and bradycardic effects in anaesthetized cats and dogs. These effects were abolished by ganglionic blockade and antagonized by haloperidol or (SR)-sulpiride suggesting a neurogenic mechanism of action, mediated by specific dopamine receptors. The renal blood flow increases to DPDA in dogs were resistant to ganglionic blockade indicating some activity at postsynaptic vascular dopamine receptors. Studies with DPDA in vivo administered via the intravertebral and intravenous routes suggested a peripheral site of action for the hypotensive effects of this compound. In vitro, in isolated perfused cat spleens prelabeled with 3H-noradrenaline, DPDA (0.01--1 microM) produced a concentration-dependent inhibition of tritium release elicited by nerve stimulation at 1 Hz which was selectively antagonized by 1 microM (SR)-sulpiride implicating presynaptic inhibitory dopamine receptors in the mediation of this effect. In isolated rabbit splenic arteries, contracted by prostaglandin-F2 alpha, dopamine,ADTN (2-amino-6,7-dihydroxytetrahydronaphthalene) and apomorphine produced concentration-dependent relaxations while DPDA exhibited only weak postsynaptic dopamine-like effects. In vivo DPDA reduced, in a frequency dependent manner, the end organ responses to sympathetic nerve stimulation in the cat nictitating membrane and in the dog renal vascular bed. Both effects were mediated through activation of presynaptic inhibitory dopamine receptors by DPDA. In conclusion these results suggest a predominantly presynaptic agonist effect for DPDA in vitro and a similarly important action in vivo, mediated mainly via dopamine receptors. Furthermore evidence is presented which suggests that pre- and postsynaptic dopamine receptors may differ in their pharmacological properties and that presynaptic dopamine receptors could be important target receptors in the development of novel antihypertensive drugs.
静脉注射N，N - 二正丙基多巴胺（DPDA：50和200微克/千克/分钟，静脉注射）会使麻醉的猫和狗产生低血压和心动过缓效应。这些效应可通过神经节阻断消除，并被氟哌啶醇或（SR）-舒必利拮抗，提示其作用机制为神经源性，由特定的多巴胺受体介导。犬体内肾血流量对DPDA的增加对神经节阻断有抗性，表明其在突触后血管多巴胺受体有一定活性。通过椎内和静脉途径体内给予DPDA的研究表明，该化合物的降压作用有外周作用部位。在体外，用3H - 去甲肾上腺素预标记的离体灌注猫脾脏中，DPDA（0.01 - 1微摩尔）对1赫兹神经刺激引起的氚释放产生浓度依赖性抑制，1微摩尔（SR）-舒必利可选择性拮抗该抑制作用，提示突触前抑制性多巴胺受体参与介导此效应。在由前列腺素 - F2α、多巴胺、ADTN（2 - 氨基 - 6,7 - 二羟基四氢萘）和阿扑吗啡收缩的离体兔脾动脉中，多巴胺产生浓度依赖性舒张，而DPDA仅表现出微弱的突触后多巴胺样效应。在体内，DPDA以频率依赖性方式降低猫瞬膜和犬肾血管床对交感神经刺激的终末器官反应。这两种效应均通过DPDA激活突触前抑制性多巴胺受体介导。总之，这些结果表明DPDA在体外主要有突触前激动剂作用，在体内也有类似重要作用，主要通过多巴胺受体介导。此外，有证据表明突触前和突触后多巴胺受体在药理学特性上可能不同，突触前多巴胺受体可能是新型抗高血压药物开发中的重要靶受体。
