Shebuski R J, Smith J M, Ruffolo R
Department of Pharmacology, Smith Kline and French Laboratories, King of Prussia, PA 19406.
Fundam Clin Pharmacol. 1989;3(3):211-21. doi: 10.1111/j.1472-8206.1989.tb00452.x.
Dopamine has been widely utilized in the treatment of acute congestive heart failure, ibopamine, the diisobutyrate ester of N-methyldopamine (epinine), is a novel inotropic agent that, unlike-dopamine, is orally active. In clinical studies at doses that produce favorable hemodynamic responses, ibopamine and dopamine can evoke a slight and transient increase in pulmonary artery pressure and pulmonary capillary wedge pressure, an effect that is no longer apparent 1 h after administration. We have previously demonstrated in anesthetized dogs that this effect is due to stimulation of alpha-adrenoceptors in the pulmonary circulation by dopamine and ibopamine, as well as by the active form of ibopamine, epinine. The aim of the present investigation was to determine how dopamine, ibopamine, and epinine interact with beta-adrenoceptors in the canine pulmonary circulation, since this activity may serve to offset the alpha-adrenoceptor-mediated pulmonary vasoconstrictor responses. Intraarterial injection of dopamine, ibopamine, and epinine resulted in dose-dependent pulmonary vasoconstrictor responses with a maximum increase of approximately 50-60% above resting pulmonary vascular tone. When animals were pretreated with propranolol (1 mg/kg iv) to block beta-adrenoceptors, pulmonary vasoconstrictor responses to dopamine were unchanged, whereas pulmonary vasopressor responses to ibopamine and epinine were significantly potentiated, especially for epinine. Upon intraduodenal administration of a therapeutically effective dose of ibopamine (i.e. 36 mg/kg) to normal dogs, virtually no pulmonary pressor response was observed. However, administration of this same dose of ibopamine to dogs pretreated with propranolol (1 mg/kg iv) resulted in a marked pulmonary pressor response. These data indicate that epinine, and therefore the parent compound ibopamine, have the capacity to stimulate beta 2-adrenoceptors in the pulmonary circulation to a far greater degree than dopamine, and that this activity serves to offset, at least in part, the alpha-adrenoceptor-mediated pulmonary vasoconstriction that occurs in response to ibopamine.
多巴胺已被广泛用于治疗急性充血性心力衰竭，异波帕明是N-甲基多巴胺（依匹宁）的二异丁酸酯，是一种新型的强心剂，与多巴胺不同，它具有口服活性。在产生有利血流动力学反应的剂量的临床研究中，异波帕明和多巴胺可引起肺动脉压和肺毛细血管楔压轻微且短暂的升高，给药1小时后这种效应不再明显。我们之前在麻醉犬中已证明，这种效应是由于多巴胺、异波帕明以及异波帕明的活性形式依匹宁对肺循环中的α-肾上腺素能受体的刺激所致。本研究的目的是确定多巴胺、异波帕明和依匹宁如何与犬肺循环中的β-肾上腺素能受体相互作用，因为这种活性可能有助于抵消α-肾上腺素能受体介导的肺血管收缩反应。动脉内注射多巴胺、异波帕明和依匹宁导致剂量依赖性的肺血管收缩反应，最大增加幅度比静息肺血管张力高出约50 - 60%。当用普萘洛尔（1 mg/kg静脉注射）预处理动物以阻断β-肾上腺素能受体时，对多巴胺的肺血管收缩反应未改变，而对异波帕明和依匹宁的肺血管升压反应显著增强，尤其是对依匹宁。给正常犬十二指肠内给予治疗有效剂量的异波帕明（即36 mg/kg）时，几乎未观察到肺升压反应。然而，给用普萘洛尔（1 mg/kg静脉注射）预处理的犬给予相同剂量的异波帕明会导致明显的肺升压反应。这些数据表明，依匹宁以及母体化合物异波帕明在肺循环中刺激β2-肾上腺素能受体的能力远大于多巴胺，并且这种活性至少部分地抵消了因异波帕明而发生的α-肾上腺素能受体介导的肺血管收缩。
