Schwinger R H, Böhm M, Schulz C, Schmidt U, Schmidt U, Schmid B, Dienemann H, Reichart B, Erdmann E
Universität München, Medizinische Klinik I, Federal Republic of Germany.
J Pharmacol Exp Ther. 1993 Apr;265(1):346-57.
The present study was aimed to characterize the effects of epinine, the metabolite of the p.o. active dopamine derivate ibopamine in human cardiovascular tissues such as myocardium, coronary artery and pulmonary artery. Isometric force of contraction was studied in electrically driven papillary muscle strips from nonfailing (brain death), moderately failing (New York Heart Association class II-III, mitral valve replacement) and terminally failing human myocardium (New York Heart Association class IV, heart transplants) as well as in auricular trabeculae (aortocoronary bypass operation). Epinine increased force development in a concentration-dependent manner. In comparison to isoprenaline, epinine had a significantly lower potency but a similar efficacy to enhance force of contraction. Depending on the degree of myocardial failure, the effectiveness of epinine was reduced, whereas the potency was similar. Only in nonfailing myocardium, epinine increased force of contraction as effectively as Ca++. Prestimulation with forskolin or milrinone enhanced the potency of the epinine-mediated inotropic effect. In contrast, the beta-1-selective antagonist CGP 207.12A [2-hydroxy-5-(2-(hydroxy-3-(4-((1-methyl-4-trifluoromethyl)-1-H-imidazol -2-yl)-phenoxy)-propyl)-aminoethoxyl)-benzamide] and the beta-2-selective antagonist ICI 118.551 [erythro-(+-)-1-(7-methylindan-4-yloxy)-3- isopropylaminobutan-2-ol-hydrochloride] shifted the concentration-response curve of epinine significantly to the right, indicating action at both beta-2 and beta-1 adrenoceptors. Epinine exerted higher affinity at beta-2 compared to beta-1 adrenoceptors in radioligand binding experiments ([125I]iodocyanopinodolol). In human coronary artery rings and pulmonary artery rings epinine alone as well as epinine in the presence of propranolol initiated a concentration-dependent increase in tension development in precontracted (prostaglandin F2 alpha, 0.3 mumol/l) as well as in non-precontracted rings. These results suggest that epinine exerts no direct vasodilatory activity in human coronary and pulmonary arteries at concentrations which are capable to produce positive inotropic activity. The supposed beneficial effects of ibopamine in the treatment of heart failure may not be due to positive inotropic actions as the concentrations producing positive inotropy are much higher than the clinically observed plasma concentrations.
本研究旨在表征表肾上腺素（epinine）的作用，表肾上腺素是口服活性多巴胺衍生物异波帕胺（ibopamine）在人体心血管组织（如心肌、冠状动脉和肺动脉）中的代谢产物。在来自非衰竭（脑死亡）、中度衰竭（纽约心脏协会II-III级，二尖瓣置换术）和终末期衰竭人体心肌（纽约心脏协会IV级，心脏移植）的电驱动乳头肌条以及心耳小梁（主动脉冠状动脉搭桥手术）中研究等长收缩力。表肾上腺素以浓度依赖性方式增加收缩力。与异丙肾上腺素相比，表肾上腺素增强收缩力的效能显著较低，但效力相似。根据心肌衰竭的程度，表肾上腺素的有效性降低，但效力相似。仅在非衰竭心肌中，表肾上腺素增加收缩力的效果与钙离子一样有效。用福司可林或米力农预刺激可增强表肾上腺素介导的变力作用的效力。相反，β1选择性拮抗剂CGP 207.12A [2-羟基-5-(2-(羟基-3-(4-((1-甲基-4-三氟甲基)-1-H-咪唑-2-基)-苯氧基)-丙基)-氨基乙氧基)-苯甲酰胺]和β2选择性拮抗剂ICI 118.551 [赤式-(±)-1-(7-甲基茚满-4-基氧基)-3-异丙氨基丁-2-醇盐酸盐]使表肾上腺素的浓度-反应曲线显著右移，表明其作用于β2和β1肾上腺素能受体。在放射性配体结合实验（[125I]碘氰苯心安）中，与β1肾上腺素能受体相比，表肾上腺素对β2肾上腺素能受体具有更高的亲和力。在人冠状动脉环和肺动脉环中，单独的表肾上腺素以及在普萘洛尔存在下的表肾上腺素在预收缩（前列腺素F2α，0.3 μmol/L）以及未预收缩的环中均引发张力发展的浓度依赖性增加。这些结果表明，在能够产生正性肌力活性的浓度下，表肾上腺素在人冠状动脉和肺动脉中不具有直接的血管舒张活性。异波帕胺在心力衰竭治疗中假定的有益作用可能并非由于正性肌力作用，因为产生正性肌力作用的浓度远高于临床观察到的血浆浓度。
