Yabana H, Nagao T, Sato M
J Cardiovasc Pharmacol. 1985 Jan-Feb;7(1):152-7. doi: 10.1097/00005344-198501000-00025.
The effects of diltiazem and some of its metabolites on the cardiovascular system were studied in anesthetized dogs and in blood-perfused canine papillary muscles. The metabolites included N-desmethyldiltiazem (MA), a newly discovered major metabolite; desacetyldiltiazem (M1); desacetyl MA (M2); O-desmethyl M1 (M4); and O-desmethyl M2 (M6). In the anesthetized dog, diltiazem and its metabolites produced a dose-dependent increase in coronary blood flow, decreases in blood pressure and heart rate, and an increase in left ventricular dP/dtmax. The ranking of coronary-vasodilating activity of diltiazem and its metabolites, in decreasing order, was diltiazem, M1, MA, M2, M4, and M6. The effects of the metabolites were more selective for coronary vasodilation than for hypotension, but their selectivities were less than that of diltiazem. Coronary vasodilation and hypotension with diltiazem and MA were of longer duration than those with their corresponding desacetyl metabolites. By close arterial administration to the blood-perfused canine papillary muscle preparation, diltiazem and its metabolites also produced coronary-vasodilating actions, whereas the negative inotropic actions were very weak. The present study revealed that the cardiovascular properties of some of diltiazem's metabolites are qualitatively the same as those of diltiazem, but the activity of diltiazem is the most potent, and MA is less active than M1.
在麻醉犬和血液灌注的犬乳头肌中研究了地尔硫䓬及其一些代谢产物对心血管系统的影响。这些代谢产物包括N - 去甲基地尔硫䓬（MA），一种新发现的主要代谢产物；去乙酰基地尔硫䓬（M1）；去乙酰基MA（M2）；O - 去甲基M1（M4）；和O - 去甲基M2（M6）。在麻醉犬中，地尔硫䓬及其代谢产物可使冠状动脉血流量呈剂量依赖性增加，血压和心率降低，左心室dP/dtmax增加。地尔硫䓬及其代谢产物的冠状动脉舒张活性由高到低排序为：地尔硫䓬、M1、MA、M2、M4和M6。代谢产物对冠状动脉舒张的作用比对低血压的作用更具选择性，但其选择性低于地尔硫䓬。地尔硫䓬和MA引起的冠状动脉舒张和低血压持续时间比其相应的去乙酰基代谢产物更长。通过向血液灌注的犬乳头肌制备物中动脉内近距离给药，地尔硫䓬及其代谢产物也产生冠状动脉舒张作用，而负性肌力作用非常弱。本研究表明，地尔硫䓬的一些代谢产物的心血管特性在性质上与地尔硫䓬相同，但地尔硫䓬的活性最强，MA的活性低于M1。
