Frangakis C J, Lanni C, Lasher K P, Bentley R G, Farah A E
Sterling-Winthrop Research Institute, Rensselaer, New York.
J Cardiovasc Pharmacol. 1989 Jun;13(6):915-24. doi: 10.1097/00005344-198906000-00015.
Milrinone (Corotrope) increased cyclic AMP levels in dog guinea pig and rat cardiac muscle. A correlation between the increase in contractile force and cyclic AMP levels in dog ventricular trabeculae was obtained when measurements were made 60-70 s after the addition of milrinone. When cyclic AMP levels were determined at the time of maximal contractile response, only concentrations of milrinone 200-300 times the inotropic dose had any effects in elevating cyclic nucleotide levels. In dog Purkinje tissue and rat cardiac muscle, milrinone had minimal or no effects on contractile force but increased cardiac cyclic AMP levels. Sequential doses of milrinone to perfused guinea pig hearts resulted in severe tachyphylaxis to the inotropic activity of milrinone. However, under these conditions, milrinone was found to elevate cardiac cyclic AMP upon each administration. Furthermore, in this preparation, cross-tachyphylaxis between Bay K 8644 and milrinone was demonstrated. The mechanism of action of Bay K 8644, which acts on sarcolemmal Ca2+, is not mediated by increases in cyclic AMP. Following development of tachyphylaxis to Bay K 8644, in the guinea pig hearts, addition of milrinone results in no increases in contractile force but a significant increase in cyclic AMP levels. In all of the instances of tachyphylaxis, isoproterenol increased both contractile force and cyclic AMP. The data are discussed and we put forth the hypothesis that increased cardiac force due to milrinone is in part due to a direct or indirect action on sarcolemmal Ca2+ channels.
米力农（科罗特罗普）可提高犬、豚鼠和大鼠心肌中的环磷酸腺苷（cAMP）水平。在犬心室小梁中加入米力农60 - 70秒后进行测量时，发现收缩力的增加与cAMP水平之间存在相关性。当在最大收缩反应时测定cAMP水平时，只有正性肌力剂量200 - 300倍的米力农浓度才对提高环核苷酸水平有任何作用。在犬浦肯野组织和大鼠心肌中，米力农对收缩力的影响极小或无影响，但可增加心脏cAMP水平。对灌注的豚鼠心脏连续给予米力农会导致对米力农的正性肌力活性产生严重快速耐受性。然而，在这些条件下，每次给予米力农时都发现其可提高心脏cAMP水平。此外，在该制剂中，证明了Bay K 8644与米力农之间存在交叉快速耐受性。作用于肌膜Ca2 +的Bay K 8644的作用机制不是由cAMP增加介导的。在豚鼠心脏中对Bay K 8644产生快速耐受性后，加入米力农不会导致收缩力增加，但会使cAMP水平显著升高。在所有快速耐受性的情况下，异丙肾上腺素均可增加收缩力和cAMP。对这些数据进行了讨论，并提出了一个假设，即米力农导致的心脏力量增加部分归因于对肌膜Ca2 +通道的直接或间接作用。
