羟苯氨酮强心作用的生化机理研究

BIOCHEMCAL MECHANISM OF THE POSITIVE INOTROPIC EFFECT OF OXYPHENAMONE

目的：研究羟苯氨酮（ｏｘｙｐｈｅｎａｍｏｎｅ，Ｏｘｙ）强心作用的生化机理。方法：采用Ｎａ＋，Ｋ＋ＡＴＰ酶活性和ｃＡＭＰＰＤＥ活性、肌浆网Ｃａ２＋ＡＴＰ酶活性和ｃＡＭＰ含量以及心肌肌原纤维Ｃａ２＋，Ｍｇ２＋ＡＴＰ酶活性等测定法，研究Ｏｘｙ对它们的影响，并与ｍｉｌｒｉｎｏｎｅ和ＭＣＩ１５４作比较。结果：Ｏｘｙ对Ｎａ＋，Ｋ＋ＡＴＰ酶和ＰＤＥ无抑制作用，也不影响心肌ｃＡＭＰ含量，但能显著增强心肌肌原纤维对Ｃａ２＋的敏感性，高浓度时轻度抑制心肌肌浆网Ｃａ２＋ＡＴＰ酶活性。结论：Ｏｘｙ的强心作用方式不同于强心苷、β受体激动剂和ＰＤＥ抑制剂等强心药，可能为一种新的钙增敏性强心药物。

AIM: To investigated the biochemical mechanisms of the positive inotropic effect of oxyphenamone(Oxy). METHODS: The assays of Na +,K + ATPase activity, cAMP dependent phosphodiesterase(cAMP PDE) activity and Ca 2+ ATPase activity in sarcoplasmic reticulum(SR) isolated from cardiac muscle, cAMP level in cardiac muscle and the cardiac myofibrillar Ca 2+ ,Mg 2+ ATPase activity were adopted and compared with those of strophanthin G(Str) and milrinone(Mil). RESULTS: Oxy at its effective concentration, showed no remarkable inhibition on Na +,K + ATPase and cAMP dependent phosphodiesterase (cAMP PDE) activities, while in parallel experiments Na +,K + ATPase and cAMP PDE activities were significantly inhibited by Str and Mil. Their IC 50 values were found to be 2 0 μmol·L -1 , and 85 μmol·L -1 , respectively. Oxy did not affect the cAMP level in cardiac muscle of guinea pig. However, Mil at 30 μmol·L -1 in control experiments increased the cAMP level by 73 6%. These results suggest that the mechanism of the positive inotropic effect of Oxy differs from that of glycosides, PDE inhibitors and β adrenergic agonists. Oxy at 100 μmol·L -1 inhibited Ca 2+ ATPase activity significantly in cardiac sarcoplasmic reticulum. Its IC 50 value was 200 μmol·L -1 . The result suggests that Oxy at high concentration exerts inhibitory effect on the Ca 2+ uptake by SR. This mechanism may be partly responsible for the positive inotropic effect of Oxy. Oxy at 50 μmol·L -1 shifted the relationship curve between pCa 2+ and myofibrillar Ca 2+ ,Mg 2+ ATPase activity to the left without affecting the maximum enzyme activity. When pCa 7, Oxy increased the myofibrillar Ca 2+ ,Mg 2+ ATPase activity in a concentration dependent manner and EC 50 value was about 10 μmol·L -1 . MCI 154 at 100 μmol·L -1 and some new derivatives of Oxy with positive inotropic effect enhanced the Ca 2+ sensitivity. Mil at 100 μmol·L -1 and some new derivatives of Oxy with no positive inotropic effect showed no effect at all. Solaro and Kitada found a positive correlation between the increase of myofibrillar Ca 2+ ,Mg 2+ ATPase activity and the enhancement of Ca 2+ sensitivity of the contractile protein system. CONCLUSION: These results demonstrate that the biochemical mechanism of the positive inotropic effect of Oxy is different from these of the cardiac glycosides, PDE inhibitors and β adrenergic agonists, therefore, it may be a novel cardiotonic agent, a calcium sensitizer.