新哒嗪酮类化合物Y909的强心作用及其作用机制研究

Studies of the positive inotropic effects of Y 909, a new pyridazinones derivative and its mechanism

目的观察哒嗪酮类新衍生物Ｙ９０９的强心作用并研究其药理作用机制。方法采用豚鼠离体左右心房和心脏制备灌注给药及心肌磷酸二酯酶（ＰＤＥ）活性测定法。结果Ｙ９０９显著增强豚鼠离体左心房和心脏的收缩力且呈剂量依赖性，其作用强度略低于米利农（Ｍｉｌ），略高于咪苯甲嗪酮（ＣＩ９３０），但均无统计学意义；不显著加快离体右心房和心脏的收缩频率并有提高离体心脏冠脉流量的作用；其正性肌力作用不被肾上腺素受体拮抗剂所阻断；对心肌ＰＤＥ活性的抑制作用显著低于Ｍｉｌ，且与其较强的正性肌力作用不平行。结论Ｙ９０９有较强的强心作用且不增加心率，作用强度接近ＣＩ９３０和Ｍｉｌ，作用机制可能同于ＣＩ９３０而不同于Ｍｉｌ，值得进一步研究。

AIM To study the effects and mechanism of a new pyridazinones derivative, Y909. METHODS The isolated guinea pig cardiac muscles and Langendorffs preparations perfusion and PDE activity assay were applied. RESULTS Y 909(1￣100 μmol·L-1) produced a concentrationdependent increase in myocardial contractility of left atria but no significant change in beat rate of right atria isolated from guinea pig. The positive inotropic effect of Y 909 could not be blocked by adrenergic receptor antagonists. In control experiments, Mil at same range of concentration produced significant chronotropic effect besides its positive inotropic one in the same cardiac preparations. Y 909 at 10 μmol·L-1 increased cardiac contractility, coronary flow and heart rate in guinea pig Langendorffs preparations by 29%, 32% and 4%, respectively. The inhibitory effect of Y 909 on intracellular cAMPPDE activity was weaker than that of Mil and was not parallel with its more potent positive inotropic effect. CONCLUSION These results suggest that Y 909 has a markedly positive inotropic effect but has no significant chronotropic effect. The pharmacological mechanism of Y 909 may be similar to that of CI 930 but different from that of Mil and Y 909 is worth to further study for developing into a new kind of cardiotonic agent.