Studies on the mechanism of action of the bipyridine milrinone on the heart

Summary Milrinone is a positive inotropic and vasodilator agent when tested in experimental animals and in human heart-failure patients. It is generally believed that milrinone acts by inhibiting phosphodiesterase IV, thus increasing cyclic AMP, [Ca^{+ +}]_i and cardiac contractile force and relaxation. Maximal force produced by milrinone is greater when single-dose response curves are compared to cumulative dose-response curves. In vitro, milrinone produces a tachyphylaxis, the extent of which is both dose- and time-dependent. Recovery of tachyphylaxis is both dose- and time-dependent and is not influenced by inhibitors of protein or RNA synthesis. There is a specific cross-tachyphylaxis between milrinone and amrinone, theophylline, papaverine, and Bay K8644. This tachyphylaxis may explain the low maximal contractile response of the cumulative dose-response observed in isolated tissues. Milrinone increased cyclic AMP in dog and guinea pig cardiac muscle. As previously shown by Endoh et al. [17], milrinone in low doses produced a biphasic effect on cyclic AMP. The early increase (first 60–70 s) in cyclic AMP shows a good correlation with contractile force changes. If cyclic AMP is determined at maximal contractile force this correlation was poor. Here we also present instances where the increase in cyclic AMP after milrinone (determined at maximal effect) does not correlate with the contractile response. The cross-tachyphylaxis of milrinone with Bay K8644 suggests that milrinone has an action on the sarcolemmal Ca⁺⁺ channels. Bay K8644 suppresses the positive inotropic effect of catecholamines by 50%, but not the cyclic AMP response. The inotropic effect of milrinone, in contrast to norepinephrine is highly sensitive to [Ca⁺⁺]₀, stimulation rate, and [K⁺]₀. In this respect milrinone behaves more like Bay K8644. We postulate that the main inotropic action of milrinone is due to a sarcolemmal effect. The early cyclic AMP production described could be in the sarcolemmal compartment and this may explain some of the similarities of milrinone’s actions with those of Bay K8644. The tachyphylaxis observed with the inotropic effect of milrinone does not extend to the decreases in relaxation time. This and other findings to be discussed suggest that the positive inotropic and reduction in relaxation time by milrinone depend on different mechanisms, possibly through differential compartmentalization of cyclic AMP.     

一氧化氮的脑血管作用研究进展

一氧化氮(NO)是一种相对稳定的通过细胞膜扩散的气体自由基,具有抑制血小板聚集、抑制血管平滑肌细胞(VSMC)、抑制血小板激活因子(PAF)诱导中性粒细胞内皮细胞相互作用、调节血管张力、稳定循环容积、介导细胞免疫和细胞毒等作用[1,2],在脑血管疾病如动脉粥样硬化(AS)、蛛网膜下腔出血(SAH)后脑血管痉挛(CVS)、缺血性脑损伤中具有重要意义。本文试图就其在脑血管方面的研究进展作一综述。1NO的来源及基本生物学特征NO的化合物有两类,一类为能释放NO或具有氧化还原作用的同系物,称外源性NO,它主要来自NO供体,如硝普钠(SNP)在体内…     

锌对心肌保护作用机理的探讨

应用电镜、电子示踪技术和立体计量测试法，从形态学上观察异丙基肾上腺素对心肌膜系统的影响及锌的保护作用，同时应用标准玻璃微电极技术和微机实时分析方法，研究异丙基肾上腺素致心肌损伤及锌对心肌保护作用的机理。实验结果表明：异丙基肾上腺素可引起心肌细胞膜系统损伤，此时心肌细胞的去极化和复极化过程均发生改变；经锌前处理后，心肌损伤程度明显减轻，心肌细胞的复极化过程得到明显改善。锌对心肌的保护作用，主要是通过阻断心肌细胞膜慢通道、减少平台期钙离子内流、防止细胞内钙超载来实现。