Antagonism of the positive dromotropic effect of isoproterenol by adenosine: role of nitric oxide, cGMP-dependent cAMP-phosphodiesterase and protein kinase G.
Antagonism of the positive dromotropic effect of isoproterenol by adenosine: role of nitric oxide, cGMP-dependent cAMP-phosphodiesterase and protein kinase G.
复制标题
DOI：
10.1006/jmcc.2000.1196
复制
发表时间：
2000-09
影响因子：
5
通讯作者：
A. Zima;A. Martynyuk;C. Seubert;T. Morey;C. Sumners;R. F. Cucchiara;D. Dennis
中科院分区：
文献类型：
--
作者：
A. Zima;A. Martynyuk;C. Seubert;T. Morey;C. Sumners;R. F. Cucchiara;D. Dennis
我们假设一氧化氮（NO）在介导腺苷对房室结传导的抗肾上腺素能效应中起重要作用。在测量房室结传导时间（心房-希氏束，A-H，间期）的豚鼠心脏中，NO合酶（NOS）抑制剂l-NMMA（100 μ m）可逆地抑制了腺苷对异丙肾上腺素（0.01 μ m）正性变导作用的80%（P=0.009，n=6）的抗肾上腺素能作用。在兔房室结肌细胞中进行的平行研究中，研究了NO介导腺苷对异丙肾上腺素诱导的A-H间期缩短的抑制作用的细胞内机制。腺苷（3 μ m）抑制异丙肾上腺素刺激的（0.1 μ m）I（Ca，L）（β-I（Ca，L））46+/-6%（P<0.001，n=17）。与离体心脏数据一致，NOS抑制剂1-NMMA（100 μ m）和L-NNA（500 μ m）分别将腺苷对β-I（Ca，L）的作用减弱69+/-8%（P<0.001，n=16）和69+/-7%（P<0.001，n=10）。NO刺激的鸟苷酸环化酶抑制剂LY 83538（40 μ m）使腺苷对β-I（Ca，L）的抑制作用降低97 ± 6%（P=0.004，n=15）。类似地，cAMP-磷酸二酯酶的非特异性抑制剂IBMX（50 μ m）使腺苷的抗肾上腺素能作用降低60%（P=0.02，n=6），而不可水解的cAMP类似物8-Br-cAMP（500 μ m）的细胞外应用阻止腺苷的这种作用。CPT-cGMP（300 μ m）激活cGMP依赖性蛋白激酶（PKG）可降低β-I（Ca，L），但其程度（16 ± 4%，P=0.025，n=12）显著小于腺苷引起的程度。NO介导腺苷对房室结传导的抗肾上腺素能作用，其机制主要涉及cGMP依赖性cAMP-磷酸二酯酶的激活和PKG的较小程度的激活。
We hypothesized that nitric oxide (NO) plays an important role in mediating the anti-adrenergic effect of adenosine on atrioventricular (AV) nodal conduction. In guinea-pig hearts instrumented for measurement of AV nodal conduction time (atrium-to-His bundle, A-H, interval), the NO synthase (NOS) inhibitor, l-NMMA (100 microm), reversibly inhibited 80% (P=0.009, n=6) of adenosine's anti-adrenergic action on the positive dromotropic effect of isoproterenol (0.01 microm). In parallel studies carried out in rabbit AV nodal myocytes, intracellular mechanisms whereby NO mediates the inhibitory effect of adenosine on isoproterenol-induced A-H interval shortening were studied. Adenosine (3 microm) inhibited isoproterenol-stimulated (0.1 microm) I(Ca,L)(beta -I(Ca,L)) by 46+/-6% (P<0.001, n=17). Consistent with isolated heart data, the NOS inhibitors, l -NMMA (100 microm) and L-NNA (500 microm) attenuated the effect of adenosine on beta -I(Ca,L)by 69+/-8% (P<0.001, n=16) and 69+/-7% (P<0.001, n=10), respectively. An inhibitor of NO-stimulated guanylyl cyclase LY83538 (40 microm) reduced the inhibitory effect of adenosine on beta -I(Ca,L)by 97+/-6% (P=0.004, n=15). Similarly, the non-specific inhibitor of cAMP-phosphodiesterases IBMX (50 microm) decreased the anti-adrenergic effect of adenosine by 60% (P=0.02, n=6), whereas the extracellular application of the non-hydrolyzeable cAMP analog 8-Br-cAMP (500 microm) prevented this action of adenosine. Activation of cGMP-dependent protein kinase (PKG) by CPT-cGMP (300 microm) diminished beta -I(Ca,L), but to a significantly smaller degree (16+/-4%, P=0.025, n=12) than that caused by adenosine. NO mediates the anti-adrenergic effect of adenosine on AV nodal conduction by a mechanism predominately involving activation of cGMP-dependent cAMP-phosphodiesterase and to a lesser extent activation of PKG.