Sato S, Sato N, Kudej R K, Uechi M, Asai K, Shen Y T, Ishikawa Y, Vatner S F, Vatner D E
Department of Medicine, Harvard Medical School, Brigham & Women's Hospital, Boston, MA 02115, USA.
J Mol Cell Cardiol. 1997 May;29(5):1387-400. doi: 10.1006/jmcc.1997.0377.
The primary goal of this study was to compare the effects of isoproterenol which stimulates beta-adrenergic receptors and forskolin, and NKH 477, a water soluble derivative of forskolin, which stimulate adenylyl cyclase in stunned myocardium of conscious pigs, previously instrumented for measurements of left ventricular pressure and dP/dt, arterial pressure, and wall thickening. Ten min of coronary artery occlusion induced transmural reductions in blood flow (radioactive microspheres) in subepicardium (-98 +/- 2%) and subendocardium (-99 +/- 1%). Wall thickening (piezoelectric crystals) fell from 2.50 +/- 0.26 mm to -0.26 +/- 0.26 mm and remained depressed at 1.37 +/- 0.19 mm after 20-30 min coronary artery reperfusion, reflecting myocardial stunning. At that time, isoproterenol (0.2 microgram/kg) increased wall thickening in stunned myocardium (+1.40 +/- 0.16 mm, P < 0.05) more than in control (+0.71 +/- 0.22 mm), while forskolin elicited the opposite effects. NKH 477 (30 micrograms/kg), which does not penetrate the blood-brain barrier, increased systolic wall thickening similarly before (+0.95 +/- 0.25 mm) and during (+1.01 +/- 0.24 mm) myocardial stunning. The reflex inotropic responses to inferior vena caval occlusion on wall thickening were diminished, P < 0.05, in the stunned myocardium (+0.53 +/- 0.05 mm) compared with control (+0.95 +/- 0.07 mm). beta-adrenergic receptor density, which was quantitated with 125I-cyanopindolol binding, was increased transmurally in stunned myocardium compared with non-ischemic myocardium (subepicardium: +23 +/- 5%, subendocardium: +34 +/- 13%, P < 0.05). Basal and forskolin-stimulated adenylyl cyclase activities were decreased slightly, but significantly, in the stunned subendocardium but not in the subepicardium, while isoproterenol stimulation of adenylyl cyclase activity showed no differences. In summary, paradoxical responses to beta-adrenergic receptor stimulation were observed in stunned myocardium, with pharmacological stimulation with isoproterenol evoking enhanced responses, and neural stimulation with inferior vena caval occlusion eliciting depressed responses. The diminished responses to forskolin in vivo, in stunned myocardium were out of proportion to the biochemical measurements, and may be attributed to neurally mediated cardiac effects of forskolin, since the responses to direct stimulation of adenylyl cyclase by NKH 477 were preserved.
本研究的主要目的是比较刺激β-肾上腺素能受体的异丙肾上腺素、福斯高林以及福斯高林的水溶性衍生物NKH 477对清醒猪顿抑心肌的影响，这些猪此前已植入仪器用于测量左心室压力和dp/dt、动脉压及室壁增厚。冠状动脉闭塞10分钟导致心外膜下（-98±2%）和心内膜下（-99±1%）血流（放射性微球）跨壁性减少。室壁增厚（压电晶体）从2.50±0.26毫米降至-0.26±0.26毫米，并在冠状动脉再灌注20 - 30分钟后仍维持在1.37±0.19毫米，反映出心肌顿抑。此时，异丙肾上腺素（0.2微克/千克）使顿抑心肌的室壁增厚增加（+1.40±0.16毫米，P<0.05），幅度大于对照组（+0.71±0.22毫米），而福斯高林则产生相反作用。不透血脑屏障的NKH 477（30微克/千克）在心肌顿抑前（+0.95±0.25毫米）和期间（+1.01±0.24毫米）使收缩期室壁增厚增加情况相似。与对照组（+0.95±0.07毫米）相比，顿抑心肌对下腔静脉闭塞的变力反射反应减弱（P<0.05）（+0.53±0.05毫米）。用125I-氰基吲哚洛尔结合法测定的β-肾上腺素能受体密度，与非缺血心肌相比，顿抑心肌跨壁性增加（心外膜下：+23±5%，心内膜下：+34±13%，P<0.05）。基础及福斯高林刺激的腺苷酸环化酶活性在心内膜下顿抑心肌中略有但显著降低，而在心外膜下则无变化，而异丙肾上腺素刺激的腺苷酸环化酶活性无差异。总之，在顿抑心肌中观察到对β-肾上腺素能受体刺激的矛盾反应，异丙肾上腺素的药理刺激引起增强反应，而下腔静脉闭塞的神经刺激引起减弱反应。顿抑心肌中体内对福斯高林的反应减弱与生化测量结果不成比例，可能归因于福斯高林的神经介导心脏效应，因为对NKH 477直接刺激腺苷酸环化酶的反应得以保留。
