Oe K, Sperlágh B, Sántha E, Matkó I, Nagashima H, Foldes F F, Vizi E S
Department of Anesthesiology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY 10467, USA.
Cardiovasc Res. 1999 Jul;43(1):125-34. doi: 10.1016/s0008-6363(99)00052-8.
The aim of this study was to show, whether ATP sensitive K+ channels (KATP channels), are involved in the modulation of norepinephrine (NE) release from the sympathetic nerves innervating the guinea-pig and human right atrium.
The resting and stimulation-evoked release of [3H]norepinephrine ([3H]NE) was measured from the isolated guinea-pig and human right atrium and the effect of activators and inhibitors of ATP sensitive K+ channels was studied.
Cromakalim (30-300 microM), a KATP channel-agonist decreased concentration-dependently the stimulation-evoked release of NE from the guinea-pig atrium, an effect, antagonized by glibenclamide, a KATP channel-antagonist (30 microM). Diazoxide (30-300 microM), another activator of the KATP channels reduced the resting release of NE, and also attenuated the evoked release at a single concentration (100 microM), and this latter action was also counteracted by glibenclamide (30 microM). Pinacidil, increased dose-dependently the resting and stimulation-evoked release of NE in a glibenclamide-sensitive manner and reversed the inhibitory effect of cromakalim (100 microM), suggesting that it acts as an antagonist. Glibenclamide (30-300 microM), by itself enhanced the stimulation-evoked release of [3H]NE, and also increased the resting release of NE. On the other hand, 5-hydroxydecanoate, an ischemia-selective inhibitor of cardiac KATP channels did not change NE release. Adenosine, (30-300 microM), an A1-receptor agonist, clonidine (3 microM), an alpha 2-adrenoceptor agonist and oxotremorine, a muscarinic receptor agonist (30 microM) all reduced the evoked release of [3H]NE, but these effects were not modified by glibenclamide (300 microM), indicating that neuronal adenosine (A1), adrenergic (alpha 2) and muscarinic (M3) receptors do not act on KATP channels. In the human right atrium, cromakalim, and diazoxide did not affect significantly the release of [3H]NE. However, glibenclamide (30-300 microM) and pinacidil (30-300 microM) enhanced dose-dependently the evoked-release of NE, and pinacidil also augmented the resting release.
Our results indicate that sympathetic nerve endings of the human and guinea-pig atrium are endowed with ATP-sensitive K+ channels. These channels responded to agonists and antagonists under the experimental conditions applied and they could modulate the release of NE thereby affecting the autonomic control of cardiac function under various physiological and pathophysiological conditions.
本研究旨在表明ATP敏感性钾通道（KATP通道）是否参与调节支配豚鼠和人类右心房的交感神经去甲肾上腺素（NE）释放。
测量分离的豚鼠和人类右心房中[3H]去甲肾上腺素（[3H]NE）的静息释放和刺激诱发释放，并研究ATP敏感性钾通道激活剂和抑制剂的作用。
KATP通道激动剂克罗卡林（30 - 300微摩尔）浓度依赖性地降低豚鼠心房刺激诱发的NE释放，该作用被KATP通道拮抗剂格列本脲（30微摩尔）拮抗。另一种KATP通道激活剂二氮嗪（30 - 300微摩尔）降低NE的静息释放，并在单一浓度（100微摩尔）时减弱诱发释放，后一种作用也被格列本脲（30微摩尔）抵消。匹那地尔以格列本脲敏感的方式剂量依赖性地增加NE的静息释放和刺激诱发释放，并逆转克罗卡林（100微摩尔）的抑制作用，表明它起拮抗剂作用。格列本脲（30 - 300微摩尔）本身增强刺激诱发的[3H]NE释放，也增加NE的静息释放。另一方面，心脏KATP通道的缺血选择性抑制剂5 - 羟基癸酸不改变NE释放。A1受体激动剂腺苷（30 - 300微摩尔）、α2肾上腺素能受体激动剂可乐定（3微摩尔）和毒蕈碱受体激动剂氧化震颤素（30微摩尔）均降低刺激诱发的[3H]NE释放，但这些作用未被格列本脲（300微摩尔）改变，表明神经元腺苷（A1）受体、肾上腺素能（α2）受体和毒蕈碱（M3）受体不作用于KATP通道。在人类右心房中，克罗卡林和二氮嗪对[3H]NE释放无明显影响。然而，格列本脲（30 - 300微摩尔）和匹那地尔（30 - 300微摩尔）剂量依赖性地增强NE的诱发释放，匹那地尔也增加静息释放。
我们的结果表明，人类和豚鼠心房的交感神经末梢具有ATP敏感性钾通道。在所用实验条件下，这些通道对激动剂和拮抗剂有反应，并且它们可以调节NE释放，从而在各种生理和病理生理条件下影响心脏功能的自主控制。
