Almond S C, Paterson D J
University Laboratory of Physiology, Parks Road, Oxford, OX1 3PT, UK.
J Mol Cell Cardiol. 2000 Nov;32(11):2065-73. doi: 10.1006/jmcc.2000.1237.
Sulphonylurea-sensitive K(+)channels (K(ATP)) have been implicated in the release of acetylcholine (ACh) from the vagus nerve in the heart. Our aim was to establish the functional significance of this and to test whether this modulation could interact with stimulation of the NO-cGMP pathway that facilitates the decrease in heart rate (HR) in response to vagal nerve stimulation (VNS). We studied the effect of activation (diazoxide, 100 microM) and inhibition (glibenclamide 30 microM or tolbutamide 5 microM) of K(ATP)channels, and activation of the NO-cGMP pathway with the NO donor, sodium nitroprusside (SNP, 20 microM) or the cGMP analogue, 8-Br-cGMP (0.5 m M) on the HR response to VNS in the isolated guinea pig (Cavia porcellus) double atrial/right vagus preparation (n=40). Tolbutamide increased the bradycardia in response to vagal stimulation at 3 and 5 Hz (P<0.05); effects that were reversed by diazoxide. Glibenclamide also significantly increased the HR response to VNS at 1 and 3 Hz (P<0.05). Diazoxide alone significantly attenuated the HR response to VNS at 5 Hz (P<0.05). Neither glibenclamide nor diazoxide affected the HR response to carbamylcholine (CCh, 50-200 n M). In the presence of a maximal dose of tolbutamide, SNP or 8-Br-cGMP further increased the HR response to VNS at 5 Hz (P<0.05). These results are consistent with the hypothesis that inhibition of sulphonylurea-sensitive channels can increase the HR response to VNS by a pre-synaptic mechanism, and that this modulation may be independent of activation of the NO-cGMP pathway.
磺酰脲类敏感钾通道（K(ATP)）与心脏迷走神经释放乙酰胆碱（ACh）有关。我们的目的是确定其功能意义，并测试这种调节是否能与促进心率（HR）降低以响应迷走神经刺激（VNS）的一氧化氮-环鸟苷酸（NO-cGMP）途径的刺激相互作用。我们研究了K(ATP)通道激活剂（二氮嗪，100微摩尔）和抑制剂（格列本脲30微摩尔或甲苯磺丁脲5微摩尔），以及用NO供体硝普钠（SNP，20微摩尔）或cGMP类似物8-溴-cGMP（0.5毫摩尔）激活NO-cGMP途径对离体豚鼠（豚鼠）双心房/右迷走神经标本（n = 40）中VNS引起的HR反应的影响。甲苯磺丁脲在3和5赫兹时增加了对迷走神经刺激的心动过缓（P<0.05）；这些作用被二氮嗪逆转。格列本脲在1和3赫兹时也显著增加了对VNS的HR反应（P<0.05）。单独使用二氮嗪在5赫兹时显著减弱了对VNS的HR反应（P<0.05）。格列本脲和二氮嗪均未影响对氨甲酰胆碱（CCh，50 - 200纳摩尔）的HR反应。在最大剂量甲苯磺丁脲存在的情况下，SNP或8-溴-cGMP在5赫兹时进一步增加了对VNS的HR反应（P<0.05）。这些结果与以下假设一致：抑制磺酰脲类敏感通道可通过突触前机制增加对VNS的HR反应，并且这种调节可能独立于NO-cGMP途径的激活。
