The Effects of Extracellular pH on Vasopressin Inhibition of ATP-Sensitive K+ Channels in Vascular Smooth Muscle Cells
The Effects of Extracellular pH on Vasopressin Inhibition of ATP-Sensitive K+ Channels in Vascular Smooth Muscle Cells
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细胞外pH值对血管平滑肌细胞ATP敏感K通道加压素抑制的影响
DOI：
10.1213/01.ane.0000290334.91624.2f
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发表时间：
2007
影响因子：
5.7
通讯作者：
Y. Nakaya
中科院分区：
文献类型：
--
作者：
T. Kawano;Katsuya Tanaka;Hossein Nazari;S. Oshita;A. Takahashi;Y. Nakaya
背景：精氨酸加压素（AVP）抑制ATP敏感性钾（KATP）通道，可能有助于恢复血管舒张性休克患者的血管张力。在本研究中，我们研究了细胞外酸化是否改变AVP对血管KATP通道的抑制作用。方法：采用细胞贴附式膜片钳技术，研究细胞外pH（pHo）对大鼠主动脉平滑肌细胞AVP-KATP通道相互作用的影响。结果：AVP浓度依赖性地抑制细胞外酸化（pHo = 6.5）诱导的KATP通道活性，半数抑制浓度（IC 50）为16.8pM。此外，在轻度（pHo = 7.0）和重度（pHo = 6.5）细胞外酸化条件下，AVP浴涂可显著抑制吡那地尔诱导的KATP通道活性，IC 50值分别为266.7和21.4 pM，但在正常pH（pHo = 7.4）或酸化条件下（pHo = 9.0）未能显著抑制。增强AVP抑制血管KATP通道的细胞外酸化过程中被消除的预处理与OPC-21268，V1受体的特异性阻滞剂，但不是由V2阻滞剂，OPC-31260。AVP诱导的抑制作用也被蛋白激酶C抑制剂calphostin C预处理所抑制。结论：我们的研究结果表明，AVP抑制细胞外酸化诱导的血管KATP通道活性，并且细胞外酸化通过V1受体-蛋白激酶C细胞信号通路增强AVP对血管KATP通道的抑制作用。AVP在酸性条件下对血管KATP通道的有效抑制可能使其适用于血管舒张性休克的管理。
BACKGROUND:Arginine vasopressin (AVP) inhibits ATP-sensitive potassium (KATP) channels and may help to restore vascular tone in patients with vasodilatory shock. In the present study, we investigated whether extracellular acidification modifies the inhibition of vascular KATP channels by AVP. METHODS:We used a cell-attached patch-clamp configuration to investigate the effects of extracellular pH (pHo) on AVP-KATP channel interaction in rat aortic smooth muscle cells. RESULTS:Bath application of AVP significantly inhibited extracellular acidification (pHo = 6.5)-induced KATP channel activity in a concentration-dependent manner, with an half-maximal inhibitory concentration (IC50) value of 16.8 pM. Furthermore, bath application of AVP significantly inhibited pinacidil-induced KATP channel activity at mild (pHo = 7.0) and severe (pHo = 6.5) extracellular acidification, with IC50 values of 266.7 and 21.4 pM, respectively, but failed to significantly inhibit at normal pH (pHo = 7.4) or under alkalosis (pHo = 9.0). Augmentation of AVP inhibition of vascular KATP channels during extracellular acidification was eliminated by pretreatment with OPC-21268, a specific blocker of the V1 receptor, but not by a V2 blocker, OPC-31260. AVP-induced inhibition was also suppressed by pretreatment with a protein kinase C inhibitor, calphostin C. CONCLUSIONS:Our results suggest that AVP inhibits extracellular acidification-induced vascular KATP channel activity, and that the inhibitory effects of AVP on vascular KATP channels are enhanced by extracellular acidification via the V1 receptor-protein kinase C cell-signaling pathway. The potent inhibition of vascular KATP channels by AVP under acidic conditions may make it suitable for management of vasodilatory shock.