Alpha 1-adrenergic inhibition of the beta-adrenergically activated Cl- current in guinea pig ventricular myocytes.
Alpha 1-adrenergic inhibition of the beta-adrenergically activated Cl- current in guinea pig ventricular myocytes.
复制标题
α1-肾上腺素能抑制豚鼠心室肌细胞中β-肾上腺素能激活的 Cl-电流。
DOI：
10.1161/01.res.78.6.1090
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发表时间：
1996
影响因子：
20.1
通讯作者：
Harvey,RD
中科院分区：
文献类型：
--
作者：
Oleksa,LM;Hool,LC;Harvey,RD
α-肾上腺素能受体刺激调节许多不同心脏离子通道的活性，包括一个或多个不同Cl−电导的基础。采用全细胞膜片钳技术研究了α-肾上腺素能刺激对豚鼠心室肌细胞β-肾上腺素能调节的Cl−电流的影响。用甲氧胺（25 - 500 μmol/L）刺激α1-肾上腺素能受体或用佛波醇12，13-二丁酸酯（PDBu，100 nmol/L）直接激活内源性蛋白激酶C（PKC）均未诱发Cl−电流。甲氧胺可抑制30 nmol/L异丙肾上腺素激活的Cl−电流，其EC 50为6.7±2.6 μmol/L，α1-肾上腺素能受体拮抗剂哌唑嗪可阻断该效应。哌唑嗪还将去甲肾上腺素激活电流的EC 50从53±7.1 nmol/L降低至18±3.8 nmol/L，表明这种内源性神经递质通过β-肾上腺素能受体刺激激活Cl−电流的能力受到其激活α-肾上腺素能受体的内在能力的限制。甲氧胺不抑制由毛喉素直接激活腺苷酸环化酶或3-异丁基-1-甲基黄嘌呤抑制磷酸二酯酶活性诱发的Cl−电流，表明α-肾上腺素能刺激抑制腺苷酸环化酶激活上游点的β-肾上腺素能反应。甲氧胺也不抑制组胺激活的Cl−电流，表明α-肾上腺素能刺激特异性抑制β-肾上腺素能受体介导的反应。甲氧胺的抑制作用没有模仿PDBu，它持续存在的双吲哚马来酰亚胺，选择性PKC抑制剂。然而，甲氧胺对异丙肾上腺素激活的Cl−电流的抑制对百日咳毒素敏感。这些结果表明，α-肾上腺素能受体刺激抑制β-肾上腺素能激活的Cl−电流，证明了α-肾上腺素能受体可能调节心脏离子通道活性的新机制。
α-Adrenergic receptor stimulation regulates the activity of a number of different cardiac ion channels, including those underlying one or more distinct Cl−conductances. The whole-cell patch-clamp technique was used in the present study to investigate the effects of α-adrenergic stimulation on the β-adrenergically regulated Cl−current in guinea pig ventricular myocytes. Neither α1-adrenergic receptor stimulation with methoxamine (25 to 500 μmol/L) nor direct activation of endogenous protein kinase C (PKC) with phorbol 12,13-dibutyrate (PDBu, 100 nmol/L) evoked a Cl−current. On the contrary, the Cl−current activated by 30 nmol/L isoproterenol was inhibited by methoxamine, with an EC50of 6.7±2.6 μmol/L, and this response was blocked by prazosin, an α1-adrenergic receptor antagonist. Prazosin also decreased the EC50for current activation by norepinephrine from 53±7.1 to 18±3.8 nmol/L, demonstrating that the ability of this endogenous neurotransmitter to activate the Cl−current through β-adrenergic receptor stimulation is limited by its intrinsic ability to also activate α-adrenergic receptors. Methoxamine did not inhibit the Cl−current evoked by either direct activation of adenylate cyclase with forskolin or inhibition of phosphodiesterase activity with 3-isobutyl-1-methylxanthine, indicating that α-adrenergic stimulation inhibits β-adrenergic responses at a point upstream of adenylate cyclase activation. Methoxamine also did not inhibit the Cl−current activated by histamine, suggesting that α-adrenergic stimulation specifically inhibits β-adrenergic receptor–mediated responses. The inhibitory effect of methoxamine was not mimicked by PDBu, and it persisted in the presence of bisindolylmaleimide, a selective PKC inhibitor. However, methoxamine inhibition of the isoproterenol-activated Cl−current was sensitive to pertussis toxin. These results suggest that α-adrenergic receptor stimulation inhibits the β-adrenergically activated Cl−current, demonstrating a novel mechanism by which α-adrenergic receptors may regulate ion channel activity in the heart.