Phorbol ester effects on coupling mechanisms during cholinergic contraction of swine tracheal smooth muscle.
Phorbol ester effects on coupling mechanisms during cholinergic contraction of swine tracheal smooth muscle.
复制标题
佛波酯对猪气管平滑肌胆碱能收缩期间耦合机制的影响。
DOI：
10.1113/jphysiol.1989.sp017602
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发表时间：
1989
期刊：
影响因子：
--
通讯作者：
Coburn,RF
中科院分区：
文献类型：
--
作者：
Baba,K;Baron,CB;Coburn,RF
1.我们研究了佛波醇酯，佛波醇12，13-二丁酸酯（PDB）对卡巴胆碱诱导的猪气管肌肉收缩的影响。PDB（1 - 10 μ M）显著抑制5.5 μ M卡巴胆碱诱导的磷酸肌醇合成，使我们能够研究（a）膜电位独立的力分量是否在卡巴胆碱刺激的气管肌肉中产生的（药物力学偶联组分）依赖于肌醇磷脂代谢的活化，和（B）卡巴胆碱诱导的膜去极化和收缩是否在肌肉中改变，其中肌醇磷脂代谢产生第二信使信号蛋白激酶C（PKC）的活化已经达到最大。2. PDB（10 μ M）的应用程序未受刺激的气管肌肉导致一个小的缓慢发展的收缩与10 mV膜去极化。PDB诱发的收缩不受Na+或Cl-离子取代或阿米洛利给药的影响，所有这些都抑制PDB诱发的膜去极化。3.在细胞外[K+]为40 - 70 mM的范围内，PDB预处理对[K+]-力或[K+]-膜电位关系没有影响。在40 mM-K+期间，PDB预处理对细胞外[Ca 2 +]-力关系没有影响。4.在有机Ca 2+拮抗剂药物的作用或浴液[Ca 2 +]减少方面，PDB处理的卡巴胆碱诱发的肌肉收缩与K+收缩相似。在低浓度卡巴胆碱，维拉帕米加PDB完全抑制力的发展。对于5.5 μ M卡巴胆碱，维拉帕米或硝苯地平加PDB抑制了超过90%的总卡巴胆碱诱导力。5.对照卡巴胆碱诱发的收缩与20 - 25 mV膜去极化相关。在PDB处理的肌肉中，卡巴胆碱诱发的收缩发生钝化去极化，即约5 mV。6. PDB处理抑制了在维持卡巴胆碱诱发收缩期间由药物力学偶联机制控制的力。依赖于药物力学偶联机制的卡巴胆碱诱导力可以通过肌醇磷脂代谢产生的信号来解释。7.在PDB处理的肌肉中，卡巴胆碱期间增强了机电耦合机制。这似乎主要是由于表面膜电压门控Ca 2+通道的性质或数量的变化。8.数据表明，PKC介导的磷酸化在控制肌醇磷脂代谢活化介导的药物力学偶联机制和表面膜离子通道作用介导的机电偶联机制方面具有重要作用。
1. We studied effects of the phorbol ester, phorbol 12,13‐dibutyrate (PDB), on carbachol‐induced contractions of swine trachealis muscle. PDB (1‐10 microM) markedly inhibited 5.5 microM‐carbachol‐induced inositol phosphate synthesis allowing us to study (a) whether the membrane potential‐independent component of force (pharmacomechanical coupling component) developed in carbachol‐stimulated trachealis muscle is dependent on activation of inositol phospholipid metabolism, and (b) whether carbachol‐induced membrane depolarization and contraction are altered in muscle where second messenger signals generated by inositol phospholipid metabolism are inhibited and activation of protein kinase C (PKC) is already maximal. 2. Application of PDB (10 microM) to unstimulated trachealis muscle resulted in a small slowly developing contraction associated with a 10 m V membrane depolarization. PDB‐evoked contractions were not influenced by Na+ or Cl‐ ion substitutions, or administration of amiloride, all of which inhibited PDB‐evoked membrane depolarization. 3. Pre‐treatment with PDB had no effect on [K+]‐force, or [K+]‐membrane potential relationships, over a range of extracellular [K+] from 40 to 70 mM. Pretreatment with PDB had no effect on extracellular [Ca2+]‐force relationships during 40 mM‐K+. 4. Carbachol‐evoked contractions of muscle treated with PDB became similar to K+ contractions in regard to effects of organic Ca2+ antagonist drugs or decrease in bathing solution [Ca2+]. At low carbachol concentrations, verapamil plus PDB completely inhibited force development. With 5.5 microM‐carbachol, over 90% of total carbachol‐induced force was inhibited by verapamil, or nifedipine, plus PDB. 5. Control carbachol‐evoked contractions were associated with 20‐25 mV membrane depolarizations. In PDB‐treated muscle, carbachol‐evoked contraction occurred with a blunted depolarization, i.e. about 5 mV. 6. Force controlled by pharmacomechanical coupling mechanisms operating during maintained carbachol‐evoked contractions was inhibited by treatment with PDB. Carbachol‐induced force dependent on pharmacomechanical coupling mechanisms could be explained by signals generated via inositol phospholipid metabolism. 7. Electromechanical coupling mechanisms were augmented during carbachol in PDB‐treated muscle. This appears to be due primarily to changes in the properties or number of surface membrane voltage‐gated Ca2+ channels. 8. Data suggest an important role of PKC‐mediated phosphorylations for control of both pharmacomechanical coupling mechanisms mediated by activation of inositol phospholipid metabolism and electromechanical coupling mechanisms mediated by effects on operation of surface membrane ion channels.