通过增加大电导钙激活钾通道（KCa通道）的开放来增强去氧肾上腺素诱导的动脉粥样硬化小鼠主动脉的节律性活动：与钾通道（Kv通道）和一氧化氮的关系
Enhanced phenylephrine-induced rhythmic activity in the atherosclerotic mouse aorta via an increase in opening of KCa channels: relation to Kv channels and nitric oxide.
作者信息
Jiang J, Thorén P, Caligiuri G, Hansson G K, Pernow J
机构信息
Department of Medicine, Division of Cardiology, Karolinska Hospital, S-171 76 Stockholm, Sweden.
出版信息
Br J Pharmacol. 1999 Oct;128(3):637-46. doi: 10.1038/sj.bjp.0702855.
Abstract
- Mice lacking the apolipoprotein E and low density lipoprotein receptor genes (E degrees xLDLR degrees ) develop atherosclerosis. The aim of this study was to investigate changes in endothelium-dependent vasodilation and vasomotion in thoracic aortic rings of E degrees xLDLR degrees mice. 2. K+-induced contractions of the aorta from E degrees xLDLR degrees mice were stronger than those from control mice. The sensitivity of E degrees xLDLR degrees aorta to phenylephrine (PE) was decreased but the maximal contractions were increased. Acetylcholine-induced, but not sodium nitroprusside-induced, relaxations of E degrees xLDLR degrees aorta was decreased. 3. PE induced rhythmic activity in both E degrees xLDLR degrees and control aorta but the amplitude was larger in E degrees xLDLR degrees than in control mice. PE-induced rhythmic activity in both E degrees xLDLR degrees and control aorta was augmented by increase in extracellular Ca2+-concentration, but was abolished by removal of the endothelium, the nitric oxide (NO) synthase inhibitor N-nitro-L-arginine methyl ester, the guanylate cyclase inhibitor LY-83583, high K+ solution and ryanodine. 4. 4-Aminopyridine, a voltage-dependent potassium (KV) channel blocker, increased basal tension and induced rhythmic activity in E degrees xLDLR degrees aorta but not in control aorta. 5. The Ca2+-activated potassium (KCa) channel blockers tetraethylammonium and charybdotoxin abolished PE-induced rhythmic activity in E degrees xLDLR degrees aorta. 6. In conclusion, opening of Kv channels in E degrees xLDLR degrees mice aorta is reduced and it is susceptible to be depolarized resulting in Ca2+ entry. The vascular smooth muscle is then dependent on compensatory mechanisms to limit Ca2+-entry. Such mechanisms may be decreased sensitivity to vasoconstrictors, or increased opening of KCa channels by NO via a cyclic GMP-dependent mechanism.
摘要
- 缺乏载脂蛋白E和低密度脂蛋白受体基因的小鼠（E°xLDLR°）会发生动脉粥样硬化。本研究的目的是调查E°xLDLR°小鼠胸主动脉环中内皮依赖性血管舒张和血管运动的变化。2. E°xLDLR°小鼠主动脉对钾离子诱导的收缩比对照小鼠更强。E°xLDLR°主动脉对去氧肾上腺素（PE）的敏感性降低，但最大收缩增加。乙酰胆碱诱导的E°xLDLR°主动脉舒张减弱，而硝普钠诱导的舒张无变化。3. PE在E°xLDLR°和对照主动脉中均诱导节律性活动，但E°xLDLR°中的幅度大于对照小鼠。细胞外钙离子浓度增加会增强PE在E°xLDLR°和对照主动脉中诱导的节律性活动，但去除内皮、一氧化氮（NO）合酶抑制剂N-硝基-L-精氨酸甲酯、鸟苷酸环化酶抑制剂LY-83583、高钾溶液和ryanodine可消除该活动。4. 4-氨基吡啶，一种电压依赖性钾（KV）通道阻滞剂，增加了E°xLDLR°主动脉的基础张力并诱导节律性活动，但对照主动脉中无此现象。5. 钙离子激活的钾（KCa）通道阻滞剂四乙铵和蝎毒素消除了PE在E°xLDLR°主动脉中诱导的节律性活动。6. 总之，E°xLDLR°小鼠主动脉中KV通道的开放减少，且易发生去极化导致钙离子内流。然后血管平滑肌依赖于代偿机制来限制钙离子内流。这些机制可能是对血管收缩剂的敏感性降低，或NO通过环鸟苷酸依赖性机制增加KCa通道的开放。
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