豚鼠离体气管中维拉帕米对Ca2+的拮抗作用及其他作用
Antagonism of Ca2+ and other actions of verapamil in guinea-pig isolated trachealis.
作者信息
Foster R W, Okpalugo B I, Small R C
出版信息
Br J Pharmacol. 1984 Mar;81(3):499-507. doi: 10.1111/j.1476-5381.1984.tb10103.x.
In trachealis bathed by a K+-rich, Ca2+-free physiological salt solution, calcium chloride (CaCl2) at 0.01 to 10 mmol l-1 evoked concentration-dependent spasm. Verapamil (0.1 to 10 mumol l-1) was an effective antagonist of CaCl2. Spasm evoked by acetylcholine, histamine, potassium chloride (KCl) and tetraethylammonium (TEA) was studied in trachealis bathed by normal Krebs solution. Verapamil (0.1 to 10 mumol l-1) markedly suppressed spasm evoked by KCl and TEA. In contrast the actions of acetylcholine and histamine were much less affected by verapamil. Spasm evoked by prostaglandin E2 was studied in trachealis bathed by Krebs solution containing indomethacin (2.8 mumol l-1). Verapamil (0.1 to 10 mumol l-1) had little or no effect against prostaglandin E2-induced spasm. Verapamil (0.1 to 10 mumol l-1) had relatively little effect on the tone of trachealis bathed by normal Krebs solution. In contrast bathing in Krebs solution lacking CaCl2 caused almost complete tone loss. Extracellular electrophysiological recording showed that verapamil (10 mumol l-1) suppressed not only TEA-evoked spasm but also TEA-evoked slow waves and spike potentials. Verapamil also abolished the transient period of slow wave activity associated with the spasm evoked by KCl. Intracellular electrophysiological recording showed that TEA-induced spike activity was resistant to tetrodotoxin (3 mumol l-1). However, verapamil (10 mumol l-1) abolished the tetrodotoxin-resistant spikes without increasing the resting membrane potential. It is concluded that verapamil suppresses TEA- or KCl-induced spasm, slow waves or spikes by inhibition of Ca2+ influx. Spasm evoked by acetylcholine, histamine and prostaglandin E2 depends on mechanisms for increasing the cytoplasmic concentration of free Ca2+ which are resistant to verapamil. The failure of verapamil markedly to depress tissue tone is consistent with the proposal that tone results from the activity of endogenous prostaglandins.
在富含钾离子、不含钙离子的生理盐溶液中浸泡的气管平滑肌中，0.01至10 mmol/L的氯化钙（CaCl₂）可引起浓度依赖性痉挛。维拉帕米（0.1至10 μmol/L）是氯化钙的有效拮抗剂。在正常 Krebs 溶液浸泡的气管平滑肌中，研究了乙酰胆碱、组胺、氯化钾（KCl）和四乙铵（TEA）引起的痉挛。维拉帕米（0.1至10 μmol/L）显著抑制了KCl和TEA引起的痉挛。相比之下，乙酰胆碱和组胺的作用受维拉帕米的影响要小得多。在含有吲哚美辛（2.8 μmol/L）的 Krebs 溶液浸泡的气管平滑肌中，研究了前列腺素E₂引起的痉挛。维拉帕米（0.1至10 μmol/L）对前列腺素E₂诱导的痉挛几乎没有或没有影响。维拉帕米（0.1至10 μmol/L）对正常 Krebs 溶液浸泡的气管平滑肌张力影响相对较小。相比之下，浸泡在不含氯化钙的Krebs溶液中几乎导致完全的张力丧失。细胞外电生理记录显示，维拉帕米（10 μmol/L）不仅抑制了TEA引起的痉挛，还抑制了TEA引起的慢波和动作电位。维拉帕米还消除了与KCl引起的痉挛相关的慢波活动的短暂时期。细胞内电生理记录显示，TEA诱导的动作电位对河豚毒素（3 μmol/L）有抗性。然而，维拉帕米（10 μmol/L）消除了对河豚毒素有抗性的动作电位，而没有增加静息膜电位。结论是，维拉帕米通过抑制钙离子内流来抑制TEA或KCl诱导的痉挛、慢波或动作电位。乙酰胆碱、组胺和前列腺素E₂引起的痉挛取决于增加细胞质游离钙离子浓度的机制，这些机制对维拉帕米有抗性。维拉帕米未能显著降低组织张力与内源性前列腺素的活性导致张力的观点一致。
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