硝酸甘油引起的冠状动脉血管舒张：质膜钙激活钾通道和细胞内钙库的参与

Coronary vasorelaxation by nitroglycerin: involvement of plasmalemmal calcium-activated K+ channels and intracellular Ca++ stores.

作者信息

Khan S A, Higdon N R, Meisheri K D

机构信息

Pharmacia & Upjohn, Inc., Kalamazoo, Michigan, USA.

出版信息

J Pharmacol Exp Ther. 1998 Mar;284(3):838-46.

PMID:9495841

Abstract

This study investigated nitroglygerin (NTG) relaxations in isolated dog coronary artery in comparison with other vascular preparations. Under maximal PNU-46619 precontraction, the coronary artery was significantly more sensitive to NTG than mesenteric artery, mesenteric vein and saphenous vein. In the coronary artery, NTG (1-100 nM) produced relaxations with EC50 = 9.4 nM. In KCl-contracted arteries (20-80 mM KCl), relaxation by NTG was progressively reduced. Relaxation responses to NTG also were inhibited significantly by potent calcium-activated K+ (BK) channel blockers, charybdotoxin (100 nM) and iberiotoxin (200 nM), but not by KATP blockers such as PNU-37883A (10 microM) or PNU-99963 (100 nM). Nitric oxide (0.1-30 nM) and acetylcholine (3-300 nM) also produced relaxations which were significantly attenuated by the BK blockers. In further experiments, NTG (1-100 nM) produced inhibition of PNU-46619-induced SR [Ca++]i release, with an IC50 of 8.5 nM, which was not affected by charybdotoxin. Furthermore, P1075 (50 nM), a KATP opener, did not inhibit agonist-stimulated SR [Ca++]i release. Ryanodine (10 microM), which acts on SR Ca++ release channels, did not alter NTG relaxations, whereas thapsigargin (0.1 microM), a selective inhibitor of SR Ca(++)-ATPase pump, produced pronounced inhibition of NTG relaxations. These results suggest that NTG, in the therapeutic concentration range, produces coronary relaxation primarily via two cellular mechanisms: plasmalemmal BK channel activation and stimulation of SR Ca(++)-ATPase to produce increased SR Ca++ accumulation. These two mechanisms apparently are equally important and act together to produce a unique vasorelaxation profile demonstrated by NTG-type coronary vasodilators.

摘要

本研究将硝酸甘油（NTG）在离体犬冠状动脉中的舒张作用与其他血管制剂进行了比较。在最大PNU - 46619预收缩作用下，冠状动脉对NTG的敏感性显著高于肠系膜动脉、肠系膜静脉和隐静脉。在冠状动脉中，NTG（1 - 100 nM）产生舒张作用，其半数有效浓度（EC50）= 9.4 nM。在氯化钾（KCl）收缩的动脉（20 - 80 mM KCl）中，NTG引起的舒张作用逐渐减弱。强效钙激活钾离子（BK）通道阻滞剂，如蝎毒素（100 nM）和iberiotoxin（200 nM），可显著抑制对NTG的舒张反应，但KATP阻滞剂，如PNU - 37883A（10 microM）或PNU - 99963（100 nM）则无此作用。一氧化氮（0.1 - 30 nM）和乙酰胆碱（3 - 300 nM）也产生舒张作用，且这些舒张作用被BK阻滞剂显著减弱。在进一步的实验中，NTG（1 - 100 nM）可抑制PNU - 46619诱导的肌浆网[Ca++]i释放，其半数抑制浓度（IC50）为8.5 nM，且不受蝎毒素影响。此外，KATP开放剂P1075（50 nM）不抑制激动剂刺激的肌浆网[Ca++]i释放。作用于肌浆网Ca++释放通道的ryanodine（10 microM）不改变NTG的舒张作用，而肌浆网Ca(++) - ATP酶泵的选择性抑制剂毒胡萝卜素（0.1 microM）则显著抑制NTG的舒张作用。这些结果表明，在治疗浓度范围内，NTG主要通过两种细胞机制产生冠状动脉舒张作用：激活质膜BK通道和刺激肌浆网Ca(++) - ATP酶以增加肌浆网Ca++蓄积。这两种机制显然同等重要，并共同作用产生NTG型冠状动脉血管扩张剂所特有的血管舒张特征。