尼可地尔、匹那地尔和硝酸甘油对大鼠离体灌注肺缺氧和高碳酸血症性肺血管收缩作用的比较。

Comparison of the effects of nicorandil, pinacidil and nitroglycerin on hypoxic and hypercapnic pulmonary vasoconstriction in the isolated perfused lung of rat.

作者信息

Dumas M, Dumas J P, Rochette L, Advenier C, Giudicelli J F

机构信息

Laboratoire de Physiopathologie et de Pharmacologie Cardiovasculaires Expérimentales, Faculté de Médecine, Dijon, France.

出版信息

Br J Pharmacol. 1996 Feb;117(4):633-8. doi: 10.1111/j.1476-5381.1996.tb15237.x.

DOI:10.1111/j.1476-5381.1996.tb15237.x

PMID:8646407

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC1909341/

Abstract

The aims of this study were to compare in the rat isolated perfused lung preparation, the dilator actions of nicorandil, pinacidil and nitroglycerin on the hypoxic pulmonary pressure response with or without hypercapnic acidosis and to investigate the possible involvement of K channels and EDRF in these effects. 2. Isolated lungs from male Wistar rats (260-320 g) were ventilated with 21%O2 + 5%CO2 + 74%N2 (normoxia) or 5%CO2 + 95%N2 (hypoxia) and perfused with a salt solution supplemented with ficoll and gassed with 40%CO2 + 60%N2 to produce hypercapnic acidosis. Glibenclamide (1 microM), charybdotoxin (0.1 microM), NG-nitro-L-arginine methyl ester (L-NAME, 100 microM) and methylene blue (30 microM) were used to block KATP channels, KCa channels, EDRF synthesis and guanylate cyclase, respectively. 3. Hypoxic pressure response was significantly increased by hypercapnic acidosis (+115%, P < 0.001), L-NAME (+111%, P < 0.001), methylene blue (+100%, P < 0.05) but not by glibenclamide or charybdotoxin. In contrast none of these inhibitors affected the hypoxic hypercapnic acidosis response. 4. Nicorandil, pinacidil and nitroglycerin caused relaxation during the hypoxic pressure response and hypoxic hypercapnic acidosis response. Nicorandil was more potent in the latter. Glibenclamide inhibited the relaxant effects of nicorandil and pinacidil but not those of nitroglycerin during hypoxia alone. In contrast, glibenclamide inhibited the relaxant effects of the three drugs during hypoxia + hypercapnia. Charybdotoxin inhibited the relaxant effect of pinacidil during normocapnia and hypoxia but not those of nicorandil or nitroglycerin. Methylene blue inhibited partially the dilator response to pinacidil but did not modify the effects of nitroglycerin or nicorandil. 5. It is concluded that in the rat isolated lung preparation, EDRF limits hypoxic pulmonary vasoconstriction but not hypoxic vasoconstriction potentiated by hypercapnic acidosis, whereas KATP or KCa channels are not involved in either case. Nicorandil and pinacidil dilate pulmonary vessels mainly through KATP channels but the effects of pinacidil may also involve an additional mechanism of action through KCa channels. Finally it is suggested that nitroglycerin may partly exert its relaxant effects through KATP channels.

摘要

本研究的目的是在大鼠离体灌注肺标本中，比较尼可地尔、匹那地尔和硝酸甘油在伴有或不伴有高碳酸性酸中毒情况下对低氧性肺压反应的舒张作用，并研究钾通道和内皮舒张因子（EDRF）在这些作用中可能的参与情况。2. 选用雄性Wistar大鼠（体重260 - 320克）的离体肺，用21%O₂ + 5%CO₂ + 74%N₂（常氧）或5%CO₂ + 95%N₂（低氧）进行通气，并灌注添加了聚蔗糖的盐溶液，同时用40%CO₂ + 60%N₂进行气体置换以产生高碳酸性酸中毒。分别使用格列本脲（1微摩尔）、蝎毒素（0.1微摩尔）、NG - 硝基 - L - 精氨酸甲酯（L - NAME，100微摩尔）和亚甲蓝（30微摩尔）来阻断ATP敏感性钾通道（KATP通道）、钙激活钾通道（KCa通道）、EDRF合成和鸟苷酸环化酶。3. 高碳酸性酸中毒（升高115%，P < 0.001）、L - NAME（升高111%，P < 0.001）、亚甲蓝（升高100%，P < 0.05）可使低氧压力反应显著增加，但格列本脲或蝎毒素无此作用。相反，这些抑制剂均不影响低氧性高碳酸性酸中毒反应。4. 尼可地尔、匹那地尔和硝酸甘油在低氧压力反应和低氧性高碳酸性酸中毒反应过程中均可引起舒张。尼可地尔在后者作用更强。单独低氧时，格列本脲可抑制尼可地尔和匹那地尔的舒张作用，但不影响硝酸甘油的舒张作用。相反，在低氧 + 高碳酸血症时，格列本脲可抑制这三种药物的舒张作用。蝎毒素在正常碳酸血症和低氧时可抑制匹那地尔的舒张作用，但不影响尼可地尔或硝酸甘油的舒张作用。亚甲蓝部分抑制匹那地尔的舒张反应，但不改变硝酸甘油或尼可地尔的作用。5. 研究得出结论：在大鼠离体肺标本中，EDRF可限制低氧性肺血管收缩，但不能限制由高碳酸性酸中毒增强的低氧性血管收缩，而在这两种情况下KATP或KCa通道均未参与。尼可地尔和匹那地尔主要通过KATP通道舒张肺血管，但匹那地尔的作用可能还涉及通过KCa通道的额外作用机制。最后表明，硝酸甘油可能部分通过KATP通道发挥其舒张作用。