Miao L, Perreault C L, Travers K E, Morgan J P
Charles A. Dana Research Institute, Beth Israel Hospital, Boston, MA, USA.
Eur J Pharmacol. 1997 Feb 26;321(2):201-8. doi: 10.1016/s0014-2999(96)00946-6.
Flosequinan is an arterial and venous dilator that also has a positive inotropic effect at relatively higher doses. The purpose of this study was to determine the mechanism of this positive inotropic effect in ferret papillary muscles loaded with the Ca2+ indicator, aequorin. Over the range of doses from 10(-6) to 10(-3) M, flosequinan produced a 61 +/- 9% increase in peak tension that was accompanied by a corresponding increase in [Ca2+]i. This positive inotropic effect was not selectively blocked by addition to the perfusate of procaine 0.6 microM, tetrodotoxin 10(-6) M or by verapamil, 5 x 10(-8) M. In contrast, the positive inotropic effect of flosequinan, but not milrinone or hydralazine, was potentiated by prior addition of ouabain 3 nM to enhance intracellular Ca2+ via reduction of the Na+/Ca2+ exchange. Moreover, antagonists of Na+/Ca2+ exchange, including cadmium 10 microM, amiloride 600 microM and choline substitution for 1/3 Na+ in the perfusate, blocked the response to flosequinan but not hydralazine or milrinone. These results indicate that flosequinan produces a positive inotropic effect by reduction of Na+/Ca2+ exchange in mammalian myocardium. Moreover, flosequinan has the potential to interact synergistically with other positive inotropic agents such as digoxin that affect Na+/Ca2+ exchange by direct or indirect actions.
氟司喹南是一种动静脉扩张剂，在相对较高剂量时也具有正性肌力作用。本研究的目的是确定在装载有钙离子指示剂水母发光蛋白的雪貂乳头肌中这种正性肌力作用的机制。在10⁻⁶至10⁻³M的剂量范围内，氟司喹南使峰值张力增加了61±9%，同时细胞内钙离子浓度[Ca²⁺]i相应增加。这种正性肌力作用不会被添加到灌注液中的0.6微摩尔普鲁卡因、10⁻⁶M河豚毒素或5×10⁻⁸M维拉帕米选择性阻断。相反，预先添加3纳摩尔哇巴因以通过减少钠钙交换来增强细胞内钙离子，可增强氟司喹南的正性肌力作用，但米力农或肼屈嗪的正性肌力作用不受影响。此外，钠钙交换拮抗剂，包括10微摩尔镉、600微摩尔阿米洛利以及用胆碱替代灌注液中三分之一的钠离子，可阻断对氟司喹南的反应，但不影响肼屈嗪或米力农。这些结果表明，氟司喹南通过减少哺乳动物心肌中的钠钙交换产生正性肌力作用。此外，氟司喹南有可能与其他正性肌力药物如地高辛协同相互作用，地高辛通过直接或间接作用影响钠钙交换。
