Adegunloye Banji, Lamarre Eric, Moreland Robert S
Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102, USA.
J Pharmacol Exp Ther. 2003 Jan;304(1):294-300. doi: 10.1124/jpet.102.042101.
This report contains results of studies designed to determine whether quinine has direct effects on myofilament Ca2+ sensitization in addition to effects on Ca2+. Quinine decreased the EC50 value and maximal contraction of intact arterial strips to histamine. Incubation of arterial strips with indomethacin or 1H-[1,2,4]oxadiazole[4,3-alpha]quinoxalin-1-one did not alter quinine inhibition, suggesting that the effect is not mediated via cyclooxygenase or cGMP. Pretreatment of strips with quinine had no effect on the histamine-dependent increases in myosin light chain phosphorylation levels. Quinine inhibited Ca2+-induced contraction in alpha-toxin permeabilized strips, but not the Ca2+-induced contraction in Triton X-100 permeabilized strips. Pretreatment of the alpha-toxin permeabilized strips with quinine before stimulation with guanosine-5'-O-(3-thio)triphosphate (GTPgammaS) did not have any effect on the response. In conclusion, quinine inhibited Ca2+-dependent contractions of the alpha-toxin permeabilized strips, which retain modulatory pathways both upstream and downstream from the contractile proteins but did not inhibit GTPgammaS-dependent contraction of the alpha-toxin permeabilized preparation important in upstream modulation of the contraction. Moreover, quinine did not inhibit the Ca2+-dependent contractions of the Triton X-100 permeabilized strips, which are devoid of all modulatory pathways. This suggests that quinine does not act upstream from or directly on the contractile proteins. A more likely site of action may be downstream of the contractile proteins and specifically at the coupling of the contractile proteins with the physiological endpoint of force development.
本报告包含多项研究结果，这些研究旨在确定奎宁除了对钙离子有作用外，是否对肌丝钙离子致敏有直接影响。奎宁降低了完整动脉条对组胺的半数有效浓度（EC50）值和最大收缩反应。用吲哚美辛或1H-[1,2,4]恶二唑[4,3-α]喹喔啉-1-酮孵育动脉条，并未改变奎宁的抑制作用，这表明该作用并非通过环氧化酶或环磷酸鸟苷（cGMP）介导。用奎宁预处理动脉条，对组胺依赖性的肌球蛋白轻链磷酸化水平升高没有影响。奎宁抑制了α-毒素通透化条带中钙离子诱导的收缩，但对Triton X-100通透化条带中钙离子诱导的收缩没有抑制作用。在用鸟苷-5'-O-(3-硫代)三磷酸（GTPγS）刺激之前，用奎宁预处理α-毒素通透化条带，对反应没有任何影响。总之，奎宁抑制了α-毒素通透化条带中钙离子依赖性收缩，该条带保留了收缩蛋白上下游的调节途径，但并未抑制α-毒素通透化制剂中GTPγS依赖性收缩，而这种收缩在收缩的上游调节中很重要。此外，奎宁并未抑制Triton X-100通透化条带中钙离子依赖性收缩，该条带缺乏所有调节途径。这表明奎宁并非作用于收缩蛋白的上游或直接作用于收缩蛋白。更可能的作用位点可能在收缩蛋白的下游，特别是在收缩蛋白与力产生的生理终点的偶联处。
