Jakubowski A, Olszanecki R, Chlopicki S
Department of Experimental Pharmacology, Jagiellonian University Medical College, Cracow, Poland.
J Physiol Pharmacol. 2004 Jun;55(2):409-21.
Although lipopolysaccharide (LPS) is recognized to induce a biphasic cardiovascular response its mechanism is not fully elucidated. In this study we analysed the involvement of PAF, TXA(2) and cysteinyl leukotrienes (cysLTs) in the acute cardiovascular effects of LPS in the isolated rat heart as well as in delayed phase of LPS response using a surrogate cellular model of the induction of NOS-2 by LPS in mouse macrophages. Perfusion of rat hearts with LPS resulted, in an immediate fall in heart contractility and coronary flow by 2.5 +/- 0.59 ml x min(-1) and 560 +/- 81 mmHg x sec(-1), respectively. This response was fully blocked by platelet activating factor (PAF) antagonist - WEB 2170 and partially inhibited, by inhibitor of cyclooxygenase (indomethacin) or by inhibitor of thromboxane synthase (camonagrel). The inhibition of leukotriene synthesis (BAY x1005) or cysLTs receptors (BAY x7195) was without effect. Administration of stable PAF analog (methylcarbamyl-PAF - MC-PAF) alone, mimicked heart response to LPS. In cultured mouse macrophages, MC-PAF did not induce NOS-2 expression and when given with LPS it slightly potentiated NOS-2 induction by LPS. However, in presence of WEB 2170 NOS-2 induction by LPS was inhibited in a dose-dependent manner. Inhibition of cyclooxygenase and leukotriene pathways had no effect on NOS-2 induced by LPS. These results indicate that PAF and TXA(2) but not cysLTs mediate the instant heart response induced by LPS, while PAF alone mediates a delayed NOS-2 induction by LPS. Accordingly, PAF may constitute the mediator that links acute and delayed phases of LPS-induced cardiovascular response.
尽管脂多糖（LPS）被认为可诱导双相心血管反应，但其机制尚未完全阐明。在本研究中，我们使用LPS在小鼠巨噬细胞中诱导NOS-2的替代细胞模型，分析了血小板活化因子（PAF）、血栓素A2（TXA₂）和半胱氨酰白三烯（cysLTs）在LPS对离体大鼠心脏急性心血管效应以及LPS反应延迟期的作用。用LPS灌注大鼠心脏导致心脏收缩力和冠状动脉流量立即下降，分别下降2.5±0.59 ml·min⁻¹和560±81 mmHg·sec⁻¹。这种反应被血小板活化因子（PAF）拮抗剂——WEB 2170完全阻断，并被环氧合酶抑制剂（吲哚美辛）或血栓素合酶抑制剂（卡莫格雷）部分抑制。白三烯合成抑制剂（BAY x1005）或cysLTs受体抑制剂（BAY x7195）无效。单独给予稳定的PAF类似物（甲基氨甲酰-PAF - MC-PAF）可模拟心脏对LPS的反应。在培养的小鼠巨噬细胞中，MC-PAF不诱导NOS-2表达，与LPS一起给予时，它会轻微增强LPS对NOS-2的诱导作用。然而，在存在WEB 2170的情况下，LPS对NOS-2的诱导作用呈剂量依赖性受到抑制。环氧合酶和白三烯途径的抑制对LPS诱导的NOS-2没有影响。这些结果表明，PAF和TXA₂而非cysLTs介导LPS诱导的即时心脏反应，而单独的PAF介导LPS延迟诱导的NOS-2。因此，PAF可能是连接LPS诱导的心血管反应急性和延迟阶段的介质。
