Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt.
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt.
Pharmacol Rep. 2019 Oct;71(5):782-793. doi: 10.1016/j.pharep.2019.04.013. Epub 2019 Apr 15.
Nicotine alleviates renal inflammation and injury induced by endotoxemia. This study investigated (i) the nicotine modulation of hemodynamic and renal vasodilatory responses to endotoxemia in rats, and (ii) roles of α7 or α4β2-nAChRs and related HSP70/TNFα/iNOS signaling in the interaction.
Endotoxemia was induced by ip lipopolysaccharide (5 mg/kg/day, for 2 days) and changes in systolic blood pressure and vasodilator responsiveness of isolated perfused kidney to acetylcholine or 5'-N-ethylcarboxamidoadenosine (NECA, adenosine receptor agonist) were evaluated.
Lipopolysaccharide had no effect on serum creatinine, reduced blood pressure, and increased renal vasodilations induced by acetylcholine or NECA in male and female preparations. Immunohistochemical analyses showed that lipopolysaccharide reduced renal HSP70 expression, but increased α7-nAChRs, α4β2-nAChRs and iNOS expressions. The co-administration of aminoguanidine (iNOS inhibitor), pentoxifylline (TNFα inhibitor), or nicotine attenuated lipopolysaccharide mediation of renal vasodilations and elevations in α7/α4β2-nAChR and iNOS expressions. Nicotine also reversed the downregulating effect of lipopolysaccharide on HSP70 expression. α7-nAChRs (methyllycaconitine citrate, MLA) or α4β2-nAChRs (dihydro-β-erythroidine, DHβE) blockade potentiated the lipopolysaccharide enhancement of renal vasodilations, and abolished the depressant effect of nicotine on lipopolysaccharide responses. A similar abolition of nicotine effects was seen after HSP70 inhibition by quercetin. Alternatively, lipopolysaccharide hypotension was eliminated in rats treated with DHβE/nicotine or quercetin/nicotine regimen in contrast to no effect for nicotine alone or combined with MLA.
These findings establish that nicotine offsets lipopolysaccharide facilitation of renal vasodilations possibly through a crosstalk between HSP70 and nAChRs of the α7 and α4β2 types.
尼古丁可减轻内毒素血症引起的肾炎症和损伤。本研究探讨了（i）尼古丁对大鼠内毒素血症时血流动力学和肾血管舒张反应的调节作用，以及（ii）α7 或α4β2-nAChRs 及其相关 HSP70/TNFα/iNOS 信号在相互作用中的作用。
通过腹腔内注射脂多糖（5mg/kg/天，持续 2 天）诱导内毒素血症，并评估大鼠离体灌注肾脏对乙酰胆碱或 5'-N-乙基羧酰胺腺苷（腺苷受体激动剂）的收缩压和血管舒张反应的变化。
脂多糖对内毒素血症大鼠的血清肌酐无影响，降低血压，并增加乙酰胆碱或 NECA 诱导的肾血管舒张。免疫组织化学分析显示，脂多糖降低了肾 HSP70 的表达，但增加了 α7-nAChRs、α4β2-nAChRs 和 iNOS 的表达。氨基胍（iNOS 抑制剂）、己酮可可碱（TNFα 抑制剂）或尼古丁的联合给药减弱了脂多糖对肾血管舒张和 α7/α4β2-nAChR 和 iNOS 表达的调节作用。尼古丁还逆转了脂多糖对 HSP70 表达的下调作用。α7-nAChRs（甲基藜芦碱柠檬酸盐，MLA）或 α4β2-nAChRs（二氢-β-erythroidine，DHβE）阻断增强了脂多糖对肾血管舒张的增强作用，并消除了尼古丁对脂多糖反应的抑制作用。用槲皮素抑制 HSP70 也会产生类似的消除尼古丁作用。相反，与单独使用尼古丁或与 MLA 联合使用相比，用 DHβE/尼古丁或槲皮素/尼古丁方案治疗的大鼠中，脂多糖性低血压被消除。
这些发现表明，尼古丁抵消了脂多糖对内毒素血症时肾血管舒张的促进作用，这可能是通过 HSP70 和 α7 和 α4β2 型 nAChRs 之间的串扰实现的。
