Investigation on atrial natriuretic peptide as an endogenous antipyretic

我们研究了钠尿肽(NP)在静脉注射致热大鼠血脑屏障内外是否起到内源性解热作用。注射细菌内毒素(脂多糖；脂多糖)。脂多糖引起三相发热，静脉注射可显著增强第二相发热。注射NP受体拮抗剂HS-142-1。相反，相同的拮抗剂(静脉注射)对静脉注射引起的发热无明显影响。注射白介素1(IL-1β，IL-1β)。静脉注射。HS-142-1可增强内毒素诱导的大鼠脾内IL-1β反应。静脉注射。心房利钠(ANP)可显著减轻内毒素诱导的发热第二时相。脑室内(i.c.v.)注射上述NP受体拮抗剂可使静脉注射引起的发热第三时相增加。同时相的内毒素给药可被心钠素减弱。当静脉注射时，拮抗剂对发热…没有影响更多的是由静脉注射诱导的。IL-1β。另一方面，我们使用原代培养的大鼠脑巨噬细胞样细胞(即小胶质细胞)来研究心钠素与其受体结合是否通过影响促炎转录因子NF-κB和AP-1的激活来抑制内毒素诱导的小胶质细胞激活。UPS刺激的小胶质细胞亚硝酸盐和IL-1浓度升高，IL-1mRNA表达增加，细胞形态由阿米巴状变为多极杆状。这些效应均被ANP显著抑制。HS-142-1可阻断ANP对内毒素诱导的亚硝酸盐反应的抑制作用。内毒素刺激的小胶质细胞中，NF-κB和AP-1活性增强，这种增强作用可被心钠素显著抑制。综上所述，这些结果表明，NP作用于血脑屏障内外，可能会抑制致热细胞因子的产生，从而抑制大鼠的发热。较少

We investigated whether natriuretic peptide (NP) acts as an endogenous antipyretic inside and/or outside the blood-brain barrier in rats made febrile by intravenous (i.v.) injection of bacterial endotoxin (lipopolysaccharide ; LPS). LPS induced a triphasic fever, the second phase of which was significantly enhanced by an i.v. injection of the NP-receptor antagonist HS-142-1. In contrast., the same antagonist (i.v.) had no effect on the fever induced by i.v. injection of interleukin-β (IL-1β). An i.v. administration of HS-142-1 enhanced the LPS (i.v.)-induced IL-1β response in the rat spleen. An i.v. treatment with atrial NP (ANP) significantly attenuated the second phase of the LPS-induced fever. Intracerebroventricular (i.c.v.) injection of the above NP-receptor antagonist resulted in an augmentation of the third phase of the fever induced by i.v. administration of LPS, the same phase that, was attenuated by ANP given i.c.v. When given i.c.v., the antagonist had no effect on the fever … More induced by i.v. IL-1β. On the other hand, we used primary cultures of rat brain macrophage-like cells (i.e., microglial cells) to investigate whether ANP binding to its receptors inhibits LPS-induced microglial activation via effects on the activation of the proinflammatory transcription factors NF-κB and AP-1. UPS-stimulated microglial cells showed increases in nitrite and IL-1 concentrations, and in the expression of IL-1 mRNA, as well as a morphological change from an amoeboid shape to a multipolar rod shape. These effects were all significantly inhibited by treatment with ANP. The inhibition by ANP of the LPS-induced nitrite response was abrogated by HS-142-1. NF-κB and AP-1 activities were enhanced in LPS-stimulated microglial cells, and these enhancements were significantly suppressed by ANP. Collectively, these results suggest that the production of pyrogenic cytokines may be inhibited by NP acting inside and outside the blood-brain barrier, leading to an inhibition of the fever in rats. Less