Effect of natriuretic peptide receptor antagonist on lipopolysaccharide-induced fever in rats: is natriuretic peptide an endogenous antipyretic?

We investigated whether natriuretic peptide (NP) acts as an endogenous antipyretic inside and/or outside the blood-brain barrier in rats made febrile by systemic administration of bacterial endotoxin (lipopolysaccharide; LPS). Intravenous (i.v.) injection of LPS induced a triphasic fever, the second phase of which was significantly enhanced by an i.v. injection of the NP receptor (A-type and B-type) antagonist HS-142-1, a glucose-caproic acid polymer. In contrast, the same antagonist (i.v.) had no effect on the fever induced by i.v. injection of interleukin (IL)-1beta. An i.v. administration of HS-142-1 enhanced the LPS (i.v.)-induced IL-1beta response in the rat spleen. An i.v. treatment with atrial NP (ANP) significantly attenuated the second phase of the LPS-induced fever. On the other hand, i.c.v. injection of the above-mentioned 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 intracerebro-ventricularly (i.c.v.), the antagonist had no effect on the fever induced by i.v. IL-1beta. Finally, the fever induced by i.c.v. injection of LPS was not affected even by an i.c.v. administration of the antagonist. These results suggest that the production of pyrogenic cytokines (such as IL-1beta) that follows i.v. LPS injection may be inhibited by NP acting outside the blood-brain barrier, leading to an inhibition of the fever. In contrast, inside the blood-brain barrier NP may inhibit cytokine-independent mechanisms present within the rat brain that mediate LPS (i.v.)-induced fever.