Inhibition of heme oxygenase in the central nervous system potentiates endotoxin-induced vasopressin release in the rat

Previous in vitro studies have shown that increases in endogenous carbon mo noxide (CO) generation via activation of the enzyme heme oxygenase (HO) wit hin the rat hypothalamus are associated with the reduced release of the neu ropeptides, vasopressin (AVP) and oxytocin, while evidence concerning corti cotrophin-releasing hormone (CRH) is controversial. The present study inves tigated whether there is also a functional relationship between the MO-CO p athway and AVP and corticosterone (Cort) in vivo. Male Wistar rats were cha llenged with bacterial lipopolysaccharide (LPS) at doses producing signific ant activation of the hypothalamo-pituitary-adrenal (HPA) axis. LPS was giv en alone or after pretreatment with the HO inhibitor Sn-protoporphyrin-9 (S nPP9). The latter was injected either intraperitoneally (i.p.) or by intrac erebroventricular (i.c.v.) route. SnPP9 given i.p. failed to modify either basal or LPS-stimulated levels of AVP and Cort. On the contrary, i.c.v. SnP P9 strongly potentiated LPS-induced AVP release and significantly enhanced basal serum Cort levels, although it failed to potentiate stimulation by LP S. The LPS + i.c.v. SnPP9 also significantly reduced the hypothalamic store s of AVP compared to controls, correlating with increased circulating level s of AVP. Taken collectively, these data are in concordance with previous i n vitro observations showing that the MO-CO pathway acts centrally to atten uate endotoxin-stimulated AVP release, while having less effects on the pit uitary-adrenal axis. (C) 1999 Elsevier Science B.V. All rights reserved.