EVIDENCE THAT CARBON-MONOXIDE STIMULATES PROSTAGLANDIN ENDOPEROXIDE SYNTHASE ACTIVITY IN RAT HYPOTHALAMIC EXPLANTS AND IN PRIMARY CULTURES OF RAT HYPOTHALAMIC ASTROCYTES

Carbon monoxide (CO) shares with nitric oxide (NO) the ability to modu late the release of hypophysiotropic peptides from rat hypothalamic ex plants. While both gases are believed to act as neural messengers in t he brain via the activation of soluble guanylyl cyclase, the latter is almost undetectable in the rat hypothalamus. NO has been shown to exe rt some of its biological actions through the modulation of prostaglan din endoperoxide synthase (PGHS) activity. We have, therefore, investi gated whether CO also can use PGHS as a signaling pathway in the hypot halamus. Endogenous CO is produced in equimolar amounts with biliverdi n (BV) by the catabolism of hemin through heme oxygenase (HO). Hemin, two inhibitors of HO, zinc-protoporphyrin-9 (ZnPP9) and tin-mesoporphy rin-9 (SnMP9), ferrous hemoglobin (Hb), indomethacin and dexamethasone (DEX) were used as pharmacological tools. Prostaglandin E2 (PGE2) rel eased from rat hypothalamic explants or primary cultures of hypothalam ic astrocytes was taken as a marker of PGHS activity. It was found tha t: (1) hemin evokes an increase in PGE2 release from hypothalamic expl ants; (2) this effect is counteracted by ZnPP9, SnMP9, Hb and indometh acin; (3) the metallo-porphyrins and indomethacin, but not Kb, are als o able to inhibit basal PGE2 release from hypothalamic explants; and ( 4) dexamethasone does not inhibit, and even potentiates, the stimulato ry effect of hemin on PGE2 release from hypothalamic astrocytes. The e vidence presented here suggests that the catabolism of endogenous or e xogenously added hemin is associated with an increase in PGE2 producti on in the rat hypothalamus, This effect can be attributed to the forma tion of CO, since the other end-product of HO, BV, does not enhance PG E2 release, Thus, at least some of the biological effects of CO at the hypothalamic level might be mediated by the activation of the PGHS pa thway.