REGULATION OF GONADOTROPIN-RELEASING-HORMONE (GNRH) SECRETION BY HEMEMOLECULES - A REGULATORY ROLE FOR CARBON-MONOXIDE

Recent studies suggest that carbon monoxide (CO), which is produced in significant quantities in many brain regions including the hypothalam us, may function as a neurotransmitter. The purpose of the present stu dy therefore was to access whether CO is capable of regulating the sec retion of the hypothalamic releasing factor, gonadotropin-releasing ho rmone (GnRH). To this end, medial basal hypothalami were obtained from estrogen-primed ovariectomized adult rats and incubated in vitro for a 1 hour preincubation period followed by a 30 minute incubation with either vehicle or test compounds. The media was then collected for GnR H determination by RIA. Hematin, a heme molecule cleaved by heme oxyge nase (HO) to yield CO, dose-dependently stimulated GnRH release with 5 0 mu M being the lowest effective dose. The effect of hematin was not due to a toxic effect as all groups responded to KCL stimulation at th e end of the experiment. The effect of hematin required HO cleavage as evidenced by the fact that the HO inhibitor, zinc protoporphyrin IX ( ZnPP), blocked the effect of hematin on GnRH release. The effect of he matin appeared to be due to its conversion to CO, as the CO scavenger molecule, hemoglobin, completely reversed the effect of hematin. Final ly, the effect of hematin did not appear to be due to the generation o f the other HO-generated product (biliverdin) since biliverdin dose-de pendently inhibited GnRH release. Taken as a whole, the present studie s provide evidence that CO is capable of modulating hypothalamic GnRH release in the female rat, suggesting that CO may function as a neurot ransmitter in the hypothalamus.