Regulation of gonadotrophin-releasing hormone (GnRH) secretion by heme molecules: 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 hypothalamus, may function as a neurotransmitter. The purpose of the present study therefore was to access whether CO is capable of regulating the secretion of the hypothalamic releasing factor, gonadotropin-releasing hormone (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 GnRH determination by RIA. Hematin, a heme molecule cleaved by heme oxygenase (HO) to yield CO, dose-dependently stimulated GnRH release with 50 microM being the lowest effective dose. The effect of hematin was not due to a toxic effect as all groups responded to KCL stimulation at the end of the experiment. The effect of hematin required HO cleavage as evidenced by the fact that the HO inhibitor, zinc protoporphyrin IZ (ZnPP), blocked the effect of hematin on GnRH release. The effect of hematin appeared to be due to its conversion to CO, as the CO scavenger molecule, hemoglobin, completely reversed the effect of hematin. Finally, the effect of hematin did not appear to be due to the generation of the other HO-generated product (biliverdin) since biliverdin dose-dependently inhibited GnRH release. Taken as a whole, the present studies provide evidence that CO is capable of modulating hypothalamic GnRH release in the female rat, suggesting that CO may function as a neurotransmitter in the hypothalamus.