CARBON-MONOXIDE AS A NOVEL NEUROENDOCRINE MODULATOR - INHIBITION OF STIMULATED CORTICOTROPIN-RELEASING HORMONE-RELEASE FROM ACUTE RAT HYPOTHALAMIC EXPLANTS

Although recent evidence suggests that the gas nitric oxide (NO) can m odulate the secretion of corticotropin-releasing hormone (CRH) from ac ute rat hypothalamic explants, another gas, carbon monoxide (CO), has been suggested to play a role in neural signaling in the brain; CO may complement the activity of NO in long term potentiation. In this stud y, we have investigated whether CO shares with NO the ability to modif y the release of CRH from the rat hypothalamus. Hemin, a specific CO p recursor through the enzyme heme oxygenase (the enzymatic pathway synt hesizing endogenous CO), was found to inhibit in a dose-dependent mann er KCl-stimulated CRH release, with a maximal effect at 1 mu M, while showing no effect on basal CRH secretion. The stimulation of CRH by in terleukin-1 beta (100 ng/ml) was also significantly antagonized by hem in (1 mu M). An inhibitor of heme oxygenase, zinc-protoporphyrin-9, ha d no effect on basal or stimulated CRH release up to a maximal dose of 10 mu M. When hemin and zinc-protoporphyrin-9 were given together, th e hemin-induced inhibition of CRH release was completely antagonized b y the enzyme inhibitor. These findings provide evidence that endogenou s CO may play a role in the control of CRH release; by analogy with NO , CO may represent a major new neuroendocrine modulator.