OXYTOCIN RELEASE IS INHIBITED BY THE GENERATION OF CARBON-MONOXIDE FROM THE RAT HYPOTHALAMUS - FURTHER EVIDENCE FOR CARBON-MONOXIDE AS A NEUROMODULATOR

Recent evidence suggests that the gas nitric oxide can modulate the se cretion of a number of hypothalamic hormones, and may be co-localized particularly to oxytocin-containing neurons. Another gas, carbon monox ide (CO), has also been suggested to play a role in neural signaling i n the brain, and the synthetic enzyme responsible for the generation o f carbon monoxide has been reported to be present in the rat hypothala mus. In this study, we have therefore investigated whether CO has the ability to modify the release of oxytocin from acute rat hypothalamic explants. Hemin, a specific CO precursor through the enzyme heme oxyge nase (the enzymatic pathway synthesizing endogenous CO, was found to i nhibit KCl-stimulated oxytocin release, with a maximal effect at 10(-5 ) M, while showing no effect on basal oxytocin secretion. The stimulat ion of oxytocin by serotonin 10 ng/ml was also significantly antagoniz ed by hemin 10(-7) M. An inhibitor of heme oxygenase, zinc-protoporphy rin-9, had no effect on basal or stimulated oxytocin release. When hem in and zinc-protoporphyrin-9 were given together, the hemin-induced in hibition of oxytocin was completely antagonized by the enzyme inhibito r. Ferrous hemoglobin A(0), a substance known to bind CO with high aff inity, had no effect on either basal or stimulated oxytocin release, b ut when hemin and ferrous hemoglobin A(0) were given together the hemi n-induced inhibition of oxytocin was completely blocked. These finding s provide evidence that endogenous CO may play a role in the control o f oxytocin release and that, by analogy with nitric oxide, CO may repr esent a major new neuroendocrine modulator.