The gases nitric oxide (NO) and carbon monoxide (CO) function as intercellular messengers in a completely novel manner, providing a medium of cellular communication quite distinct from the classical neuroregulators. These agents will diffuse according to their physicochemical characteristics, in evanescent 'puffs' with spherical limits, unconstrained by formal cell boundaries. Most work has concentrated on their roles in inflammation and control of the vascular tree, but there is now extensive data attesting to a complex involvement in the neuroendocrine axis, particularly the hypothalamo-pituitary-adrenal (HPA) axis. We have established that both NO and CO are powerful inhibitors to the release of corticotrophin releasing hormone (CRH) and vasopressin from the rat hypothalamus and attenuate stimulation of these peptides by cytokines, and their synthetic enzymes are present in the nuclei of origin of these hormones. Exposure of hypothalami to lipopolysaccharide in vitro led to an unexpected fall in both CRH and vasopressin. However, CO antagonism led to potent stimulation of vasopressin release. Blockade of NO synthase in vivo leads to the enhancement of ACTH and corticosterone release in response to inflammatory stressors, while antagonism of CO synthesis leads to an exaggerated rise in endotoxin-stimulated vasopressin, but not of corticosterone. These results suggest that both NO and CO are important components of the HPA axis, and may act to counter-regulate stimulation of this axis in response to inflammatory stimuli. In the human, it seems likely that a failure of formation of CO in acute porphyria may be responsible for some of its clinical manifestation, such as paroxysmal hypertension and the syndrome of inappropriate antidiuretic hormone.
I am most grateful to all my collaborators in these studies particularly Mary Forsling (Dept. of Physiology, UMDS, London, UK), Pierluigi Navarra (Dept. of Pharmacology, Catholic University, Rome, Italy), and Alfredo Costa (Institute of Neurology, IRCCS C. Mondino, Pavia, Italy)
03 - 05 Nov 2003
Society for Endocrinology