MEDIATION BY NITRIC-OXIDE OF THE CARBACHOL-INDUCED CORTICOSTERONE SECRETION IN RATS

Nitric oxide synthase, an enzyme responsible for nitric oxide (NO) for mation has been found in the hypothalamic paraventricular nucleus and median eminence, structures closely associated with regulation of the pituitary activity, and the pituitary gland itself. Nitric oxide modul ates the stimulated release of CRH from the rat hypothalamus in vitro, which suggests its role in regulating the secretion of ACTH from the pituitary corticotrops and of corticosterone from the adrenal cortex. The purpose of the present study was to elucidate the yet unknown role of endogenous NO in the HPA response to central cholinergic stimulati on in conscious rats. Neither L-arginine an NO precursor, nor the NO s ynthase blockers N omega-nitro-L-arginine methyl eater (L-NAME) and N omega-nitro-L-arginine (L-NNA) caused any consistent changes in the ba sal serum corticosterone levels. L-arginine, given in higher doses (12 0-150 mg/kg ip) 15 min prior to icv carbachol (2 mu g), markedly dimin ished the carbachol-induced rise in corticosterone secretion. Systemic pretreatment with the nitric oxide synthase inhibitor L-NAME (5 mg/kg ) significantly raised the carbachol-elicited corticosterone response, while addition of L-arginine completely blocked the effect of L-NAME. A similar increase in the carbachol-induced corticosterone response w as produced by icy pretreatment with L-NAME (2 mu g), indicating a cen tral site of the NO interaction with cholinergic stimulation of the HP A response. L-NAME is a weak inhibitor of neuronal NOS itself and must first be de-estrified to N omega-nitro-L-arginine to potently inhibit this enzyme. Systemic (10 mg/kg) and icy (1 mu g) pretreatment with L -NNA enhanced more effectively the carbachol-induced rise in corticost erone secretion than did pretreatment with L-NAME by either route. The se results are the first direct evidence that endogenous NO significan tly inhibits the HPA response to central cholinergic, muscarinic recep tor stimulation under in vivo conditions.