Nitric oxide synthase-containing cells were visualized in the anterior pituitary gland by immunocytochemistry. Consequently, we began an evaluation of the possible role of NO in the control of anterior pituitary function.Prolactin is normally under inhibitory hypothalamic control, and in vitro the gland secretes large quantities of the hormone. When hemipituitaries were incubated for 30 min in the presence of sodium nitroprusside, a releaser of NO, prolactin release was inhibited. This suppression was completely blocked by the scavenger of NO, hemoglobin. Analogs of arginine, such as NG-monomethyl-L-arginine (NMMA, where NG is the terminal guanidino nitrogen) and nitroarginine methyl ester, inhibit NO synthase. Incubation of hemipituitaries with either of these compounds significantly increased prolactin release. Since in other tissues most of the actions of NO are mediated by activation of soluble guanylate cyclase with the formation of cyclic GMP, we evaluated the effects of cyclic GMP on prolactin release. Cyclic GMP (10 mM) produced an "40%o reduction in prolactin release. Prolactin release in vivo and in vitro can be stimulated by several peptides, which include vasoactive intestinal polypeptide and substance P. Consequently, we evaluated the possible role of NO in these stimulations by incubating the glands in the presence of either of these peptides alone or in combination with NMMA. In the case of vasoactive intestinal polypeptide, the significant stimulation of prolactin release was augmented by NMMA to give an additive effect. In the case of substance P, there was a smaller but significant release of prolactin that was not significantly augmented by NMMA. We conclude that NO has little effect on the stimulatory action of these two peptides on prolactin release. Dopamine (0.1 ,uM), an inhibitor of prolactin release, reduced prolactin release, and this inhibitory action was significantly blocked by either hemoglobin (20 jig/ml) or NMMA and was completely blocked by 1 mM nitroarginine methyl ester. Atrial natriuretic factor at 1 ,uM also reduced prolactin release, and its action was completely blocked by NMMA. In contrast to these results with prolactin, luteinizing hormone (LH) was measured in the same medium in which the effect of nitroprusside was tested on prolactin release, there was no effect of nitroprusside, hemoglobin, or the combination of nitroprusside and hemoglobin on luteinizing hormone release. Therefore, in contrast to its inhibitory action on prolactin release NO had no effect on luteinizing hormone release. Immunocytochemical studies by others have shown that NO synthase is present in the folliculostellate cells and also the gonadotrophs of the pituitary gland. We conclude that NO produced by either of these cell types may diffuse to the lactotropes, where it can inhibit prolactin release. NO appears to play little role in the The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accorda...

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To evaluate a possible role of histamine in the CNS control of prolactin and gonadotropin release, adult ovariectomized rats, with stainless steel cannulae implanted in the 3rd ventricle, were given s.c. injections of 10 µg of estradiol benzoate. 48 h later, 2 µl of 0.9% NaCl alone or of saline containing 1, 5, 25 or 125 µg of histamine dihydrochloride was microinjected into the ventricle. Immediately before and then 15, 30 and 60 min after, blood samples were withdrawn from etherized rats for radioimmunoassay (RIA) of serum prolactin, LH and FSH. In the histamine-injected rats, an increase in prolactin titers was observed and was highly significant in groups receiving the higher doses. A small yet significant release of LH, but not of FSH, was also observed. When 25 µg of histamine was injected directly into the pituitary or into the jugular vein, no elevations were observed, indicating a site of action in the brain. Restraint stress elevated serum prolactin and lowered serum LH and FSH in ovariectomized rats. These responses were blocked by the intrajugular injection of diphenhydramine (5 mg/kg). It is suggested that histamine may be involved in the hypothalamic control of prolactin release and possibly of gonadotropin release.