Biosynthesis of nitric oxide from l-arginine: A pathway for the regulation of cell function and communication

Understanding of the organization and function of a newly identified neuronal messenger molecule, nitric oxide, has progressed rapidly. Nitric oxide synthase has been purified and molecularly cloned from brain. Its localization is exclusively neuronal and endothelial. The catalytic activity of nitric oxide synthase accounts for the NADPH diaphorase staining of neurons that are uniquely resistant ot toxic insults and neurodegenerative disorders. Nitric oxide has diverse functions. In platelets it inhibits their aggregation, in macrophages it mediates cytotoxicity, and in blood vessels it acts as a vasodilator. In the nervous system nitric oxide may be the retrograde transmitter in long-term potentiation. It is the “neurotransmitter” of cerebral vasodilator nerves and the inhibitory “neurotransmitter” of the motor neurons of the intestines. Nitric oxide in situations of excessive production may function as neurotoxin, suggesting a role for nitric oxide in neurodegenerative disorders.

A novel neuronal messenger molecule in brain: the free radical, nitric oxide.

THE CLASSICAL CONCEPT of neuroendocrine control of the pituitary as proposed by Harris stipulates that the endocrine functions of the anterior pituitary are controlled by hypothalamic releasing factors or release-inhibiting factors. It was postulated that these factors are present in hypothalamic neurons which project into the median eminence (ME) of the basal hypothalamus and end in contact with the hypothalamic-hypophyseal portal vessels (1). It has subsequently been shown that growth hormone (GH) secretion is regulated by both stimulatory and inhibitory factors of hypothalamic origin. Like other anterior pituitary hormones, GH is secreted episodically. In all mammalian species so far studied spontaneous episodes of GH secretion occur several times over a 24-h period (2–8). Particularly in the adult male rat there is a striking regularity in the GH pulses which occur at 3- to 4-h intervals and reach levels of several hundred ng/ml.

Sexual dimorphism in the control of growth hormone secretion.

To evaluate gonadotropin release in polycystic ovary syndrome (PCO), one or more of the following hypothalamic-pituitary function tests were performed on 24 patients with the syndrome. These tests included (a) the pulsatile pattern and day-to-day fluctuation of gonadotropin release; (b) effects of exogenous estrogen and antiestrogen (clomiphene) administration on gonadotropin release; and (c) pituitary responsiveness to maximal (150 mug) and submaximal (10 mug) luteinizing hormone-releasing factor (LRF) injections. In 10 of the 14 patients sampled frequently (15 min) for 6 h, luteinizing hormone (LH) levels were elevated above the concentration seen in normal cycling women (except the LH surge). These high LH concentrations appeared to be maintained by and temporally related to the presence of exaggerated pulsatile LH release, either in the form of enhanced amplitude or increased frequency. In all subjects, levels of follicle-stimulating hormone (FSH) were low or low normal, and a pulsatile pattern was not discernible. In four patients, daily sampling revealed marked day-to-day fluctuation of LH but not FSH. That the elevated LH levels were not related to a defect in the negative-feedback effect of estrogen was suggested by the appropriate fall of LH in four patients given an acute intravenous infusion of 17beta-estradiol. This infusion had no effect on FSH levels. In addition, clomiphene elicited rises of both LH and FSH that were comparable to the ones observed in normal women given the same treatment. The clomiphene study also suggested that the positive-feed-back mechanism of estrogen on LH release was intact when the preovulatory rises of 17beta-estradiol induced appropriate LH surges. The elevated LH levels appeared to be related to a heightened pituitary responsiveness to the LRF. This was found in the 11 and 2 patients given maximal (150 mug) and submaximal (10 mug) doses of LRF, respectively. The augmented pituitary sensitivity for LH release correlated with the basal levels of both estrone (P less than 0.025) and 17beta-estradiol (P less than 0.02). The net increase in FSH was significantly greater (P less than 0.001) in the PCO patients than the normal women with maximal doses of LRF. With the smaller dose study none of the injections had a discernible effect on FSH concentrations in either subject. The disparity between LH and FSH secretion could be explained by the preferential inhibitory action of estrogen on FSH release, coupled with a relative insensitivity of FSH release. These data indicate that in these PCO patients the abnormalities of the hypothalamic-pituitary regulation of gonadotropin secretion was not an inherent defect but represented a functional derangement consequent to inappropriate estrogen feedback, which led to a vicious cycle of chronic anovulation and inappropriate gonadotropin secretion.

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Characterization of the inappropriate gonadotropin secretion in polycystic ovary syndrome.

Inhibition of gastrin and gastric-acid secretion by growth-hormone release-inhibiting hormone

Concomitant administration of somatostatin and thyrotropin-releasing factor (TRF) significantly inhibited the release of TSH induced by TRF without affecting the simultaneous secretion of prolactin (PRL) in normal adult subjects. However, within our experimental design (iv bolus of 250 μg TRF plus 500 μg somatostatin followed by constant infusion of 500 μg somatostatin over 45 min) the inhibition of TSH release by somatostatin was incomplete. The present study demonstrates that somatostatin in humans not only exerts an inhibitory effect on growth hormone secretion but also on TSH release in response to TRF. These findings suggest an interrelationship between the regulation of growth hormone and TSH secretion.

Inhibition by somatostatin on the release of TSH induced in man by thyrotropin-releasing factor.

Synthetic (linear) somatostatin (SRIF, somatotropin-release inhibiting factor) abolished the elevation of serum GH concentration induced in normal human subjects by the administration of L-dopa and arginine. Within the dose used (250 μg, iv and 500 μg constant infusion) somatostatin. did not inhibit the rise in circulating PRL normally observed with arginine infusion nor did it modify basal levels of serum GH, TSH, PRL, FSH and LH.

Inhibition of growth hormone release in humans by somatostatin.

In order to delineate the estrogen-pituitary feedback, the acute and chronic effects of estrogen administration in hypogonadal subjects were determined by serial assessment of pituitary gonadotropin responsiveness to synthetic LRF. Rapid increase in circulating estradiol (E2) concentrations to pharmacological levels via constant E2 infusion (50 μg/hr) induced a prompt and marked diminution in pituitary responsiveness to LRF. This finding indicates a direct inhibitory action of estradiol on the pituitary gonadotrophs' sensitivity to LRF which may represent an important component of the negative feedback system on gonadotropin release. When chronic administration of smaller doses of ethinyl estradiol (EE, 1 μg/kg/day × 4 weeks) was assessed before and at weekly intervals during treatment, the pituitary responsiveness to LRF showed a biphasic course of LH release; an initial augmentation with a slower response was found during the first and second weeks of treatment; during the third and fourth week...

Modulation of pituitary responsiveness to LRF by estrogen.

To evaluate the effect on testicular function of the sleep related LH rise in pubertal subjects, identical twin boys (JA-1; JA-2) in stage 2 of puberty were studied for 36 hours using a frequent sampling technique. While each subject was awake the mean ± S.E. testosterone (T) level was 257 ± 41 and 325 ± 31 pg/ml for JA-1 and JA-2 respectively. Each night with the commencement of sleep, sharp increases of T and LH but not FSH levels occurred. The nocturnal elevations of T reached peaks of 1887 and 1833 pg/ml for the same respective subjects and were always preceded by the sleep related LH rises. The interval between the nocturnal LH r i se and the beginning of the subsequent T elevation was 40-80 minutes. This data suggests that in adolescent boys the sleep related LH increase stimulates a nocturnal rise of T. This androgen increase could account for some of the early pubertal changes seen in males.

The nocturnal rise of plasma testosterone in pubertal boys.

The synthetic linear tetradecapeptide, somatostatin, (125–250 μg bolus followed by constant infusion of 9–10 μg/min) was given over the first 90 min of sleep on 2 nights to each of 4 normal young men and on one night to an acromegalic patient. Complete inhibition of the sleep-related physiologic peak in nychthemeral hGH release was seen during infusion on all 8 nights in normal subjects and a 50% reduction was seen in the acromegalic. This occurred without alteration in sleep in the first cycle. Thus, potent SRIF activity in re physiologic and pathologic hGH release was exhibited by somatostatin.

T. M. Siler

Papers

Inhibition by somatostatin on the release of TSH induced in man by thyrotropin-releasing factor.

Inhibition of growth hormone release in humans by somatostatin.

Modulation of pituitary responsiveness to LRF by estrogen.

The nocturnal rise of plasma testosterone in pubertal boys.

Inhibition of the sleep-related peak in physiologic human growth hormone release by somatostatin.