Hikaru Ohta

Role of vasoactive intestinal polypeptide (VIP) in regulating the pituitary function in man.

Intramuscular injection of synthetic VIP (200 micrograms) resulted in a rapid increase in plasma prolactin (PRL) concentrations in normal women, which was accompanied by the 4- to 7-fold increase in plasma VIP levels. Mean (+/- SE) peak values of plasma PRL obtained 15 min after the injection of VIP were higher than those of saline control (28.1 +/- 6.7 ng/ml vs. 11.4 +/- 1.6 ng/ml, p less than 0.05). Plasma growth hormone (GH) and cortisol levels were not affected by VIP in normal subjects. VIP injection raised plasma PRL levels (greater than 120% of the basal value) in all of 5 patients with prolactinoma. In 3 of 8 acromegalic patients, plasma GH was increased (greater than 150% of the basal value) by VIP injection. In the in vitro experiments, VIP (10(-8), 10(-7) and 10(-6) M) stimulated PRL release in a dose-related manner from the superfused pituitary adenoma cells obtained from two patients with prolactinoma. VIP-induced GH release from the superfused pituitary adenoma cells was also shown in 5 out of 6 acromegalic patients. VIP concentrations in the CSF were increased in most patients with hyperprolactinemia and a few cases with acromegaly. These findings indicate that VIP may play a role in regulating PRL secretion in man and may affect GH secretion from pituitary adenoma in acromegaly.

Serotonin stimulates vasoactive intestinal polypeptide release from rat hypothalamus in vitro

Abstract The effect of serotonin (5-HT) on the release of immunoreactive vasoactive intestinal polypeptide (VIP) from rat hypothalamus was examined in vitro with a perifusion system. 5-HT (10 −6 M) and high potassium (56 mM) stimulated VIP release in a calcium-dependent manner. VIP release induced by 5-HT was blunted by cyproheptadine (10 −5 M). These findings suggest that 5-HT has a stimulating effect on VIP release from the hypothalamus.

Inhibition by antiserum to Vasoactive Intestinal Polypeptide (VIP) of prolactin secretion induced by serotonin in the rat

Intraventricular (i.c.v.) injection of serotonin (5HT) or intravenous (i.v.) injection of 5-hydroxytryptophan (5HTP), a precursor of 5HT, raised plasma prolactin (PRL) levels in urethane-anesthetized rats pretreated with normal rabbit serum. When the animals were injected i.c.v. or i.v. with specific anti-VIP rabbit serum, the plasma PRL responses to 5HT and 5HTP were blunted. These findings suggest that hypothalamic VIP is involved, at least in part, in PRL secretion induced by central serotonergic stimulation in the rat.

Further evidence that peptide histidine isoleucine (PHI) may function as a prolactin releasing factor in rats

Intraventricular administration of peptide histidine isoleucine (PHI) (200 ng, 1, 5 and 10 micrograms/rat) resulted in a significant and dose-related increase in plasma prolactin (PRL) levels in urethane-anesthetized rats and in conscious rats with intraatrial and intraventricular catheters. Intravenous injection of PHI (10 micrograms/rat) also raised plasma PRL levels in these animals. In in vitro studies, PRL release from superfused rat anterior pituitary cells was stimulated by PHI (10(-9), 10(-8) and 10(-7) M) in a dose-related manner. The stimulating effect of PHI (10(-7)M) on PRL release in vitro was as potent as that of vasoactive intestinal polypeptide (VIP) (10(-7) M) and was observed even in the presence of dopamine (10(-7) M). These results suggest that PHI plays a stimulating role in regulating PRL secretion by acting, at least in part, directly on the pituitary in the rat.

Involvement of Hypothalamic Vasoactive Intestinal Polypeptide (VIP) in Prolactin Secretion Induced by Serotonin in Rats

Abstract To study the possible involvement of hypothalamic vasoactive intestinal polypeptide (VIP) in regulating the secretion of prolactin (PRL), the effect of anti-VIP rabbit serum on serotonin (5-HT)-induced PRL release was examined in urethane-anesthetized male rats. Anti-VIP serum (AVS) or normal rabbit serum (NRS) was infused into a single hypophysial portal vessel of the rat for 40 min at a rate of 2 μl/min with the aid of a fine glass cannula and 5-HT was injected into a lateral ventricle 10 min after the start of the infusion. Intraventricular injection of 5-HT (10 μg/rat) caused an increase in plasma PRL levels in control animals infused with NRS and 5-HT-induced PRL release was blunted in animals infused with AVS (mean±SE peak plasma PRL: 118.9±19.8 ng/ml vs 54.7±16.2 ng/ml, p<0.05). These findings suggest that the secretion of PRL induced by 5-HT is mediated, at least in part, by hypothalamic VIP release into the hypophysial portal blood in the rat.

Central effects of DN1417, a novel TRH analog, on plasma glucose and catecholamines in conscious rats

Intracerebroventricular (icv) injection of DN1417 (0.3, 3 and 30 nmol/rat), a TRH analog, resulted in a dose-related increase in plasma glucose, epinephrine and norepinephrine levels in conscious male rats. The effects of DN1417 were more potent and longer-lasting than those of TRH on a molar basis. Intravenous injection of DN1417 (30 nmol/rat) did not change plasma glucose, epinephrine and norepinephrine levels. Pretreatment with hexamethonium (1.5 mg/100 g body wt, iv, 2 min before) inhibited plasma glucose, epinephrine and norepinephrine responses to DN1417 (3 nmol/rat, icv). DN1417 did not change plasma glucose, epinephrine and norepinephrine levels in rats after total adrenalectomy. In the animals pretreated with cysteamine (30 mg/100 g body wt, sc, 4 h before), basal plasma glucose, epinephrine and norepinephrine levels were raised, and exaggerated responses of plasma glucose, epinephrine and norepinephrine to DN1417 (3 nmol/rat, icv) were obtained. These results indicate that DN1417 has a potent and long-lasting effect in the central nervous system in stimulating the secretion of catecholamines through the autonomic nervous system, which is associated with an elevation of plasma glucose and that endogenous hypothalamic somatostatin may inhibit the action of DN1417.

Inhibition by Antiserum to Rat Growth Hormone-Releasing Factor of Growth Hormone Secretion Induced by A Met5-Enkephalin Analog, FK33-824, in Rats

Abstract A Met5-enkephalin analog, FK33-824 (5, 10 and 20 ug/100 g body wt, iv) caused a dose-related increase in plasma growth hormone (GH) in urethane-anesthetized male rats. Pretreatmentwith cysteamine (30 mg/100 g body wt, sc), a depletor of hypothalamic somatostatin, increased the plasma GH response to FK33-824 (10 ug/100 g body wt, iv). Antiserum specific for rat GH-releasing factor (GRF)(0.5 ml/rat, iv) blunted GH release induced by FK33-824 (10 ug/100 g body wt, iv) in rats with or without cysteamine pretreatment. These results suggest that GH secretion induced by the opioid peptide is mediated, at least in part, by hypothalamic GRF in the rat.

Further Evidence that Central Neurotensin Inhibits Pituitary Prolactin Secretion by Stimulating Dopamine Release from the Hypothalamus

Abstract Intracerebroventricular (icv) injection of neurotensin (NT) (2 μg/rat) suppressed prolactin (PRL) release induced by L-5-hydroxytryptophan (1 mg/100 g body wt, iv), prostaglandin E2 (1 μg/rat, icv), and FK33-824 (10 μg/100 g body wt, iv), a Met5-enkephalin analog, in urethane-anesthetized or conscious rats. In contrast, NT did not suppress elevated plasma PRL levels sustained by a large dose of domperidone (10 μg/100 g body wt, iv), a peripheral dopamine antagonist. In in vitro experiments, NT (10-5 M) stimulated dopamine release from perifused rat hypothalamic fragments. These results suggest that central NT inhibits PRL secretion by stimulating dopamine release from the hypothalamus into hypophysical portal blood in the rat.

Central Inhibitory Action of TRH on Prolactin Secretion in the Rat

Abstract Intravenous (iv) injection of FK33-824 ([D-Ala2, MePhe4, Met-(0)5-ol]-enkephalin, 8 and 16 nmole/100 g body wt), a potent Met5-enkephalin analog, and domperidone (1.2, 2.4, and 24 nmole/100 g body wt), a dopamine antagonist, resulted in a dose-related increase in plasma prolactin (PRL) levels in urethane-anesthetized male rats. PRL release induced by FK33-824 (16 nmole/100 g body wt, iv) was inhibited by intraventricular (icv) injection of TRH (0.6 nmole/rat). DN-1417 (γ-butyrolactone-γ-carbonyl-histidyl-prolinamide citrate, 0.6 nmole/rat, icv), a TRH analog, also blunted PRL release induced by FK33-824. PRL release induced by a smaller dose of domperidone (1.2 nmole/100 g body wt, iv) was blunted by TRH and DN-1417, whereas both peptides failed to suppress elevated PRL levels induced by larger doses of domperidone. These results suggest that TRH not only stimulates PRL secretion by acting directly at the pituitary, but has an inhibitory action on PRL release through activation of the central dopaminergic mechanism.

Glucagon-induced somatostatin release from perifused rat hypothalamus: Calcium dependency and effect of cysteamine treatment ☆

Somatostatin (SRIF) release from rat hypothalamus was investigated in vitro with a perifusion system. Glucagon (1 microM) and high potassium concentrations (56 mM) stimulated SRIF release in a calcium-dependent manner. Pretreatment of the rat with cysteamine (30 mg/100 g body weight, 7 h earlier) significantly reduced SRIF release from the hypothalamus in glucagon- and high potassium-stimulated states as well as in the basal state. SRIF release from rat hypothalamus was also stimulated by both dibutyryl cyclic AMP (1 mM) and theophylline (3 mM). These results suggest that glucagon, acting in a calcium-dependent manner and possibly through the adenylate cyclase-cyclic AMP system, stimulates SRIF release from rat hypothalamus and that cysteamine treatment reduces releasable SRIF in the hypothalamus.