Mitsuhiro Nagata

Reserpine-induced depletion of neuropeptide Y in the guinea-pig: tissue-specific effects and mechanisms of action

The effects of treatment with reserpine (5 mg.kg-1, s.c., 24 h prior to sacrifice) or 6-hydroxydopamine (6-OHDA; 250 mg.kg-1, s.c., for 4 days, one week before sacrifice) on the content of neuropeptide Y (NPY)-like immunoreactivity (LI) and noradrenaline (NA) were compared in a variety of tissues from the guinea-pig. Reserpine and 6-OHDA treatment markedly reduced the NA content of all peripheral organs investigated. Reserpine treatment also caused depletion of the content of NPY-LI in larger blood vessels and in organs containing mainly perivascular nerves. Furthermore, reserpine treatment depleted NPY-LI in the heart, spleen and adrenal gland. In other organs dominated by parenchymal adrenergic innervation such as genital organs (vas deferens, uterus) or iris, treatment with 6-OHDA but not reserpine caused significant depletions of NPY-LI. The urinary bladder and gastrointestinal tract seem to be mainly innervated by non-adrenergic NPY-containing neurons resistant to reserpine and 6-OHDA treatment. The content of NPY-LI was elevated in sympathetic ganglia after reserpine treatment while no increase in axonal transport occurred in the sciatic nerve. Cerebellum was the only studied area in the central nervous system where the NPY content was depleted by reserpine or 6-OHDA treatment suggesting presence of NPY-LI in perivascular nerves. The reserpine-induced depletion of NPY-LI in the spleen, kidney and skeletal muscle was prevented by preganglionic denervation. This suggests that enhanced nerve impulse discharge in sympathetic nerves caused a situation where NPY release exceeded the amount which could be replaced by axonal transport.(ABSTRACT TRUNCATED AT 250 WORDS)

Possible roles of central cholinergic nicotinic mechanisms in regulation of gastric functions

The effect of nicotine microinjected into various hypothalamic regions and ala cinerea on gastric acid output and mucosal blood flow was examined in rats anesthetized with urethane. After administration of nicotine, 3 nmol, a marked increase in gastric acid output was observed in rats in which the tip of the micropipette was applied to the caudal portion of the ventromedial hypothalamus (VMH) and ala cinerea. Microinjection of physiological saline into ala cinerea also enhanced gastric acid output. Nicotine was without effect when microinjected into other hypothalamic regions. The increase in gastric acid output induced by microinjection of nicotine into the caudal portion of VMH was completely blocked by the concomitant administration of hexamethonium, 50 nmol, but was not modified in reserpine-pretreated animals. Intraventricularly applied nicotine increased the gastric acid output; this increase was abolished following bilateral destruction of VMH. The increase in gastric acid output was always in parallel with the increase in mucosal blood flow. These results suggest that cholinergic nicotinic receptors in the VMH are concerned with central regulation of gastric functions.

Nicotine applied into the dorsal motor nucleus of the vagus inhibits enhanced gastric acid output and mucosal blood flow in rats

The effects of nicotine microinjected into several brain regions on the centrally elevated gastric acid output and mucosal blood flow (MBF) were examined in anesthetized rats. Intravenous administration of 2-deoxy-D-glucose (2-DG) induced increases in gastric acid output and MBF. These increases were inhibited dose dependently by nicotine microinjected into the dorsal motor nucleus of the vagus (NDV) but not into various hypothalamic regions. This effect of nicotine was abolished with concomitantly administered hexamethonium and was not observed in reserpine-pretreated animals. Electrical stimulation of the lateral hypothalamic area (LHA) induced an increase in gastric acid output. This increase was completely inhibited when nicotine was microinjected into the NDV 5 min before stimulation. This inhibitory effect of nicotine was abolished by concomitantly administered hexamethonium and by intraventricular pretreatment with phentolamine, but not with propranolol. These results suggest that activation of nicotinic receptors within the NDV releases noradrenaline and that there is a resultant inhibition of gastric acid output and MBF.

Differential effects of clonidine and reserpine treatment on neuropeptide Y content in some sympathetically innervated tissues of the guinea-pig.

The effects of treatment with reserpine and/or the selective alpha 2-adrenoreceptor agonists clonidine and oxymetazoline on tissue levels of neuropeptide Y (NPY)-like immunoreactivity (-LI) and noradrenaline (NA) were studied in the guinea-pig. Clonidine treatment was associated with an increase in the levels of NPY-LI in the right atrium in a time- and dose-dependent manner. A significant (45%) elevation of the right atrial content of NPY-LI was present 2 h after administration of clonidine (50 micrograms kg-1 s.c.). After 24 h of repeated clonidine treatment the atrial levels of NPY-LI had increased by 95%. Following chronic clonidine treatment for two weeks, however, the right atrial NPY levels were similar to those in control animals. The corresponding cell-body content of NPY-LI in the stellate ganglion, remained unaffected by clonidine treatment. The levels of NPY-LI were also increased in the gastrocnemius muscle, spleen and adrenal gland after clonidine treatment while no changes were detected in the vas deferens or hypothalamus. The reserpine-induced reduction of NPY-LI in the right atrium, spleen, gastrocnemius muscle and adrenal gland was markedly inhibited by concomitant clonidine treatment while no effect was observed on NA depletion. The adrenoreceptor antagonists phentolamine, prazosin and yohimbine all inhibited the increase in cardiac content of NPY-LI seen after clonidine treatment. No elevation of tissue content of NPY-LI was observed after oxymetazoline (50 micrograms kg-1 s.c.) which, however, reversed the reserpine-induced depletion of NPY-LI. The reserpine-induced increase in content of NPY-LI in the stellate ganglion was also inhibited by clonidine and oxymetazoline.(ABSTRACT TRUNCATED AT 250 WORDS)

Central noradrenergic-cholinergic interaction in regulation of gastric acid secretion in rats

Possible roles of noradrenaline (NA) and acetylcholine (ACh) within the lateral hypothalamic area (LHA) in regulation of gastric acid secretion were examined in urethane anesthetized rats. When NA 30 nmoles was given into the LHA, the gastric acid output decreased and this inhibitory effect of NA was potentiated in rats pretreated with reserpine (2 mg/kg, i.p., 20 hr). Even in a dose of 3 nmoles which was without effect in non-treated control animals, there was a remarkable decrease in acid output. In these reserpinized animals, ACh in a dose of 30 nmoles induced a remarkable increase in acid output, while in the controls this ACh-induced increase was observed only with a 10 times higher dose. In the rats not given reserpine, the cholinergic muscarinic agonist bethanechol (10 nmoles) increased the gastric acid output while nicotine (30 nmoles) was without effect. Therefore, in rats, the central noradrenergic inhibitory mechanisms related to regulation of gastric function may be present at the level of LHA as well as at the ala cinerea (area of the dorsal motor nucleus of vagi and the nucleus tractus solitarius). In addition, in the LHA, a cholinergic muscarinic mechanism which elevates gastric acid secretion may be antagonized by a noradrenergic inhibitory mechanism.

Effects of intracerebrovetricularly applied nicotine on enhanced gastric acid secretion and mucosal blood flow in rats

The effects of intracerebroventricularly administered nicotine on the elevated levels of gastric acid output and mucosal blood flow (MBF) were examined in anesthetized rats. Intravenous administration of both 2-deoxy-D-glucose (2-DG) and pentagastrin induced marked increases in gastric function and the intraventricularly applied nicotine diminished the increases induced by 2-DG but not those due to pentagastrin. This effect of nicotine was inhibited when hexamethonium was given concomitantly. In reserpinized rats, this inhibitory effect of nicotine on the 2-DG-induced increases in gastric function was abolished. Electrical stimulation of the lateral hypothalamic area induced increases in gastric function and these increases were also inhibited by intraventricularly administered nicotine. These results indicate that centrally administered nicotine has an inhibitory effect on both acid secretion and MBF, when these gastric parameters are maintained at relatively higher levels by central activation. Central noradrenergic inhibitory mechanisms in the regulation of gastric function may relate to the inhibitory effects of nicotine.

Dual effect of nicotine injected in the cerebral ventricles on rat gastric motility

Intracerebroventricularly (i.c.v.) administered nicotine 50 and 100 nmol produced dual changes, an early decrease and a successive increase in gastric motility in urethane-anesthetized rats in which an intragastric balloon had been placed. These dual effects of nicotine were significantly antagonized by simultaneously administered hexamethonium i.c.v. but not by splanchnicectomy or by pretreatment with reserpine. Both atropine pretreatment and vagotomy abolished the stimulating effect of nicotine on gastric motility. Nicotine administered i.c.v. to bilaterally vagotomized rats did not affect gastric motility which was however enhanced by electrical stimulation of the vagus nerve. These observations suggest that central activation of the vagal cholinergic component results in excitation and central activation of the vagal non-adrenergic inhibitory component with i.c.v. administered nicotine results in inhibition of gastric motility. Sympathoadrenal systems and central monoaminergic mechanisms are probably not involved in the inhibitory effect of i.c.v. administered nicotine on gastric motility.

Central noradrenergic inhibition of gastric motility in rats

The roles of central noradrenergic mechanisms in the regulation of gastric motility were investigated in urethane-anesthetized rats in whom an intragastric balloon had been placed. Noradrenaline 100 nmol administered intracerebroventricularly (i.c.v.) significantly decreased spontaneous contractions of the stomach and this decrease in gastric motility was not observed in bilaterally vagotomized animals. Intracisternally administered (i.c.) noradrenaline (10 nmol) induced a decrease in gastric motility comparable to that elicited by noradrenaline 100 nmol i.c.v. Phentolamine 10 nmol i.c. but not the same dose of propranolol i.c. significantly antagonized the noradrenaline (10 nmol)-induced inhibition of gastric motility. These results suggest that alpha-adrenoceptor-mediated noradrenergic mechanisms in the brain stem are involved in the inhibitory regulation of gastric motility.