Tetsuya Inui

Calcitonin gene-related peptide : a neurotransmitter involved in capsaicin-sensitive afferent nerve-mediated gastric mucosal protection

Calcitonin gene-related peptide (CGRP), a potent vasodilating peptide, is present in primary afferent neurons of the gastric mucosa. However, its functional role in the stomach is not well established. The present study was undertaken to elucidate the involvement of gastric CGRP in the mechanism of protection against mucosal damage. Newborn Wistar rats were made CGRP-deficient by intraperitoneal injection of a sensory neurotoxin, capsaicin. All the experiments were performed 2.5 months after birth. The formation of mucosal lesions by administration of indomethacin to CGRP-deficient rats was significantly enhanced in comparison with that in normal rats. Intragastric administration of capsaicin significantly reduced the indomethacin-induced gastric mucosal lesions in normal rats. Pretreatment with a CGRP antagonist abolished the protective action of intragastric capsaicin against damaging agents. In isolated perfused stomach from normal rats, acute arterial infusion of capsaicin significantly reduced the perfusion pressure of the left gastric artery, with a simultaneous increase in CGRP and somatostatin secretion. The reduction of perfusion pressure and the increase of somatostatin secretion were inhibited by concomitant administration of a CGRP antagonist. In contrast, capsaicin infusion had no effect in CGRP-deficient rats. These results suggest that CGRP in the stomach plays a pivotal role in protection against gastric mucosal damage by indomethacin, possibly through an increase in gastric blood flow and somatostatin secretion.

Calcitonin Gene—Related Peptide and Induction of Hyperglycemia in Conscious Rats In Vivo

The effect of calcitonin gene-related peptide (CGRP) on glucose metabolism was investigated in conscious and unrestrained rats in vivo. Intravenous injection of rat CGRP (5.67 and 0.567 nmol/kg) caused a significant, dose-dependent increase in plasma glucose concentration and a simultaneous dose-dependent increase in plasma insulin level. In contrast, plasma glucagon level was not changed. On the other hand, intravenous infusion of CGRP (46.6 pmol · kg−1 · min−1) decreased tolerance to intragastric administration of glucose (IGGTT). Plasma insulin response to IGGTT, however, was not affected by CGRP infusion. Moreover, although intravenous injection of CGRP (5.67 nmol/kg) elicited a significant increase in plasma epinephrine and norepinephrine concentrations, concomitant administration of epinephrine and norepinephrine, inducing a more prominent rise in plasma catecholamines than those induced by CGRP, affected neither plasma glucose nor insulin levels. Finally, plasma insulin levels obtained by simulating CGRP-induced changes in plasma glucose or glucose plus catecholamine levels by infusion of glucose or glucose plus catecholamines were not different from those induced by CGRP injection. These results suggest that CGRP has a hyperglycemic action that is not mediated by sympathetic outflow in conscious rats, and inhibition of insulin secretion, if any, does not play a major role in this hyperglycemic action of CGRP. We have demonstrated specific CGRP receptors linked to adenylate cyclase activation in rat liver plasma membranes; this hyperglycemic effect of CGRP in vivo may be partly due to its direct action on the liver.

Presence and release of calcitonin gene-related peptide in rat stomach

Immunoreactive (IR)-calcitonin gene-related peptide (CGRP) was identified throughout the entire stomach of rats, being most highly concentrated in the pyloric region, and the concentrations in muscular layers being higher than those in mucosal layers. In addition, IR-CGRP was also present in the venous effluent from isolated perfused rat stomach, and its release was stimulated by dibutyryl cyclic AMP or theophylline but not by glucagon. Gel chromatography as well as HPLC of both tissue extracts and gastric perfusate showed three identical major peaks of IR-CGRP, one of which coeluted with synthetic CGRP. These results suggest that CGRP in the stomach plays a role in the regulation of gastric function.

Prostaglandin E2 and F2α inhibit growth of human gastric carcinoma cell line KATO III with simultaneous stimulation of cyclic AMP production

The effects of prostaglandins (PGs) on the growth of human gastric carcinoma cell line KATO III were investigated. PGE2 as well as PGF2 alpha significantly and dose-dependently inhibited the growth of this gastric carcinoma cell line (PGE2 greater than PGF2 alpha). This inhibition of cell growth by the PGs was associated with the increase in cyclic AMP production (PGE2 greater than PGF2 alpha), whereas inositol-phospholipid turnover was not affected by either PGE2 or PGF2 alpha as assessed by the formation of 3H-inositol phosphates. Furthermore, the proliferation of these gastric carcinoma cells was also suppressed by the administration of forskolin as well as of dibutyryl cyclic AMP. These results suggest that PGE2 and PGF2 alpha inhibit the growth of cultured human gastric carcinoma cells KATO III via stimulation of cyclic AMP production.

Glucose stimulates insulin release without altering cyclic AMP production or inositolphospholipid turnover in freshly obtained human insulinoma cells

Glucose, forskolin, IBMX and carbachol all stimulated insulin release from freshly obtained human insulinoma cells. In these same cells, cellular cyclic AMP levels were raised by forskolin and IBMX but not by glucose and carbachol. On the other hand, of all the insulin secretagogues examined, only carbachol stimulated the formation of 3H-inositol trisphosphate in these cells. Thus, in these insulinoma cells, glucose apparently induces insulin secretion without altering cyclic AMP production or inositolphospholipid turnover.