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Here we show the increased hepatocyte growth factor (HGF) and cyclooxygenase-2 (COX-2) expression in gastric mucosa of rats which have developed a reserpine-induced ulcer. Such an increase of HGF and COX-2 expression was blunted in rats pretreated with adrenomedullin. Pretreatment with adrenomedullin and the adrenomedullin22-52 fragment did not result in changes of HGF and COX-2 expression, compared to the reserpine and adrenomedullin treated group. Pretreatment with adrenomedullin and the calcitonin gene-related peptide8-37 fragment (CGRP8-37) increased HGF and COX-2 expression, compared to the reserpine and adrenomedullin treated group. Our results suggest that the inhibitory effect of adrenomedullin on the expression of HGF and COX-2 is mediated by CGRP receptors.

Here, we show an increase in c-Met receptor expression during reserpine-induced gastric damage in the rat, as assessed by immunohistochemistry. Pretreatment of animals with adrenomedullin prevented this increase in c-Met expression. c-Met immunoreactivity was localized in gastric glands. c-Met immunoreactivity was associated with increased phosphorylation of c-Met receptor and extracellular signal-regulated kinase (ERK(1/2)). Our results suggest that both adrenomedullin and c-Met act as parallel defence mechanisms during pharmacologically induced gastric mucosa injury.

Adrenomedullin intracerebroventricularly administered (0.1 to 20 ng/rat i.c.v.), showed significant gastroprotective activity in a dose-dependent manner. When the peptide was intravenously administered (1 to 1000 ng/kg i.v.) it did not show significant gastroprotective activity in the same test. The gastroprotective effect of the peptide (10 ng/rat) was abolished by bilateral adrenalectomy, by pretreatment with the beta-adrenoceptor antagonist, propranolol (1 mg/kg i.p.), or by a calcitonin gene-related peptide (CGRP) receptor antagonist, CGRP-(8-37) fragment (1 or 10 ng/rat i.c.v.). This study showed that adrenomedullin is protective against reserpine-induced gastric lesions, that the action involves sympathetic nerve activity, and moreover interferes with CGRP receptors.

Subcutaneous administration of amylin (20-40 micrograms/kg) prevented, in a dose-dependent manner, reserpine- and serotonin-induced gastric damage, but the anti-ulcer effect was not present when lesions were induced by pylorus ligation. The protective effect of amylin was inhibited by pretreatment with capsicin as well as CGRP-(8-37), a calcitonin gene-related peptide (CGRP) and amylin receptor antagonist, and was significantly reduced by domperidone, a dopamine D2 receptor antagonist, or neostigmine, an inhibitor of acetylcholinesterase. Our data suggest that the gastroprotective activity of amylin in some experimental models of gastric ulcers involves capsaicin-sensitive fibers and CGRP receptors. Moreover, the peptide interferes, at least in part, with the dopaminergic and parasympathetic systems.

The anti-ulcer activity of calcitonin gene-related peptide (CGRP) was inhibited, in a dose-dependent manner, by pretreatment with NG-nitro-L-arginine methyl ester, an inhibitor of nitric oxide synthase. Our results suggest that endogenous nitric oxide is involved in the anti-ulcer activity of CGRP.

Intravenous administration of calcitonin gene-related peptide (CGRP) prevented in a dose-dependent manner reserpine-induced gastric mucosal damage, but failed to affect the lesions produced by ethanol administration. In pylorus-ligated rats, CGRP significantly reduced gastric volume, total acid and peptic activity output as well as ulcer formation. These protective effects of CGRP were not present when rats were pretreated with cysteamine. Our data suggest that CGRP exerts its antisecretory and antiulcer activity, at least in part, by interfering with somatostatin transmission.

We investigated the effect of the administration of rat parathyroid hormone-(1-34) on acute or chronic inflammatory processes in different experimental animal models. Fragment 1-34 of parathyroid hormone had an inhibitory effect in all inflammatory acute tests. The dose-response experiments showed that the maximal anti-inflammatory and anti-exudative effects appeared at the dose of 3.30 and 0.33 micrograms/kg, respectively. The anti-inflammatory effect was observed in the first phase of the inflammatory process. In the carrageenin-induced edema test the anti-inflammatory activity began to decline after 180 min. In contrast, this peptide was inactive in the inflammatory chronic test we used.

The effect of peripherally administered cyproheptadine or reserpine and the administration of 5,7-dihydroxytryptamine (5,7-DHT) in the nucleus raphe dorsalis on the analgesic activity of salmon calcitonin (sCT) injected into the lateral ventricle were investigated in male rats. Cyproheptadine or reserpine, given respectively 30 min or 24 h before the peptide, completely abolished the analgesic activity at all the times studied. However, when reserpine was given before the peptide it increased the effect of sCT at 30 (P less than 0.01), 60 (P less than 0.001), 120 (P less than 0.01) and 180 (P less than 0.01) min. 5,7-DHT injected in the nucleus raphe dorsalis 15 days before the peptide led to complete abolition of the analgesic activity. If neurotoxin was injected 4 days before sCT, the effect of the peptide was significant (P less than 0.05) only at 60 min. The results obtained confirm that the analgesic activity of sCT may involve central serotonergic pathway(s), and that the midbrain raphe nuclei 5-HT content is an important focus for this activity.