Endogenous prostaglandin I2 regulates the neural emergency system through release of calcitonin gene related peptide

Abstract

Background: We previously reported that endogenous prostaglandin I 2 , generated by a mild irritant, sensitised calcitonin gene related peptide (CGRP) containing sensory nerves and facilitated the release of CGRP and gastric mucosal protection against ethanol. Administration of capsaicin also inhibited ethanol induced gastric mucosal injury through immediate release of CGRP from primary sensory neurones, which is termed the neural emergency system. In the present study, we tested whether endogenous prostaglandin I 2 also modulates the cytoprotective action of capsaicin using prostaglandin I receptor knockout mice (IP −/− ). Methods: The stomachs of IP −/− or their wild-type counterparts (IP +/+ ), anaesthetised with urethane (1.225 g/kg), were doubly cannulated from the oesophageal and duodenal sides, and the gastric mucosa was perfused (1 ml/min) with physiological saline. Perfusate was changed to 50% ethanol alone, or 50% ethanol containing capsaicin (16∼1600 µM). The injured area was estimated at the end of each perfusion experiment. In some animals, CGRP-(8-37), a CGRP antagonist (0.3 mg/kg), or indomethacin (1 mg/kg) was intravenously injected before perfusion of 50% ethanol containing capsaicin. Results: Capsaicin inhibited the injured area in a dose dependent manner. Fifty per cent ethanol containing capsaicin (480 µM) immediately increased intragastric levels of CGRP although 50% ethanol alone did not. The protective action of capsaicin (480 µM) against ethanol was completely abolished by intravenous injection of CGRP-(8-37). Indomethacin also inhibited the protective action of capsaicin, and this was accompanied by reduced levels of intragastric CGRP. Intragastric levels of prostaglandin E 2 were not increased by capsaicin treatment but those of 6-keto-prostaglandin F 1α , a metabolite of prostaglandin I 2 , were markedly increased. No protective action of capsaicin was observed in IP −/− which lacked the ability to increase intragastric CGRP levels in response to ethanol containing capsaicin. The CGRP content of the stomach from untreated IP −/− did not differ from those in IP +/+ . Capsaicin (160 µM) together with intragastric perfusion of beraprost sodium (PGI 2 analogue, 2.5 µg/ml) showed enhanced protection against ethanol induced injury. This enhanced protection was completely blocked by intravenous injection of CGRP-(8-37). Conclusions: The present results suggest that endogenous prostaglandin I 2 enhances the protective action of the capsaicin mediated neural emergency system against ethanol induced gastric mucosal injury through enhancement of CGRP release.

Characterization of the non‐adrenergic/non‐cholinergic response to perivascular nerve stimulation in the double‐perfused mesenteric bed of the mouse

“…Such stimulation also triggers the release of immunoreactive CGRP from the arterial mesenteric bed, as previously reported also in a mouse gastric mucosa model (Arai et al, 2003) but not in the venous circuit. Thus, we suggest that the endogenous neuropeptide CGRP acts as a physiological antagonist of adrenergic/cholinergic-induced increases of perfusion pressure in the mesenteric pre-capillary circuits of the mouse.…”

“…For measurements of immunoreactive CGRP release after PNS, an enzyme immunoassay (EIA) for rat CGRP (EIA Kit no 589001, Cayman Chemicals, distributed by Cedor Lane, Canada) with a 100% cross-reactivity with the same peptide of murine origin (Arai et al, 2003 and Cayman Chemicals) was used. After stabilization, 10 min (basal) perfusates were collected before and following PNS.…”

Calcitonin Gene-Related Peptide Ameliorates Hyperoxia-Induced Lung Injury in Neonatal Rats

“…In addition, as one of the prostaglandins, PGI2 can exert anti-inflammatory effects by inhibiting the production of TNF through inhibition of its transcription (Jorres et al 1997). Despite this effect, CGRP treatment has been demonstrated to increase the endothelial production of prostaglandin I2 (Arai et al 2003). Other studies have further demonstrated that adrenomedulin, a peptide structurally related to CGRP, can act via both CGRP and adrenomedulin receptors to mediate its effects.…”

Roles of thromboxane A2 and prostacyclin in the development of atherosclerosis in apoE-deficient mice

“…These receptors are encoded by distinct genes and are expressed differentially in the body. With the use of homologous recombination, we have generated mice that lack either TP or IP individually and have subjected the mice to models of various diseases to analyze the roles of TXA 2 and PGI 2 (19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29). In this work, we have cross-bred TP-and IP-deficient (TP -/-and IP -/-) mice with apoE -/-mice and have analyzed the roles played by TXA 2 and PGI 2 in atherosclerotic lesion development.…”