Stable Thyrotropin-releasing Hormone Analog Research Articles

Medullary Sites of Action of the TRH Analogue, RX 77368, for Stimulation of Gastric Acid Secretion in the Rat

Brain and spinal sites of action of the stable thyrotropin-releasing hormone (TRH) analogue, RX 77368 [pGlu-His-(3,3'-dimethyl)-Pro-NH2], for stimulation of gastric acid secretion have been investigated in urethane-anesthetized rats with gastric fistula. RX 77368 microinjected at a 7.7-pmol dose into the dorsal vagal complex or nucleus ambiguus stimulated gastric acid secretion to 62.2 +/- 15.9 and 45.3 +/- 14.3 mumol/h, respectively, whereas in the vehicle-treated group acid secretion was 0.5 +/- 1.0 mumol/h. A 10-fold higher dose of RX 77368 was inefficient when microinjected into the medial septum, central amygdala, or lateral hypothalamus. The gastric secretory response to microinjection of RX 77368 into the nucleus ambiguus was dose related (0.7-77 pmol), long-lasting (greater than 90 min), and blocked by vagotomy. TRH (144 pmol) injected into the nucleus ambiguus also stimulated gastric acid secretion but was less potent than the stable TRH analogue, whereas the unrelated peptide, oxytocin, was inactive. Intrathecal injection of RX 77368 at doses up to 2500 pmol did not modify gastric acid secretion. These results demonstrate that the dorsal vagal complex and nucleus ambiguus are TRH sites of action for stimulation of gastric acid secretion through vagal dependent pathways. These findings, added to the high concentrations of TRH-like immunoreactivity and receptors present in these nuclei, suggest a possible role of medullary TRH in the vagal regulation of gastric acid secretion.

Central nervous system action of calcitonin to alter experimental gastric ulcers in rats

The central nervous system action of calcitonin to influence various experimental models of gastric ulcers and gastric function was studied in rats fasted for 24 h. Intracisternal injection of salmon calcitonin (5 μg) completely suppressed gastric ulcerations induced by exposure to cold restraint stress, intracisternal injection of a stable thyrotropin-releasing hormone analogue, or peroral administration of aspirin. By contrast, intracisternal calcitonin enhanced gastric lesions elicited by peroral administration of 40% ethanol or 0.6 N HCl. Calcitonin action was dose-dependent (0.01–1 μg) and central nervous system mediated inasmuch as intravenous calcitonin, given at a dose 50-fold higher than that effective intracisternally, did not significantly modify gastric mucosal injuries elicited by aspirin or ethanol. Intracisternal injection of calcitonin at 0.01 μg inhibited gastric acid output by 90% in pylorus-ligated rats and suppressed gastric emptying of a liquid meal by 63%–94% in doses ranging from 0.01 to 5 μg. Prostaglandin generation in the gastric mucosa was not modified by intracisternal injection of calcitonin. These results demonstrate that intracisternal calcitonin acts within the brain to potently prevent ulcer formation elicited by stress, thyrotropin-releasing hormone analogue, or aspirin, but is not cytoprotective against necrotizing agents. Calcitonin action is not related to modification of gastric prostaglandin generation but it may involve the inhibition of gastric secretory and motor function.

Thyrotropin-releasing hormone (TRH) acts centrally to stimulate gastric contractility in rats

Changes in gastric contractility induced by intracisternal (ic) injection of thyrotropin-releasing hormone (TRH) or a stable TRH analog, RX77368 [p-Glu-His-(3,3′-dimethyl)-Pro NH2] were investigated in 24 h fasted-conscious rats. Gastric contractility was monitored using chronically implanted extraluminal force transducers sutured to the corpus. Response elicited by a standard meal was used as a physiologic standard. Intracisternal injection of TRH (1ug) or RX77368 (100 ng), unlike saline, stimulated high amplitude gastric contractions. The stimulation of gastric contractions induced by ic RX77368 was dose dependent (3–100 ng), rapid in onset, long lasting and not mimicked by the intravenous route of administration. Atropine (0.1 mg/kg) partially antagonized and vagotomy totally blocked the RX77368 (100 ng, ic)-induced stimulation of gastric contractility. These results demonstrated that TRH or RX77368 acts within the brain to elicit potent contractions of the stomach; TRH action appears vagally mediated probably through cholinergic mechanism.