Effects of water-immersion-induced stress and intraperitoneal administration of brain-gut peptides upon immunoreactive thyrotropin-releasing hormone and prostaglandin E2 concentrations in the rat stomach

The effects of water-immersion-induced stress and intraperitoneal (i.p.) administration of selected neuropeptides on the levels of thyrotropin-releasing hormone (TRH) and prostaglandin E₂ (PGE₂) were studied in the rat stomach. Water-immersion caused a significant decrease in immunoreactive-TRH (irTRH) concentrations in the stomach, and a significant increase in ir-TRH concentrations in the gastric juice. The concentrations of PGE₂ were significantly increased at 0.5-4hrs, and significantly decreased at 6-8 hrs after water-immersion. In the experiment of i.p. administration of selected neuropeptides, the level of irTRH in the stomach was significantly decreased after VIP injection,whereas it was significantly increased after β-endorphin injection. The concentration of PGE₂ was significantly decreased in the stomach after i.p. administration of TRH and VIP. However, it did not change after β-endorphin injection. These results indicate that some neuropeptides may participate in regulating the endogenous level of PGE₂ and that these interrelations between neuropeptides and PGE₂ may be important as ulcerogenic factors in stress ulcers induced by water-immersion in the rat. A protion of this work was presented at the 31st annual meeting Of the Japanese Society of Gastroenrology, October 1989 in Ashikawa, Japan.     

The role of thyrotropin-releasing hormone (TRH) in the pathogenesis of water-immersion stress in rats—inhibition of TRH release from the stomach by atropine,ranitidine or omeprazole—

The role of thyrotropin-releasing hormone (TRH) in the development of gastric erosions and ulcers induced by water-immersion stress was studied. Intraperitoneally administered bethanechol induced a decrease in the gastric wall immunoreactive TRH (ir-TRH) concentrations and an increase in gastric juice ir-TRH concentrations in a dose-related manner, while atropine induced an increase in gastric wall ir-TRH concentrations and a decrease in gastric juice ir-TRH concentrations under non-stress condition. Intraperitoneally administered omeprazole did not influence gastric wall ir-TRH concentrations but elevated gastric pH. Water-immersion stress induced a decrease in gastric wall ir-TRH concentrations and an increase in gastric juice ir-TRH concentrations with a decrease in gastric pH prior to ulcer formation. Pretreatment with atropine or ranitidine inhibited the development of stress ulcers, reduced changes in ir-TRH concentrations in the gastric wall and gastric juice, and induced an increase in gastric pH. Omeprazole inhibited stress ulcer formation and changes in gastric wall and gastric juice ir-TRH concentrations. These results suggest that TRH release from the stomach wall into gastric juice is of importance in the pathogenesis of stress ulcer and that its release is mediated by both muscarinergic and histaminergic (H₂) systems. Furthermore, omeprazole has an inhibitory effect on TRH release under stress ulcer.     

Effect of luminal administration of thyrotropin-releasing hormone or somatostatin on gastric pH and interaction of these peptides in rats.

The effect of intraluminal administration of thyrotropin-releasing hormone (TRH) on gastric pH and release of luminal somatostatin, and a possible interrelationship between TRH and somatostatin in the rat stomach were studied. TRH was administered into the stomach via an intragastric tube at various doses (50 pg/kg-10 micrograms/kg) and gastric pH was measured after 15 min. The intraluminal administration of TRH significantly decreased gastric pH at doses over 1.0 ng/kg. Time-course studies at a dose of 100 ng/kg TRH exhibited a significant decrease in gastric pH at 15, 30 and 60 min. Furthermore, TRH administration caused a significant increase in immunoreactive-somatostatin (ir-somatostatin) concentrations in the gastric wall and a significant decrease in ir-somatostatin concentrations in the gastric juice. On the other hand, intraluminal administration of somatostatin caused a significant increase in ir-TRH concentrations in the gastric wall and a significant decrease in ir-TRH concentrations in the gastric juice, and significantly raised gastric pH at 5 min. These findings suggest that luminal TRH may exert a regulatory effect on gastric acid secretion, and that TRH may have a possible interaction with somatostatin in the modulation of gastric acid secretion.     

Effect of cold-restraint stress on immunoreactive thyrotropin-releasing hormone and immunoreactive somatostatin in the rat stomach

The effects of cold-restraint stress on immunoreactive thyrotropin-releasing hormone (ir-TRH) and immunoreactive somatostatin (ir-SOM) concentrations in the rat stomach were investigated. Rats immobilized with a spring-loaded metallic plate were placed in a room maintained at 4°C for 1–3 h and then decapitated serially for investigation. Gastric ir-TRH and ir-SOM concentrations were measured by individual radioimmunoassays. Cold-restraint stress induced gastric mucosal lesions as well as a decrease of the ir-TRH concentration in the glandular stomach, an increase of the ir-TRH concentration in the gastric juice, and a decrease in gastric pH. In contrast, this stress caused an increase of ir-SOM in the glandular stomach and a decrease of ir-SOM in the gastric juice. However, cold or restraint stress alone did not induce gastric mucosal lesions or changes in gastric ir-TRH and ir-SOM concentrations or the gastric pH. To clarify the endocrine influence of peripheral TRH, pretreatment with thyroid hormone was performed to inhibit elevation of the serum TRH level during cold-restraint stress. Despite this pretreatment, cold-restraint stress still induced ulcer formation, along with changes in gastric ir-TRH and ir-SOM concentrations and gastric pH. These findings suggest that changes in gastric ir-TRH and ir-SOM concentrations may be closely related to ulcer formation due to cold-restraint, and that TRH may act in a paracrine manner in the stomach.     

The effects of histamine on the concentrations of immunoreactive thyrotropin-releasing hormone in the stomach and hypothalamus in rats

The effects of histamine and its related compounds on the concentrations of immunoreactive thyrotropin-releasing hormone (ir-TRH) in the stomach, gastric juice and hypothalamus in rats were studied. Histamine, ranitidine or ethanolamine was injected intraperitoneally, and the rats were decapitated at various times after the injection. Ir-TRH concentrations in the stomach, gastric juice and hypothalamus were measured by a radioimmunoassay. Ir-TRH concentrations in the stomach decreased significantly after histamine injection and increased significantly after ranitidine injection in a dose-dependent manner, but did not change with ethanolamine. Ir-TRH concentrations in the gastric juice increased in a dose-dependent manner, peaking at 30 min after histamine injection, and its effect was blocked with ranitidine. Ir-TRH concentrations in the hypothalamus elevated significantly after histamine injection and reduced significantly after ranitidine injection, but did not change with ethanolamine. The effects of histamine on ir-TRH concentrations in the stomach and hypothalamus were significantly blocked with ranitidine, but not with ethanolamine. These findings suggest that histamine stimulates ir-TRH release from the stomach and inhibits ir-TRH release from the hypothalamus, and that these effects of histamine on ir-TRH release are mediated via an H2-receptor.     

The effects of histamine on the concentrations of immunoreactive thyrotropin-releasing hormone in the stomach and hypothalamus in rats

The effects of histamine and its related compounds on the concentrations of immunoreactive thyrotropin-releasing hormone (ir-TRH) in the stomach, gastric juice and hypothalamus in rats were studied. Histamine, ranitidine or ethanolamine was injected intraperitoneally, and the rats were decapitated at various times after the injection. Ir-TRH concentrations in the stomach, gastric juice and hypothalamus were measured by a radioimmunoassay. Ir-TRH concentrations in the stomach decreased significantly after histamine injection and increased significantly after ranitidine injection in a dose-dependent manner, but did not change with ethanolamine. Ir-TRH concentrations in the gastric juice increased in a dose-dependent manner, peaking at 30 min after histamine injection, and its effect was blocked with ranitidine. Ir-TRH concentrations in the hypothalamus elevated significantly after histamine injection and reduced significantly after ranitidine injection, but did not change with ethanolamine. The effects of histamine on ir-TRH concentrations in the stomach and hypothalamus were significantly blocked with ranitidine, but not with ethanol-amine. These findings suggest that histamine stimulates ir-TRH release from the stomach and inhibits ir-TRH release from the hypothalamus, and that these effects of histamine on ir-TRH release are mediated via an H₂-receptor. Portions of this work were presented at the 75th annual meeting of Japanese Society of Gastroenterology. March 1989 in Yokohama, Japan.     

Bombesin inhibits thyrotrophin secretion in rats

The effects of peripheral administration of bombesin on thyrotrophin-releasing hormone (TRH) and thyrotrophin (TSH) secretion in rats were studied. Bombesin (200 micrograms/kg) was injected iv, and the rats were serially decapitated. TRH, TSH and thyroid hormone were measured by radioimmunoassay. The hypothalamic immunoreactive TRH (ir-TRH) content increased significantly after bombesin injection, whereas plasma concentrations tended to decrease, but not significantly. Plasma TSH levels decreased significantly in a dose-related manner with a nadir at 40 min after the injection. Plasma thyroid hormone levels did not change significantly. Plasma ir-TRH and TSH responses to cold were inhibited by bombesin, but the plasma TSH response to TRH was not affected. In the pimozide- or para-chlorophenylalanine pre-treated group, the inhibitory effect of bombesin on TSH levels was prevented, but not in the L-Dopa- or 5-hydroxytryptophan pre-treated group. These drugs alone had no effect on plasma TSH levels in terms of the dose used. The inactivation of TRH immunoreactivity in plasma or hypothalamus in vitro after bombesin injection did not differ from that of the controls. These findings suggest that bombesin acts on the hypothalamus to inhibit TRH release, and that its effects are at least partially modified by amines of the central nervous system.     

Effects of eledoisin on thyrotrophin secretion in rats

The effect of peripheral administration of eledoisin on thyrotrophin-releasing hormone (TRH) and thyrotrophin (TSH) secretion in rats were studied. Eledoisin (500 micrograms/kg) was injected iv, and the rats were serially decapitated. TRH, TSH and thyroid hormone were measured by radioimmunoassay. The hypothalamic immunoreactive TRH (ir-TRH) content increased significantly after eledoisin injection, whereas its plasma concentration tended to decrease, but not significantly. Plasma TSH levels decreased significantly in a dose-related manner with a nadir at 40 min after the injection. Plasma thyroid hormone levels did not change significantly. Plasma ir-TRH and TSH responses to cold were inhibited by eledoisin, but the plasma TSH response to TRH was not affected. In the pimozide- or para-chlorophenylalanine-pretreated group, the inhibitory effect of eledoisin on TSH levels was prevented, but not in the L-dopa- or 5-hydroxytryptophan-pretreated group. These drugs alone did not affect plasma TSH levels at the dose used. The inactivation of TRH immunoreactivity by plasma or hypothalamus in vitro after eledoisin injection did not differ from that of controls. These findings suggest that eledoisin acts on the hypothalamus to inhibit TRH release, and its effects are modified by amines of the central nervous system.     

Effect of Preinduction of Heat-Shock Proteins on Acetic Acid-Induced Small Intestinal Lesions in Rats

Bowel dysfunction such as irritable bowelsyndrome caused by stress is well described. Previousreports suggest that stress is known to cause therelease of endogenous substances such as catecholamine, beta-endorphine, 5-hydroxytryptamine,corticotropin-releasing factor, andthyrotropin-releasing hormone (TRH). However, the roleplayed by these neurohormonal mediators in boweldysfunction under stress conditions is not well known. We investigatedthe influence of water-immersion stress or TRHadministration on the expression of 60-kDa, 72-kDa, and90-kDa heat-shock proteins (HSP60, HSP72, and HSP90, respectively) in rat small intestinal mucosa byWestern blot and immunohistochemical analyses. Thecytoprotective function of preinduced HSPs onexperimentally induced mucosal damage also was studied.In order to investigate the influence ofpreinduction of HSP60 on small intestinal damage, thesmall intestinal lumen was perfused with 1.5% aceticacid 1 ml/min for 15 min with or without pretreatmentwith water-immersion stress or TRH administration.Expression of HSP60 was significantly increased bywater-immersion stress or TRH administration in thesmall intestinal mucosa, whereas HSP72 and HSP90 did not increase. Interestingly, expression of thisprotein showed the biphasic peak pattern afterwater-immersion stress or TRH administration. Each peakwas observed 3-6 hr and 21-24 hr after the initiation of water-immersion stress or TRHadministration. Immunohistochemical study also showed asignificant increment of HSP60 in both the cytoplasm andnuclei of the small intestinal mucosal cells. Nohistopathologic alteration was observed in rat small intestinalmucosa after each treatment. Small intestinal damagecaused by 1.5% acetic acid perfusion was not influencedby preinduction of HSP60. We demonstrated that waterimmersion stress or TRH administrationspecifically induced HSP60, although preinduction ofthis protein did not show a cytoprotective function inthe small intestinal mucosa.     

beta-Neoendorphin inhibits thyrotrophin secretion in rats

The effects of beta-neoendorphin on thyrotrophin-releasing hormone (TRH) and thyrotrophin (TSH) secretion in rats were studied. beta-neoendorphin (500 micrograms/kg) was injected iv, and the rats were decapitated serially. TRH, TSH, thyroxine (T4) and 3,3',5-triiodothyronine (T3) were measured by means of a specific radioimmunoassay for each. Hypothalamic immunoreactive TRH (ir-TRH) content increased significantly after beta-neoendorphin injection, and plasma concentrations tended to decrease, but not significantly so. Plasma TSH levels decreased significantly in a dose-related manner with a nadir at 40 min. Plasma T4 and T3 levels did not change after the injection. Plasma ir-TRH and TSH responses to cold were significantly inhibited by beta-neoendorphin, but the plasma TSH response to TRH was not. Naloxone partially prevented the inhibitory effect of beta-neoendorphin on TSH release. In the haloperidol- or 5-hydroxytryptophan-pretreated group, the inhibitory effect of beta-neoendorphin on TSH release was prevented, but not in the L-dopa- or para-chlorophenylalanine-pretreated group. These drugs alone did not affect plasma TSH levels at the dose used. These findings suggest that beta-neoendorphin acts on the hypothalamus by inhibiting TRH release, which may be modified by amines of the central nervous system.     

Circadian rhythm of urinary somatostatin-like immunoreactivity (SLI) and its contents in several organs after oral TRH administration in rats

Urinary SLI was measured every six hours for twenty four hours in rats fed a regular diet. Previously, we found that the urinary SLI increased after the administration of TRH intravenously. In the present study, in order to reveal the localization of increased SLI, we measured the contents in the hypothalamus, pituitary, thyroid, stomach and pancreas after the oral TRH administration. (1) The rat urinary SLI levels showed a circadian rhythm. The maximum level of SLI was collected from 0.00--6.00 a.m. (89.4 +/- 8.6 pg/6 hrs) (mean +/- SEM). This level was reduced during the daytime 6.00 a.m.--6.00 p.m. The minimum level was obtained from 6.00 p.m.--0.00 a.m. (49.3 +/- 7.2 pg/6 hrs). (2) The rats were decapitated at three and six hours after the oral TRH (500 micrograms/ml) administration. The SLI content was measured by RIA after extraction from each organ with 2.5 ml of 2 M acetic acid. The pituitary SLI content was reduced three hours after the oral TRH administration. The thyroid SLI content was reduced six hours after the oral TRH administration. The hypothalamic, gastric and pancreatic SLI contents didn't change at three and six hours after the oral TRH administration. As the result, the data suggest that augmentation by the oral TRH administration of urinary SLI was caused by its effect on the both the pituitary and the thyroid.     

Concentrations of immunoreactive thyrotropin-releasing hormone in spinal cord of patients with amyotrophic lateral sclerosis

Concentrations of immunoreactive thyrotropin-releasing hormone (ir-TRH) were measured by specific radioimmunoassay in the spinal cord of six patients with amyotrophic lateral sclerosis (ALS) and seven with non-neurological diseases. Ir-TRH concentrations were the highest in the anterior horn, compared with other areas of the spinal cord, both in non-neurological diseases and ALS. Ir-TRH concentrations in the anterior horn of ALS were significantly lower than in non-neurological diseases, but were the same in both groups in other parts of the spinal cord (e.g. posterior horn, frontal part, lateral and central part, posterior part). Ir-TRH concentrations in rat spinal cords were stable for up to seven hours when spinal cord was stored after death at 4 degrees C or 22 degrees C. An elution profile of methanol-extracted human spinal cord on Sephandex G-10 column was identical to that of synthetic TRH. The cell population in the anterior horn in ALS was decreased markedly. The findings suggest that TRH is present in the human spinal cord and its decreased concentrations in the anterior horn of ALS may be due to a decrease in the cell population.     

Roles of nocturnal melatonin and the pineal gland in modulation of water-immersion restraint stress-induced gastric mucosal lesions in rats

The roles of melatonin and the pineal gland in the circadian variation of water-immersion restraint stress-induced gastric mucosal lesions in rats were investigated. Fasted rats were subjected to water-immersion restraint stress during both the diurnal and nocturnal phases of a light:dark cycle. Pinealectomized and sham-operated rats were also subjected to water-immersion restraint stress at night. The lesion area after 4 hr of stress during the dark phase was significantly lower than in light-phase controls. Pinealectomy increased the lesion area in the dark phase, compared to the sham operation, but this effect was counteracted by intracisternal melatonin preadministration at a dose of 100 ng/rat. Melatonin concentrations in control rats during the light phase were significantly increased 4 hr after water-immersion restraint stress. In contrast, melatonin concentrations 4 hr after water-immersion restraint stress in the dark phase were significantly depressed compared with the control levels at the corresponding time. Melatonin levels after stress exposure were markedly decreased in pinealectomized rats as compared with sham-operated rats. These results suggest that circadian rhythm has an important role in the formation of stress-induced gastric mucosal lesions in rats and that melatonin responses to water-immersion restraint stress differ between day and night. The pineal gland modulates the stress response and melatonin contributes to gastric protection via a mechanism involving the central nervous system.     

Effects of dopexamine on regional blood flow and leukotriene production in multiple splanchnic sites in endotoxemic rats

BACKGROUND/AIMS: This work examines the effects of lipopolysaccharide (LPS) on splanchnic blood flow and tests the potential effect of dopexamine in preventing LPS-induced decrease in splanchnic blood flow, also analyzing its influence on regional leukotriene production. METHODOLOGY: Male Sprague-Dawley rats were grouped and subjected to i.v. administration (time 0) of the lipopolysaccharide (10mg/kg) or vehicles with some rats receiving dopexamine (2microg/kg/min) (times 2 hrs to 6 hrs) infusion and compared. Microdialysis collection for analyzing leukotrienes concentrations and direct splanchnic laser Doppler flowmetry were started at times 0 to 6 hrs. RESULTS: Mean arterial pressure decreased markedly in LPS-injected animals and it decreased further gradually during observation period. A marked increase in mean arterial pressure was noted following concomitant administration of dopexamine with LPS. CONCLUSIONS: Impaired splanchnic blood flow in the stomach, jejunum and ileum after LPS injection has been attenuated following infusion of dopexamine. The changes in regional blood flow in the specific splanchnic area correlate closely with the systemic mean arterial pressure in this early sepsis model. Increased leukotriene production following LPS injection also has been attenuated in the stomach, jejunum and ileum following dopexamine infusion, and the increase of leukotriene production also correlates closely with systemic mean arterial pressure.     

Effect of prostaglandin E1 on vasoactive intestinal polypeptide release from the hypothalamus and on prolactin secretion from the pituitary in rats

In order to elucidate the mechanisms by which prostaglandin (PG) affects PRL secretion, the effect of PGE1 on vasoactive intestinal polypeptide (VIP) release from the rat hypothalamus was examined by determining plasma VIP levels in rat hypophysial portal blood in vivo and VIP release from the perifused hypothalamus in vitro. Intraventricular injection of PGE1 (1 and 5 micrograms/rat) caused a 2- to 3-fold increase in the concentration of plasma VIP in hypophysial portal blood in anesthetized rats. The flow rate of portal blood was slightly increased after the injection of PGE1. VIP release from the perifused rat hypothalamus was stimulated by high potassium levels (56 mM). The infusion of PGE1 (10 microM) resulted in a significant increase in VIP release from the hypothalamus in vitro. Both these responses were calcium dependent. The intraventricular injection of PGE1 (1 and 5 micrograms/rat) resulted in a dose-related increase in peripheral plasma PRL levels in the rat. These findings suggest that PGE1 plays a stimulatory role in regulating VIP release from the hypothalamus into hypophysial portal blood and causes PRL secretion from the pituitary in rats.     

Oral but not parenteral aspirin upregulates COX-2 expression in rat stomachs. a relationship between COX-2 expression and PG deficiency

AIM: We compared the ulcerogenic effects of aspirin (ASA) and indomethacin in the rat gastric mucosa depending on the route of administration, together with the expression of COX-2. METHODS: Animals fasted for 18 h were given ASA or indomethacin, either p.o. or s.c., and the stomach was examined 4 h later. RESULTS: Indomethacin decreased mucosal PGE(2 )level, increased gastric motility, and caused gastric lesions with the up-regulation of COX-2 expression, irrespective of the route of administration. ASA induced both damage and COX-2 expression in the stomach when given p.o. but not s.c., despite decreasing the PGE(2) level similarly via either route of administration. Gastric motility was temporarily increased and gastric potential difference (PD) was markedly decreased by ASA given p.o. PGE(2) and atropine, although preventing ASA-induced gastric lesions as well as hypermotility, affected neither the COX-2 expression nor PD reduction induced by p.o. ASA. By contrast, the COX-2 expression induced by indomethacin was prevented by both PGE(2) and atropine. CONCLUSION: ASA given p.o. caused damage in the stomach, together with the up-regulation of COX-2 expression, and this expression may be due to the topical irritative action, rather than being a result of PG deficiency. The expression of COX-2 after indomethacin is associated with gastric hypermotility due to PG deficiency.     

Vasoactive intestinal peptide increases intracellular free calcium in rat and human pituitary tumour cells in vitro

Prolactin secretion by a human pituitary tumour cell line produced in our laboratory was stimulated by TRH, vasoactive intestinal peptide (VIP) and epithelial growth factor (EGF). All raised the intracellular concentration of free calcium (Ca2+ i) of cells loaded with a fluorescent quinoline Ca2+ indicator in suspension, but the effect of TRH was much more rapid and less prolonged than that of VIP and EGF. Both TRH and VIP also increased Ca2+ i in GH3 rat pituitary tumour cells, but in this cell line the effect of VIP was only found in attached cells grown on cover-slips. In both human and rat cell lines, the increase in Ca2+ i produced by TRH was independent of extracellular calcium, whereas this was a requirement for the action of VIP and EGF. It is concluded that the prolactin secretagogues, VIP and probably EGF, increase Ca2+ i through an effect on plasma membrane calcium channels and that this effect differs from that of TRH.     

Functional Mechanism Underlying COX-2 Expression Following Administration of Indomethacin in Rat Stomachs: Importance of Gastric Hypermotility

The expression of COX-2 is up-regulated in the rat stomach after administration of indomethacin, and the inhibition of this enzyme may be a key to NSAID-induced gastric damage. The present study investigated the mechanism for COX-2 expression induced in the rat stomach by indomethacin, in relation with the ulcerogenic processes. The animals were given indomethacin or SC-560 p.o., and the gastric mucosa was examined 8 hr later. Indomethacin decreased the mucosal PGE2 content and produced gross damage with gastric hypermotility and the expression of COX-2 mRNA in the mucosa. Although SC-560 did not produce damage, this agent caused a decrease in the PGE2 content and an increase in gastric motility as well as the up-regulation of COX-2 expression, and provoked damage in the presence of rofecoxib. Gastric lesions induced by indomethacin were prevented by both atropine (even in the presence of exogenous HCl) and omeprazole, although the hypermotility response was inhibited only by atropine. The COX-2 expression induced by indomethacin or SC-560 was inhibited by atropine, even in the presence of exogenous HCl, while omeprazole had no effect. The mucosal PGE2 content was decreased by SC-560 at 2 hr but recovered 8 hr later, and this recovery of PGE2 was attenuated by both atropine and rofecoxib but not omeprazole. These results suggested that the COX-2 expression in the stomach following treatment with indomethacin is functionally associated with gastric hypermotility response induced by COX-1 inhibition. Luminal acid does not play a role in the up-regulation of COX-2 expression in the stomach following administration of indomethacin.     

Effect of thyrotropin-releasing hormone on growth hormone release in normal subjects pretreated with human pancreatic growth hormone-releasing factor 1-44 pulsatile administration

Growth hormone (GH) increase after thyrotropin-releasing hormone (TRH) has been documented in many pathological conditions. In order to evaluate whether exposure to growth hormone-releasing factor (GRF) might contribute to this effect in normal subjects, we studied GH responses to placebo, TRH, GRF and GRF plus TRH either in basal condition or after GRF administration. Ten subjects received placebo, TRH, GRF and GRF plus TRH on four separate occasions. GRF induced a clear rise in plasma GH, statistically different from those obtained after placebo or TRH (p less than 0.01). TRH was completely ineffective in both stimulating GH release and amplifying the secretory GH response to GRF. Twenty subjects, subdivided in four groups, received 3 consecutive intravenous GRF boli at two-hour intervals. Two hours later they were given a fourth stimulus: 5 had another 25 micrograms GRF i.v., 5 had 200 micrograms TRH i.v., 5 were tested with simultaneous 25 micrograms GRF and 200 micrograms TRH i.v. injection, and 5 with 1 ml saline. GH secretory responses were quantitated by determining the net incremental area under the curve (nAUC) over 60 min after the administration of each stimulus. The pattern of GH secretion after 1-3 GRF boli was not statistically different among the four groups. Plasma GH nAUC was higher after the first GRF injection than after the following ones (p less than 0.01). The administration of a fourth GRF bolus also caused a GH increase which was significantly smaller than that after the first one (p less than 0.01), but greater than that after placebo (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Cold stress or a pyrogenic substance elevates thyrotropin-releasing hormone levels in the rat hypothalamus and induces thermogenic reactions

Both thyrotropin-releasing hormone (TRH) levels in the hypothalamus and thermoregulatory responses were assessed in rats after they had been equilibrated to each of three ambient temperatures (Ta: 8, 22 and 30 degrees C) tested. Cold exposure, in addition to elevating TRH levels in the hypothalamus, led to increased metabolism and cutaneous vasoconstriction in rats at Ta = 8 degrees C. In contrast, heat exposure resulted in decreased metabolism and cutaneous vasodilatation in rats accompanied by no change in hypothalamic TRH levels at Ta = 30 degrees C. In addition, rats were chronically implanted with a cerebroventricular cannula to allow administration of the pyrogenic substance polyriboinosinic acid-polyribocytidylic acis (Poly I:C) into the brain at Ta = 22 degrees C. Intracerebroventricular administration of Poly I:C, in addition to elevating hypothalamic TRH levels, produced a fever with a latency of onset of about 30 min. The fever induced by Poly I:C was brought about by increased metabolism and cutaneous vasoconstriction in rats. The results suggest that either cold stress or Poly I:C injection elevates TRH levels in rat hypothalamus and thus induces thermogenic reactions.