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Biomedical subjects

U Knigge

Publications and source records attributed to U Knigge.

At least 55 records · Page 3Linked to original sources

On the effects of human galanin in man.

Human galanin was recently isolated and sequenced and was found to differ from porcine galanin, hitherto used for studies in humans, in several important respects. We therefore synthesized and purified human galanin and infused it i.v. at a rate of 74 pmol.kg-1.min-1 into six healthy volunteers for 60 min during a hyperglycaemic clamp. The clamp was achieved by i.v. infusion of glucose at a rate which in a control experiment had been demonstrated to maintain the plasma glucose level at 12-13 mmol/l for 90 min. Galanin concentrations reached a plateau of approximately 1500 pmol/l throughout the infusion as opposed to pre-infusion and control levels of 20-30 pmol/l. The glucose levels obtained in the two experiments were indistinguishable. Plasma levels of C-peptide and insulin increased significantly in both experiments and the dynamic concentration curves were almost identical. Glucagon concentrations in plasma decreased significantly and similarly. Growth hormone levels, however, increased eight-fold during galanin infusions. Galanin was eliminated from plasma with a half-life of 3.7 +/- 0.4 min, similar to that of porcine galanin. It is concluded that human galanin powerfully stimulates growth hormone secretion in man, but has no effect on pancreatic endocrine secretion or glucose metabolism in the concentrations obtained in this study.

Adult↗

Effect of diazepam on endocrine and cardiovascular responses to head-up tilt in humans.

Effects of the GABAergic drug diazepam (0.15 mg kg-1, i.v.) on cardiovascular and endocrine responses to 50 degrees head-up tilt were evaluated in seven men. During the initial phase of tilt (normotensive phase), increases in heart rate (HR) and total peripheral resistance (TPR) and decreases in cardiac output were unaffected by diazepam. Also the associated increase in plasma noradrenaline did not change, while response in plasma ACTH was diminished and in plasma cortisol abolished by diazepam (F(1,10) = 6.45; P < 0.03). After 42 +/- 4 min of sustained tilt with saline (control) and 47 +/- 6 min (n.s.) after diazepam, presyncopal symptoms appeared (hypotensive phase) associated with decreases in HR, MAP, and TPR (P < 0.01). This episode induced a 2-3-fold increase in plasma ACTH, beta-endorphin, prolactin, cortisol (< 0.01), and a moderate increase in plasma adrenaline (P < 0.05). Diazepam did not significantly change cardiovascular and endocrine responses to the hypotensive phase of tilt. Results indicate that diazepam attenuates the cortisol part of pituitary-adrenal responses to moderate, but not to severe, central hypovolaemia in humans with no effect on cardiovascular tolerance.

Adult↗

Effect of serotonin receptor blockade on endocrine and cardiovascular responses to head-up tilt in humans.

Effects of blockade of serotonin (5-HT) receptors on the integrated cardiovascular and endocrine adaptations during head-up tilt were investigated in normal men. In control experiments 50 degrees head-up tilt increased heart rate (HR), total peripheral resistance (TPR), plasma renin activity (PRA) and sympathetic activity (plasma noradrenaline; NA). A moderate increase in pituitary-adrenal hormones (plasma ACTH, beta-END and cortisol) was observed. After a mean tilt time of 30 +/- 5 min (n = 20) presyncopal symptoms associated with decreases in HR, TPR and arterial pressure occurred. At this time pituitary hormones, cortisol, adrenomedullary (plasma adrenaline; A) as well as vagal activity (plasma pancreatic polypeptide) were markedly increased, whereas sympathetic activity (plasma NA) decreased. The 5-HT1+2 receptor antagonist methysergide did not significantly interfere with cardiovascular variables but attenuated the response of NA, prolactin (PRL), beta-endorphin (beta-END) and PRA (P < 0.02). The 5-HT2-receptor antagonist ketanserin reduced the tolerated tilt time (10 +/- 4 vs. 32 +/- 2 min; P < 0.0003, n = 7) but had no significant effects on hormonal variables. The 5-HT3-receptor antagonist ondansetron abolished the adrenomedullary response to hypotension without affecting cardiovascular tolerance or the activity of the pituitary-adrenal axis. The results suggest that serotonergic mechanisms may be involved in the integrated cardiovascular and endocrine responses to central blood volume depletion in humans.

Adrenocorticotropic Hormone↗

Enhanced heart rate response to haemorrhage by ileus in the pig.

Effects of ileus on cardiovascular and hormonal responses to haemorrhage were evaluated in 10 anaesthetized pigs. Ileus was induced and the bleeding sequence repeated on the following day. Before ileus, a resting heart rate (HR) of 105 (range 83-140) beats min-1 remained unchanged until haemorrhage amounted to 15% of the blood volume. With a blood loss of 28% HR increased to a maximum of 162 (126-245) beats min-1. In contrast, ileus increased HR upon initiation of haemorrhage from a similar resting value to a maximum of 200 (152-250) beats min-1 (P < 0.0005). There were neither statistical differences in mean arterial pressure, cardiac output, central venous pressure, thoracic electrical impedance, pulmonary arterial mean pressure, pulmonary wedge pressure, pulmonary and systemic vascular resistances, nor in plasma concentrations of dopamine, adrenaline, vasopressin and aldosterone during haemorrhage before and after ileus. Plasma noradrenaline increased more with haemorrhage after than before ileus: from 2.8 (1.2-5.0) to 13 (2.3-59.0) vs. 3.0 (1.5-4.2) to 3.6 (2.7-17.5) nmol l-1 (P < 0.005). Also, the pancreatic polypeptide response to haemorrhage was enlarged with ileus (29 (0-60) to 90 (45-145) vs. 23 (0-64) to 57 (27-106) pmol l-1 (P < 0.005)). No significant differences could be detected in cardiovascular and hormonal responses to haemorrhage before and after a sham-operation in three pigs. Results demonstrate an immediate and enhanced HR response to haemorrhage in the pig with ileus, reflected in sympathetic activation as indicated by plasma noradrenaline.

Animals↗

Involvement of vasopressin in histamine- and stress-induced prolactin release: permissive, mediating or potentiating role?

Arginine vasopressin (AVP) appears to be involved in the histamine (HA)- and stress-induced prolactin (PRL) release. The present investigation was performed in male rats to clarify whether the role of AVP in HA- and restraint stress-induced secretion of PRL is mediating (i.e., the effect of HA or stress is transmitted via AVP) or permissive (i.e., the presence of AVP is required to obtain a stimulatory effect of HA or stress on PRL secretion). Furthermore, we studied whether AVP possessed a potentiating effect on the HA- or stress-induced PRL release. PRL secretion was stimulated 14- to 17-fold by intracerebroventricular infusion of HA (270 nmol) or by 5 min of restraint stress. These effects were inhibited about 80% by immunoneutralization of endogenous AVP with a specific AVP antiserum (abAVP). When specific AVP V1- or V2-receptor agonists, which were not bound by the AVP antiserum, were administered intravenously together with the AVP antiserum, the PRL response to HA or restraint stress was partly (> 50%) reestablished. This effect was observed at low (1.2 or 0.1 nmol) as well as high (3.8 or 0.4 nmol) doses of agonists and when these were administered alone or in combination. In non-immunoneutralized animals, separate administration of agonists at low or high doses as well as combined administration of agonists at low doses had no or only a minor effect on PRL secretion, while combined administration of V1- and V2-agonist in high doses stimulated PRL secretion 6-fold. Taken together, these observations indicate that AVP has a permissive role.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Effect of selective serotonin receptor agonists on prolactin secretion in male rats.

The effect of different serotonin (5-HT) receptor agonists on the release of prolactin (PRL) was investigated in conscious male rats. The 5-HT1 receptor agonists 5-carboxamidotryptamine and RU 24969 stimulated the PRL secretion dose dependently. RU 24969 possessed almost the same potency and efficacy (maximal effect) as 5-HT, while 5-carboxamidotryptamine was more potent and had a higher efficacy. The 5-HT1 + 2 receptor agonist MK 212 stimulated the PRL secretion only at high doses. The 5-HT2 receptor agonist S(alpha)methyl-5-HT and the 5-HT3 receptor agonist 2-methyl-5-HT had minor or no effect on the PRL secretion. The PRL-releasing effect of submaximal doses of 5-carboxamidotryptamine and RU 24969 was blocked by the 5-HT1 + 2 receptor antagonist methysergide and enhanced by other 5-HT agonists, but was unaffected by the 5-HT2 and 5-HT3 receptor antagonists. MK 212, S(alpha)methyl-5-HT, and--in particular--2-methyl-5-HT potentiated the effect of 5-carboxamidotryptamine. Likewise, 2-methyl-5-HT potentiated the effect of RU 24969, while MK 212 or S(alpha)methyl-5-HT had an additive to slightly potentiating effect. The findings show that 5-HT stimulates PRL secretion via 5-HT1 as well as 5-HT2 receptors and that activation of 5-HT2 and 5-HT3 receptors significantly augment the PRL-stimulating effect of 5-HT1 receptor activation. This indicates that the 5-HT receptor subtypes may interact functionally in the mediation of the PRL-releasing effect of the serotonergic system.

Animals↗

Involvement of vasopressin V1- and V2-receptors in histamine-and stress-induced secretion of ACTH and beta-endorphin.

Arginine-vasopressin (AVP) seems to be involved in the histamine (HA)-and stress-induced release of ACTH and beta-endorphin (beta-END). We studied the effect of selective AVP V1-or V2-receptor blockade on the ACTH and beta-END response to HA or restraint stress in conscious male rats. HA (270 nmol) administered intracerebroventricularly or 5 min of restraint stress caused a 3-to 7-fold increase in the plasma levels of ACTH and beta-END immunoreactivity (beta-ENDir). Pretreatment of the animals with the nonselective V1+2-receptor antagonist [1-Pmp-2-D-Phe-4-Ile-8-Arg]vasopressin, which was administered intravenously in a low (23 nmol) or a high dose (90 nmol) inhibited the HA-or restraint stress-induced secretion of ACTH and beta-ENDir 60 and 25-70%, respectively. Pretreatment with equipotent doses of the selective V1-receptor antagonist [1-(p-tBu)Pmp-2-Tyr(O-Me)-8-D-Arg]vasopressin (25 nmol) and/or the selective V2-receptor antagonist [1-Pmp-2-D-Ile-4-Ile-8-Arg]vasopressin (7.0 nmol) attenuated the response of ACTH and beta-ENDir to HA or restraint stress by 60-80 and 40-60%, respectively. In general, these doses of antagonists had no effect on basal hormone levels. We conclude that AVP takes part in the mediation of HA- and restraint stress-induced ACTH and beta-END secretion. This effect seems to be mediated via both AVP V1- and V2-receptors or a less selective receptor with ligand specificity for both V1- and V2-receptor antagonists.

Adrenocorticotropic Hormone↗

Responses of anterior pituitary hormones and hypothalamic histamine to blockade of histamine synthesis and to selective activation or inactivation of presynaptic histamine H3 receptors in stressed rats.

The stress-induced release of anterior pituitary hormones and changes in hypothalamic content of histamine (HA) and its metabolite tele-methylHA (t-meHA) were studied in male rats during inhibition of HA synthesis or activation or blockade of HA H3 receptors. Pretreatment with the HA synthesis inhibitor alpha-fluoromethylhistidine (alpha-FMH; 200 micrograms intracerebroventricularly (icv) at -120 min) or the specific H3 receptor agonist R(alpha)methylhistamine (RmHA; 10 mg/kg intraperitoneally (ip) at -180 and -60 min) inhibited by 30-80% the responses of prolactin (PRL), corticotropin (ACTH) and beta-endorphin (beta-END) immunoreactivity to 1, 2.5 or 5 min of restraint stress (p < 0.05-0.01), but had no effect on basal secretion of the hormones. The inhibitory effect of the H3 receptor agonist RmHA (10 mg/kg x 2) on the hormone response to 5 min of restraint stress was prevented by simultaneous ip administration of the H3 receptor antagonist thioperamide. alpha-FMH reduced the hypothalamic content of HA 60% and that of t-meHA 30%, while RmHA had no effect on the HA content. Restraint stress for 5 min did not affect the HA and t-meHA contents, which may be due to the short duration of stress exposure. Pretreatment with the H3 receptor antagonist thioperamide (5 or 10 mg/kg ip at -120 min) had no effect on basal or restraint stress-induced release of PRL, ACTH or beta-END, although the compound increased the hypothalamic content of t-meHA 2-fold.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenocorticotropic Hormone↗

Impaired histamine- and stress-induced secretion of ACTH and beta-endorphin in vasopressin-deficient Brattleboro rats.

Arginine vasopressin (AVP), corticotropin-releasing hormone (CRH) and catecholamines seem to be involved in the histamine- (HA) and/or stress-induced release of the pro-opiomelanocortin-derived peptides adrenocorticotropic hormone (ACTH) and beta-endorphin (beta-END). The AVP component of the regulatory mechanism can be specifically studied in Brattleboro rats which lack AVP. These animals may therefore serve as a useful biological model for investigating the importance of AVP in the ACTH and beta-END response to HA and stress. On this background, we studied the ACTH and beta-END response to HA or restraint stress in conscious, male dizygotic AVP-deficient Brattleboro rats (DI) and compared the hypothalamic content of CRH and catecholamines in these rats with that of nondiabetic isogenic Long-Evans rats (LE). In addition, we studied the hypothalamic AVP content in LE rats after HA infusion or exposure to restraint stress. HA (270 nmol) administered intracerebroventricularly (i.c.v.) or 5 min of restraint stress caused a 6- to 7-fold increase in plasma concentrations of ACTH and beta-END in LE rats but only a 2- to 3-fold increase in DI rats (p < 0.01 vs. LE). The basal hypothalamic content of CRH and catecholamines (epinephrine, norepinephrine, and dopamine) was similar in DI and LE rats. The hypothalamic AVP content in LE rats was unaffected by central HA infusion or restraint stress and was undetectable in DI rats. We conclude that inherited lack of AVP impaired the ACTH and beta-END response to central HA administration as well as to restraint stress, suggesting that AVP is important for the mediation of these responses.

Adrenocorticotropic Hormone↗

Permissive, mediating and potentiating effects of vasopressin in the ACTH and beta-endorphin response to histamine and restraint stress.

We investigated in conscious, male rats (1) whether the role of arginine-vasopressin (AVP) in histamine (HA)- and/or restraint stress-induced stimulation of ACTH and beta-endorphin (beta-END) secretion is mediating and/or permissive and (2) whether AVP possesses a potentiating effect on HA- or stress-induced release of ACTH and beta-END. Administration of a specific V1 receptor agonist stimulated ACTH and beta-END secretion dose-dependently while a V2 receptor agonist had no stimulating effect. ACTH and beta-END secretion was stimulated 2- to 3-fold by intracerebroventricular (i.c.v.) infusion of HA (270 nmol) or by 5 min of restraint stress. These effects were inhibited approximately 80% by immunoneutralization of endogenous AVP using a specific AVP antiserum. When the 'AVP tone' was restored in immunoneutralized animals by administration of the specific AVP V1 receptor agonist, which was not bound by the AVP antiserum and had no ACTH and beta-END-releasing effect in the dose used, the ACTH and beta-END response to HA or restraint stress was almost completely reestablished. The specific AVP V2 receptor agonist, which was not bound by the AVP antiserum, reestablished only in part the response of ACTH and beta-END to HA or restraint stress in immunoneutralized animals. AVP administered in doses which had no or minimal ACTH or beta-END releasing effect in itself enhanced the ACTH or beta-END response to submaximal stimulation with HA or restraint stress.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenocorticotropic Hormone↗

Insulin/hypoglycemia-induced adrenocorticotropin and beta-endorphin release: involvement of hypothalamic histaminergic neurons.

We have previously found that histamine (HA) is involved in the mediation of restraint- and ether stress-induced release of the POMC-derived peptides ACTH and beta-endorphin (beta-END). In the present study we investigated the possible involvement of hypothalamic histaminergic neurons in the mediation of insulin/hypoglycemia-induced release of ACTH and beta-END in conscious male rats. To do so, hypoglycemia stress was performed during 1) inhibition of HA synthesis, 2) activation of inhibitory presynaptic HA H3-auto-receptors, or 3) blockade of postsynaptic HA H1- or H2-receptors. Hypoglycemia (plasma glucose, 2.2 +/- 0.3 nmol) induced by insulin (3 IU/kg, ip) caused a 3- to 5-fold increase in the plasma concentrations of ACTH and beta-END. A negative exponential correlation was found between the plasma glucose concentration and the ACTH and beta-END levels. Pretreatment of the animals with the HA synthesis inhibitor alpha-fluoromethylhistidine (1.0 mumol) intracerebroventricularly (icv) in a lateral ventricle, inhibited the ACTH and beta-END responses to insulin/hypoglycemia by 60%. When administered ip (100 mumol/kg), the synthesis inhibitor decreased the beta-END response 50%, but did not affect ACTH secretion significantly. Pretreatment of the rats with the H3-receptor agonist R(alpha)methylhistamine (50 mumol/kg, ip, twice) inhibited the secretory responses of ACTH and beta-END to insulin/hypoglycemia by 60-80%. This inhibitory effect of R(alpha)methylhistamine was reversed by prior administration of the specific H3-receptor antagonist thioperamide. Administration of the H1-antagonists mepyramine and cetirizine dose-dependently inhibited the ACTH and beta-END responses to insulin/hypoglycemia, with the highest dose (mepyramine, 350 nmol, icv; cetirizine, 40 mumol/kg, ip) inhibiting the response by 80-100%. The H1-antagonist SKF-93944 (226 nmol, icv) inhibited the ACTH response, but had no effect on the beta-END response. Administration of the H2-antagonists cimetidine (400 nmol, icv) and ranitidine (400 nmol, icv) inhibited the ACTH and beta-END responses to insulin/hypoglycemia by 50-80%. We conclude that histaminergic neurons are involved in the mediation of the insulin/hypoglycemia-induced release of ACTH and beta-END and that the effect is mediated via activation of primarily postsynaptic H1-receptors and, to a lesser extent, H2-receptors.

Adrenocorticotropic Hormone↗

Postoperative morbidity among symptom-free alcohol misusers.

Retrospective studies suggest that there is an increased postoperative morbidity among alcohol misusers. We have prospectively studied the risk of alcohol intake among patients undergoing surgery. We investigated 15 symptom-free subjects who required colorectal surgery and who were drinking at least 60 g of alcohol per day. These patients were matched for sex, nutrition, age, weight, cardiovascular and pulmonary disease, diagnosis, anaesthesia, and surgery to 15 control subjects who were consuming below 25 g of alcohol daily. Those drinking at least 60 g of alcohol per day developed more postoperative complications than controls (67% vs 20%, p less than 0.05) and hospital stay was prolonged (20 vs 12 days, p less than 0.05). Preoperatively, alcohol misusers had reduced left ventricular ejection fraction (median, 54% vs 68%, p less than 0.01). Delayed hypersensitivity responses were smaller in the alcohol group before (53 mm2 vs 78 mm2, p less than 0.05) and after (18 mm2 vs 55 mm2, p less than 0.01) surgery. Alcohol misusers had longer bleeding times during the first postoperative week (p less than 0.01). Surgical stress responses, as assessed by changes in plasma cortisol and catecholamines, were higher among alcoholics (p less than 0.05). Postoperative morbidity is increased in symptom-free alcohol misusers. The mechanism is probably subclinical cardiac insufficiency, immunosuppression, and decreased haemostatic function. Preoperative alcohol consumption may be a more important risk factor than previously thought.

Aged↗

Pituitary-adrenal responses to head-up tilt in humans: effect of H1- and H2-receptor blockade.

Effects of the histamine H1- or H2-receptor antagonists mepyramine (Mep) and cimetidine (Cim) on neuroendocrine and cardiovascular responses to 50 degrees head-up tilt were evaluated in seven human males. Central hypovolemia was characterized by two phases. The first is a normotensive phase with increases in heart rate (HR), total peripheral resistance (TPR), and decrease in cardiac output. Plasma adrenocorticotropic hormone, beta-endorphin, cortisol, catecholamines, and renin activity increased moderately. Normotension lasted 39 +/- 7 min during infusion of saline but was reduced by Mep [18 +/- 3 min, F(2,12) = 9.60, P less than 0.01] and was unaffected by Cim (44 +/- 4 min). The second is a hypotensive phase associated with presyncopal symptoms (hypovolemic shock) and decreases in HR and TPR and a further increase in pituitary-adrenal and sympathoadrenal activity. Decreases in mean arterial pressure and TPR were augmented by Mep, which inhibited release of norepinephrine. Cim inhibited epinephrine release without affecting the development of hypovolemic shock. It is concluded that histaminergic mechanisms are involved in activation of the sympathoadrenal system but not in the pituitary-adrenal axis during central hypovolemia in humans.

Adult↗

Involvement of 5-HT1, 5-HT2, and 5-HT3 receptors in the mediation of the prolactin response to serotonin and 5-hydroxytryptophan.

Serotonin (5-HT) is involved in the neuroendocrine regulation of prolactin (PRL) secretion as a stimulator. Within the last decade several 5-HT receptor types have been identified, but their individual role in the mediation of the PRL response to 5-HT is only partly understood. We investigated in conscious male rats the effect of different 5-HT1, 5-HT2, and 5-HT3 receptor antagonists on the PRL response to 5-HT or to the 5-HT precursor 5-hydroxytrytophan (5-HTP) which was administered in combination with the 5-HT reuptake inhibitor fluoxetine. 5-HT (0.5-5.0 mg/kg BW i.v.) or 5-HTP (25-100 mg/kg i.p.) in combination with saline or fluoxetine (10 mg/kg i.p.) increased the plasma PRL concentration dose-dependently. Pretreatment with the 5-HT1+2 receptor antagonist methysergide (2.5 mg/kg i.p.) prevented the stimulatory effect of 5-HT or 5-HTP + fluoxetine. Pretreatment with the 5-HT2 receptor antagonists ketanserin or LY 53857 (2.5 mg/kg i.p.) inhibited the PRL response to 5-HT by approximately 80% and to 5-HTP + fluoxetine approximately 100%. A higher dose (10 mg/kg) of the 5-HT2 receptor antagonists possessed only 50% inhibitory effect. Pretreatment with the 5-HT3 receptor antagonists ICS 205-930 or GR 38032F (0.05-2.5 mg/kg i.p.) inhibited the PRL response induced by 5-HT or by 5-HTP + fluoxetine. The maximal inhibitory effect (approximately 80%) was obtained by a dose of 0.1 mg/kg of both compounds.(ABSTRACT TRUNCATED AT 250 WORDS)

5-Hydroxytryptophan↗

Effect of serotonin 5-HT1, 5-HT2, and 5-HT3 receptor antagonists on the prolactin response to restraint and ether stress.

Serotonin (5-HT) appears to be involved in the central control of the prolactin (PRL) response to suckling and estrogen. Furthermore, 5-HT may participate in the mediation of stress-induced PRL release. In order further to elucidate the role of 5-HT and the type of 5-HT receptor(s) involved in the PRL response to stress, we investigated the effect of blockade of 5-HT1, 5-HT2 or 5-HT3 receptors on the restraint or ether stress-induced release of PRL in male rats. Pretreatment with the 5-HT1 + 2 receptor antagonist methysergide (0.5 or 2.5 mg/kg i.p.) inhibited or prevented the PRL response to restraint or ether stress. Pretreatment with the 5-HT2 receptor antagonists ketanserin or LY 53857 (0.5 or 2.5 mg/kg i.p.) inhibited the response to restraint or ether stress approximately 30 or 60%, respectively. Higher doses of both 5-HT2 receptor antagonists (10 mg/kg i.p.) had a minor inhibitory effect (5-30% for ketanserin and 50% for LY 53857). Prior intraperitoneal administration of the 5-HT3 receptor antagonists ICS 205-930 or GR 38032F (0.05-2.5 mg/kg i.p.) inhibited the restraint stress-induced PRL release dose-dependently. Both compounds inhibited the PRL response to ether stress, but only the effect of GR was dose-related. The maximal inhibitory effect (70% inhibition of the PRL response to restraint or ether stress) was obtained for both compounds at a dose of 0.1 mg/kg. We conclude that serotonergic neurons are involved in the mediation of the stress-induced PRL release by activation of 5-HT1, 5-HT2 as well as 5-HT3 receptors.

Animals↗

Histamine- and stress-induced secretion of ACTH and beta-endorphin: involvement of corticotropin-releasing hormone and vasopressin.

Histamine (HA) stimulates the release of the pro-opiomelanocortin (POMC)-derived peptides ACTH, beta-endorphin (beta-END), beta-lipotropin and alpha-melanocyte-stimulating hormone, and HA is involved in the mediation of the stress-induced release of these peptides. The effect of HA is indirect and may involve the hypothalamic regulating factors, corticotropin-releasing hormone (CRH) and/or arginine-vasopressin (AVP). We studied the effect of immunoneutralization with specific antisera against CRH or AVP on the response of ACTH and beta-END to HA, restraint stress, CRH, AVP or a posterior pituitary extract in male rats. Intracerebroventricular infusion of HA (34-540 nmol) increased the plasma levels of ACTH and beta-END immunoreactivity (beta-ENDir) in a dose-dependent manner. Pretreatment with antiserum to CRH or AVP prevented the ACTH response to 270 nmol HA and inhibited the beta-ENDir response by 30-60%. One to five minutes of restraint stress caused an increase in the plasma levels of ACTH and beta-ENDir. The increase was dependent on the duration of stress exposure. Pretreatment with CRH antiserum abolished the ACTH response to 5 min of restraint stress and inhibited the beta-ENDir response by 60%. Immunoneutralization with AVP antiserum had only half the inhibitory effect of that seen with CRH antiserum. CRH (100 pmol i.v.) increased the plasma levels of ACTH and beta-ENDir. This effect was abolished by pretreatment with CRH antiserum, whereas pretreatment with AVP antiserum prevented the CRH-induced ACTH release and inhibited the beta-ENDir response by 50%. AVP (24-800 pmol i.v.) stimulated ACTH and beta-ENDir in a dose-dependent manner. CRH and AVP antisera each prevented the effect of AVP (800 pmol) on ACTH secretion, whereas the beta-ENDir response to AVP was only inhibited by about 60% by the antisera. An extract of the posterior pituitary gland administered in a dose corresponding to 0.15 or 0.5 pituitary equivalents had no effect on ACTH secretion, while 1.0 pituitary equivalent increased the ACTH concentration in plasma. This effect was abolished by AVP antiserum. The posterior pituitary extract caused a dose-dependent rise in plasma beta-ENDir which might be due to an unavoidable contamination of the posterior pituitary extract by a small amount of beta-END from the intermediate lobe. Consistent with this view, AVP antiserum had no effect on the rise in the plasma concentration of beta-ENDir following administration of the posterior pituitary extract.(ABSTRACT TRUNCATED AT 400 WORDS)

Adrenocorticotropic Hormone↗

Histamine H1 and H2 receptor activation stimulates ACTH and beta-endorphin secretion by increasing corticotropin-releasing hormone in the hypophyseal portal blood.

Histamine (HA) stimulates the release of adrenocorticotropic hormone (ACTH) and beta-endorphin (beta-END) via activation of central postsynaptic H1 or H2 receptors. The effect of HA is indirect and may involve the hypothalamic regulating factors corticotropin-releasing hormone (CRH), arginine vasopressin, or oxytocin (OT). We studied the effect of specific HA H1 or H2 receptor agonists on the concentration of CRH and OT in hypophyseal portal blood in urethane-anesthetized male rats. In addition we investigated the effect of the agonists on ACTH and beta-END immunoreactivity in peripheral plasma in conscious male rats pretreated with antiserum to CRH. Intracerebroventricular administration of the H1 receptor agonist 2-thiazolylethylamine (2-TEA) or the H2 receptor agonist 4-methylhistamine (4-MeHA) increased the CRH concentration in pituitary portal blood by 80-90% when compared to preinfusion levels (p < 0.05). Central infusion of saline had no effect. The level of OT in the pituitary portal blood was not affected by 2-TEA or 4-MeHA when compared to saline-treated rats. Intracerebroventricular infusion of 2-TEA or 4-MeHA increased the ACTH concentration in peripheral plasma 3- or 4-fold, respectively (p < 0.01). Pretreatment with a specific CRH antiserum (abCRH) inhibited the responses by 50 and 70%, respectively (p < 0.01). Intracerebroventricular administration of 2-TEA or 4-MeHA increased the beta-END immunoreactivity in peripheral plasma 3- or 2-fold, respectively (p < 0.01). These effects were inhibited by 80-90%, when rats were pretreated with abCRH (p < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenocorticotropic Hormone↗

Gastrin-releasing peptide stimulation of corticotropin secretion in male rats.

Gastrin-releasing peptide (GRP; mammalian bombesin) may be involved in the neuroendocrine regulation of pituitary hormone secretion. We investigated the effect of GRP on ACTH secretion in conscious male rats. GRP (7-700 pmol) stimulated ACTH secretion dose-dependently after intracerebroventricular (icv) administration but had no effect after iv administration. GRP infused icv in a dose of 7 pmol, which alone increased ACTH 1.5-fold, potentiated the ACTH-releasing effect of arginine vasopressin (AVP; 80 pmol iv) and corticotropin-releasing hormone (CRH; 100 pmol iv). A higher dose of GRP (70 pmol icv), which stimulated ACTH secretion 2-fold, potentiated the effect of 80 and 400 pmol AVP iv, but had only additive effect on the ACTH response to 800 pmol AVP iv or 100 pmol CRH iv. GRP infused iv in a dose of 210 pmol, which in itself had no effect on ACTH secretion, potentiated the ACTH-stimulating effect of AVP and CRH approximately 2.5-fold. The effect of GRP (icv or iv) on AVP or CRH-stimulated ACTH release was only slightly smaller than the effect of combined administration of AVP and CRH (80 + 100 pmol iv). The ACTH-stimulating effect of GRP (700 pmol icv) was inhibited about 60% by pretreatment with either CRH or AVP antiserum and prevented by combined pretreatment with the antisera. The results indicate that: 1) GRP affects ACTH secretion indirectly at a suprapituitary level--possibly in the hypothalamus--by stimulating the release of AVP and CRH to the pituitary portal blood; and 2) GRP acts directly at the pituitary level to augment the effect of AVP and CRH on the corticotrophs. We suggest that GRP is involved in the multifactorial regulation of ACTH secretion.

Adrenocorticotropic Hormone↗