Differential effect of serotonin 5-HT(1A) receptor antagonists on the secretion of corticotropin and prolactin

Serotonin (5-HT) participates in the neuroendocrine regulation of corticotropin (ACTH) and prolactin (PRL) secretion. We investigated the involvement of the 5-HT(1A) receptor in the mediation of ACTH and PRL response to the 5-HT(1A) receptor agonists 8-OH-DPAT and 5-HT, the 5-HT precursor 5-hydroxytryptophan (5-HTP) and restraint stress in male rats. Prior intracerebroventricular (i.c.v.) infusion of the 5-HT(1A) antagonists WAY-100635 and LY-206130 inhibited PRL and ACTH responses to i.c.v. infusion of 8-OH-DPAT, 5-HT as well as to 5-HTP administered systemically in combination with the 5-HT reuptake inhibitor fluoxetine (Flx). Infused i.c.v. NAN-190 inhibited the ACTH response to 8-OH-DPAT i.c.v. Intraperitoneal (i.p.) pretreatment with WAY-100635 inhibited ACTH and PRL responses to 8-OH-DPAT, whereas LY-206130 only inhibited the PRL response and NAN-190 had no effect. Injected i.p., the antagonists had no effect on 5-HT-induced hormone secretion, whereas the ACTH-stimulating effect of 5-HTP + Flx was increased by WAY and NAN. A 5-min restraint stress increased ACTH and PRL secretion; the ACTH, but not the PRL response to stress was inhibited by prior administration of WAY-100635 or LY-206130 either i.c.v. or i.p. NAN-190 had no effect on any stress response tested. It is concluded that (1) the three 5-HT(1A) antagonists used in our study have differential effects on stimulated hormone responses, (2) the antagonists exert different effects when administered systemically or centrally, and (3) the 5-HT(1A) receptor is involved in restraint stress-induced ACTH, but not PRL secretion.     

Corticotropin and cortisol secretion after central 5-hydroxytryptamine-1A (5-HT1A) receptor activation: effects of 5-HT receptor and beta-adrenoceptor antagonists

To explore the involvement of 5-hydroxytryptamine-1A (5-HT1A) receptors in hypothalamic-pituitary-adrenal (HPA) axis regulation, various doses of ipsapirone (IPS), a centrally acting pyrimidinylpiperazine with considerable affinity and selectivity for 5-HT1A recognition sites, were administered to normal subjects. IPS dose-dependently increased plasma ACTH concentrations from -78 +/- 63 to 614 +/- 250 pmol.min/L (P less than 0.01) and plasma cortisol concentrations from -10.8 +/- 2.9 x 10(3) to 21.3 +/- 8.2 x 10(3) nmol.min/L (P less than 0.01) at a dose of 0.3 mg/kg in six men. The nonselective 5-HT receptor antagonist metergoline which acts at both 5-HT1 and 5-HT2 receptors partially blocked the HPA response to IPS in six women and three men. The mean maximal integrated ACTH response decreased from 746 +/- 297 to 40 +/- 146 pmol/min.L (P less than 0.05), and the increase in cortisol was attenuated from 22.9 +/- 9.9 x 10(3) to 11.9 +/- 6.3 x 10(3) nmol.min/L (P less than 0.05). The nonselective beta-adrenergic and selective 5-HT1A/1B receptor antagonist (+/-)pindolol was without effect on basal HPA activity, but completely antagonized the IPS-induced plasma ACTH and cortisol responses. The mean maximal integrated ACTH response decreased to 8.0 +/- 78 pmol.min/L (P less than 0.05), and the cortisol response was reduced to -2.3 +/- 6.5 x 10(3) nmol.min/L (P less than 0.05). The selective beta 1-adrenoceptor antagonist betaxolol did not significantly alter the IPS-induced HPA response.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of serotonin4 (5-HT4) receptor agonists on aldosterone secretion in idiopathic hyperaldosteronism

Serotonin (5-HT) stimulates aldosterone secretion in man through 5-HT4 receptors positively coupled to adenylyl cyclase. In particular, it has been shown that oral administration of a single dose of the 5-HT4 receptor agonist cisapride induces a significant increase in plasma aldosterone levels (PAL) in healthy volunteers. Idiopathic hyperaldosteronism (IH) is a rare disorder characterized by hypertension, hypokalemia and bilateral adrenal hypersecretion of aldosterone. In patients with IH, administration of the 5-HT precursor 5-hydroxytryptophan (5-HTP) is followed by a significant increase in PAL. 5-HTP-induced aldosterone secretion has been attributed to the activation of central serotonergic pathways. The aim of the present study was to evaluate the effect of the oral administration of a single dose of cisapride (10 mg) on aldosterone secretion in 15 patients with IH, in a simple blind fashion versus placebo. Cisapride induced a significant increase in PAL but did not affect renin, cortisol and potassium levels. The present study demonstrates that 5-HT4 receptor agonists are able to stimulate aldosterone secretion in patients with IH. These data also indicate that hyperplastic glomerulosa tissue, like normal glomerulosa cells, expresses a functional 5-HT4 receptor. Therefore, 5-HT4 receptor antagonists may represent a new approach in the treatment of primary hyperaldosteronism.     

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.     

5-HT1 and 5-HT2 receptor agonists blunt +/- -alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)-stimulated GH secretion in prepubertal male rats

OBJECTIVE: Excitatory amino acids, gamma-amino butyric acid (GABA), serotonin and catecholamines are involved in the control of GH secretion. The actions of these neurotransmitters are interconnected, and recently we showed that the stimulatory effect of GABA was blocked by MK-801, an antagonist of N-methyl-D-aspartate receptors. The present experiments were carried out to analyze the interrelationships between +/- -alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors and serotoninergic and catecholaminergic pathways in the control of GH secretion in prepubertal (16-23-day-old) male rats. DESIGN AND METHODS: The GH response to AMPA was analyzed in animals pretreated with 5-hydroxytryptophan methyl ester (5-HTP) plus fluoxetine (a precursor of 5-hydroxytryptamine (5-HT) synthesis and a blocker of 5-HT re-uptake), R (+)-8-hydroxydipropylaminotetralin hydrobromide (8-OH-DPAT, an agonist of the 5-HT1 receptors), +/- -2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI) and alpha-methyl-5-hydroxytryptamine (agonists of 5-HT2 receptors), I-phenylbiguanide (an agonist of 5-HT3 receptors), or alpha-methyl-p-tyrosine (alpha-MPT) and diethyldithiocarbamate (DDC) (blockers of catecholamine synthesis). RESULTS: Basal GH secretion remained unchanged in prepubertal rats after activation of the serotoninergic system or blockade of catecholamine synthesis. The stimulatory effect of AMPA on GH secretion was blocked after activation of the serotoninergic system, through specific 5-HT1 and 5-HT2 receptor agonists. In contrast, activation of 5-HT3 receptors potentiated AMPA-stimulated GH secretion. CONCLUSIONS: Serotoninergic receptors modulate the stimulatory effect of AMPA on GH secretion in prepubertal male rats.     

Influence of 5-HT1 and 5-HT2 receptor antagonists on insulin-induced adrenomedullary catecholamine release.

Previous works have indicated that insulin stress activates the serotonin (5-HT) and sympathoadrenal systems in the fasted rat. In addition, recent studies have shown that activation of either the 5-HT1A, the 5-HT1C or the 5-HT2 receptor triggers adrenal catecholamine release. Then, the aim of this study was to investigate whether brain 5-HT, by means of these receptors, mediates insulin-induced adrenal catecholamine release. For that purpose, both plasma epinephrine (Epi), norepinephrine (NE) and glucose levels were measured in conscious rats bearing intracardiac catheters. The intravenous administration of insulin (1 IU/kg) triggered hypoglycemia throughout the following 120 min in both fed and overnight fasted rats. Insulin stress elicited within 30 min a 5- and 38-fold increase in plasma Epi levels in fed and fasted rats, respectively. This change was associated with significant elevations in plasma NE levels in the fasted rats only. The intravenous administration of the mixed 5-HT1A receptor/beta-adrenoceptor blocker (-)-propranolol (5 mg/kg) to fasted rats did not modify plasma glucose and catecholamine peak responses to insulin; however, at later times, insulin triggered hypoglycemic convulsions in (-)-propranolol- but not in saline-pretreated rats. Besides, pretreatments with the 5-HT1C/5-HT2 receptor blocker LY 53857 (0.5 mg/kg), or the 5-HT1/5-HT2 receptor antagonist metergoline (3 mg/kg), did not diminish plasma catecholamine responses to insulin stress. Similarly, none of these antagonists affected plasma glucose recovery. These results seem to indicate that the sympathoadrenal response to insulin administration is not mediated by 5-HT.     

Production and metabolism of serotonin (5-HT) by the human adrenal cortex: paracrine stimulation of aldosterone secretion by 5-HT

In the human adrenal cortex, serotonin (5-HT) is contained in mast-like cells, and we have shown that 5-HT stimulates aldosterone secretion, suggesting that 5-HT may control glomerulosa cells through a paracrine mechanism. Concurrently, the presence of 5-hydroxyindolacetic acid in human adrenocortical extracts indicates that 5-HT may be metabolized after local release by mast cells. The aim of the present study was to investigate in vitro the production and metabolism of 5-HT by the human adrenal cortex. Perifused adrenal slices released spontaneously detectable amounts of 5-HT (0.74 +/- 0.38 fmol/mg wet tissue.min). The mast cell-depleting drug compound 48/80 induced a burst of 5-HT secretion followed by a gradual increase in aldosterone production. Administration of the specific 5-HT(4) receptor antagonist GR 113808 (10(-6) M) did not affect compound 48/80-induced 5-HT release but abolished the stimulatory effect of compound 48/80 on aldosterone secretion, indicating that 5-HT released locally is responsible for a paracrine control of steroidogenesis. Incubation of cells from the human adrenal cortex with 5-HT (10(-5) M) provoked the formation of the 5-HT metabolite 5-hydroxytryptophol. The type A monoamine oxidase (MAO) inhibitor clorgyline (10(-6) M) suppressed the metabolism of 5-HT into 5-hydroxytryptophol. Immunocytochemical staining of cultured cells revealed the presence of a subpopulation of MAO-A-positive cells. Double labeling with an antiserum against chromogranin A showed that MAO-A was actually contained in chromaffin cells. Similarly, immunohistochemical staining of adrenal slices showed that MAO-A was expressed in chromaffin cells located both in the medulla and in intracortical rays. In conclusion, the present study shows that, in the human adrenal cortex, 5-HT, released by mast-cells, may stimulate aldosterone secretion in a paracrine manner. Our data also indicate that 5-HT is metabolized by MAO-A located in intracortical chromaffin cells.     

Structural requirements for 5-HT2A and 5-HT1A serotonin receptor potentiation by the biologically active lipid oleamide

Oleamide is an endogenous fatty acid primary amide that possesses sleep-inducing properties in animals and that has been shown to effect serotonergic receptor responses and block gap junction communication. Herein, the potentiation of the 5-HT_1A receptor response is disclosed, and a study of the structural features of oleamide required for potentiation of the 5-HT_2A and 5-HT_1A response to serotonin (5-HT) is described. Of the naturally occurring fatty acids, the primary amide of oleic acid (oleamide) is the most effective at potentiating the 5-HT_2A receptor response. The structural features required for activity were found to be highly selective. The presence, position, and stereochemistry of the Δ⁹-cis double bond is required, and even subtle structural variations reduce or eliminate activity. Secondary or tertiary amides may replace the primary amide but follow a well defined relationship requiring small amide substituents, suggesting that the carboxamide serves as a hydrogen bond acceptor but not donor. Alternative modifications at the carboxamide as well as modifications of the methyl terminus or the hydrocarbon region spanning the carboxamide and double bond typically eliminate activity. A less extensive study of the 5-HT_1A potentiation revealed that it is more tolerant and accommodates a wider range of structural modifications. An interesting set of analogs was identified that inhibit rather than potentiate the 5-HT_2A, but not the 5-HT_1A, receptor response, further suggesting that such analogs may permit the selective modulation of serotonin receptor subtypes and even have opposing effects on the different subtypes.     

5-HT1 and 5-HT2 receptor activation reduces N-methyl-D-aspartate (NMDA)-stimulated LH secretion in prepubertal male and female rats

OBJECTIVE: Excitatory amino acids and serotonin are involved in the control of gonadotropin secretion. The actions of these neurotransmitters are interconnected and recently we have reported that 5-HT(1) and 5-HT(2) receptor agonists blunted (+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)-stimulated GH secretion in prepubertal rats. The present experiments were carried out to analyze the effects of activation of different 5-hydroxytryptamine (5-HT) receptor subtypes on gonadotropin secretion and their role in the N-methyl-d-aspartate (NMDA)-stimulated LH release. DESIGN AND METHODS: We analyzed the gonadotropin secretion after manipulation of serotoninergic and aminoacidergic systems and their interactions in 5-, 16- and 23-day-old male and female rats. To this end, serum LH and FSH concentrations were measured in rats treated with 5-hydroxytryptophan methyl ester (5-HTP) (a precursor of 5-HT synthesis) plus Fluoxetine (Fx, a blocker of 5-HT reuptake), d,l-p-chlorophenyl-alanine methyl ester (PCPA, a blocker of 5-HT synthesis), R-(+)-8-hydroxydipropylaminotetralin hydrobromide (8-OH-DPAT, an agonist of 5-HT(1A) receptors), (+/-)-2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI) and alpha-methyl-5-hydroxytryptamine (alpha-Me-5-HT, agonists of 5-HT(2) receptors), and 1-Phenylbiguanide (1-PHE an agonist of 5-HT(3) receptors). In addition, the effects of 8-OH-DPAT and DOI on NMDA-stimulated LH secretion were analyzed. RESULTS: Neither the activation nor blockade of the serotoninergic system modified LH secretion. Basal gonadotropin secretion remained unchanged in 23-day-old male and female rats after activation of 5-HT(1A), 5-HT(2) and 5-HT(3) receptors. The stimulatory effect of NMDA on LH secretion was blocked in both sexes after activation of the serotoninergic system, through specific 5-HT(1) and 5-HT(2) receptor agonists. CONCLUSIONS: Activation of serotoninergic receptors decreased the stimulatory effect of NMDA on LH secretion in prepubertal male and female rats.     

The effects of metergoline and other serotonin receptor antagonists on serum corticosterone in rats.

Metergoline antagonized the elevation of serum corticosterone by quipazine in rats. The ED50 of metergoline was less than 0.1 mg/kg, ip, and the effects of a 3 mg/kg dose persisted for more than 24 h. Metergoline did not antagonize the elevation of serum corticosterone by theophylline or ketamine (i.e. did not prevent corticosterone release nonspecifically) and did not affect the concentration of quipazine in the brain. Since quipazine is a serotonin receptor agonist, the antagonistic effects of metergoline may have been due to competition with quipazine at serotonin receptor sites in the brain. Some other agents capable of blocking serotonin receptors also antagonzied the elevation of serum corticosterone by quipazine. These included LY53857, which gave complete blockade at 3 mg/kg, and cyproheptadine and spiperone, which gave significant but incomplete antagonism at 1 mg/kg. Methysergide at 3 mg/kg did not alter the effect of quipazine. Metergoline did not antagonize the elevation of serum corticosterone by other agents throught to act via serotoninergic mechanisms, namely fluoxetine, fenfluramine, L-5-hydroxytryptophan, N,N-demthyl-5-methoxytryptamine, and 1-(m-trifluoromethylphenyl)piperazine. Thus, the interactions between metergoline and quipazine may have occurred at receptors that are not serotonin receptors or that represent a subset of serotonin receptors not mediating the actions of serotoninergic agents other than quipazine.     

Differential central effects of mineralocorticoid and glucocorticoid agonists and antagonists on blood pressure

Systolic blood pressure was measured, using an indirect tail method, in conscious male rats at several time intervals after the intracerebroventricular injection of mineralo-and glucocorticoid agonists and antagonists. Intracerebroventricular administration of the antimineralocorticoid RU 28318 (10 ng) decreased blood pressure, while the antiglucocorticoid RU 38486 (10 ng) caused an increase, which was slower in onset and of longer duration. The effect of the antimineralocorticoid was maximal at 8 h and had disappeared after 24 h. The antiglucocorticoid had a significant effect 24 and 48 h after injection. Neither antagonist was effective when administered sc at the same dose (10 ng). Intracerebroventricular administration of aldosterone (10 ng) and the selective glucocorticoid agonist RU 28362 (10 ng) increased and decreased blood pressure, respectively. Corticosterone given intracerebroventricularly (10-100 ng) did not affect blood pressure unless the dose was increased to 1 microgram. Two weeks after adrenalectomy a decrease in blood pressure was observed when the rats were given 0.9% saline instead of water to drink. Replacement therapy with corticosterone (12.5-mg steroid pellet, sc) restored blood pressure to the level in the sham-operated controls. The chronically elevated level of circulating corticosterone produced by a 100-mg sc corticosterone pellet increased blood pressure. The 12.5-and 100-mg sc corticosterone pellets resulted in plasma corticosterone levels of approximately 3 and 20 micrograms/100 ml, respectively. Intracerebroventricular administration of the glucocorticoid and mineralocorticoid antagonists (10 ng) increased and decreased, respectively, the blood pressure of the adrenalectomized rats receiving corticosterone substitution. From these data we conclude that corticosteroids can affect the central regulation of blood pressure. The mineralo- and glucocorticoids have opposite effects, which differ in onset and duration. The mineralocorticoids increased blood pressure, whereas the glucocorticoid decreased it.     

Autoradiographic analyses of the effects of adrenalectomy and corticosterone on 5-HT1A and 5-HT1B receptors in the dorsal hippocampus and cortex of the rat.

Quantitative autoradiography was used to evaluate the effects of adrenalectomy (ADX) and corticosterone (CORT) on binding at 5-HT1A and 5-HT1B receptors in the dorsal hippocampus and cortex of the rat. ADX increased binding of [3H]8-hydroxy-2-(di-n-propylamino)tetralin at 5-HT1A receptors in the oriens and lacunosum moleculare layers of CA2 and CA3, in the lacunosum moleculare layer of CA4 region, and in the dentate gyrus. In restraint-stressed ADX rats, binding was increased only in the oriens and lacunosum moleculare layers of CA2. Restoration of baseline levels of CORT reversed the effects of ADX on 5-HT1A receptors in the hippocampus, while high levels of CORT decreased binding at 5-HT1A receptors in the dentate gyrus. No treatment affected binding at 5-HT1A receptors in the CA1 region of the hippocampus or in the cortex. ADX increased binding of [125I]iodocyanopindolol at 5-HT1B receptors in the infrapyramidal dentate, but this effect was not observed in ADX rats that were restrained. CORT treatment in both ADX and SHAM (adrenally intact) rats resulted in binding at 5-HT1B receptors that was lower than that in untreated ADX and SHAM rats in the infrapyramidal dentate, and lower than that in ADX rats in the suprapyramidal dentate and CA4. In ADX and SHAM rats, CORT also reduced binding at 5-HT1B receptors in area 2 of the cortex. It is suggested that decreases in binding at 5-HT1A and 5-HT1B/1D receptors resulting from chronic exposure to high levels of CORT may also occur in animals that fail to adapt to chronic severe stress. Such changes in binding may play important roles in the etiology of depression.     

Analgesic effects of 5-HT3 receptor antagonists.

Current research suggests an involvement of 5-HT3 receptors in peripheral and central perception and processing of pain as well as in inflammation. Tropisetron and other selective 5-HT3 receptor antagonists have been used successfully for pain reduction and treatment of related symptoms in patients diagnosed with fibromyalgia. This article proposes a concept of the underlying pathophysiology and mechanisms of action of 5-HT3 receptor antagonists in the context of the relevant clinical data on their application in patients with rheumatic disease.     

Effects of 5-HT2B, 5-HT3 and 5-HT4 receptor antagonists on gastrointestinal motor activity in dogs

AIM:To study the effects of 5-hydroxytryptamine(5-HT)receptor antagonists on normal colonic motor activity in conscious dogs.METHODS:Colonic motor activity was recorded using a strain gauge force transducer in 5 dogs before and after 5-HT2B,5-HT3 and 5-HT4 receptor antagonist administration.The force transducers were implanted on the serosal surfaces of the gastric antrum,terminal ileum,ileocecal sphincter and colon.Test materials or vehicle alone was administered as an intravenous bolus injection during a quiescent period of the whole colon in the interdigestive state.The effects of these receptor antagonists on normal gastrointestinal motor activity were analyzed.RESULTS:5-HT2B,5-HT3 and 5-HT4 receptor antagonists had no contractile effect on the fasting canine terminal ileum.The 5-HT3 and 5-HT4 receptor antagonists inhibited phaseⅢof the interdigestive motor complex of the antrum and significantly inhibited colonic motor activity.In the proximal colon,the inhibitory effect was dose dependent.Dose dependency,however,was not observed in the distal colon.The 5-HT2B receptor antagonist had no contractile effect on normal colonic motor activity.CONCLUSION:The 5-HT3 and 5-HT4 receptor antagonists inhibited normal colonic motor activity.The5-HT2B receptor antagonist had no contractile effect on normal colonic motor activity.     

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)     

Differential effects of agonists of aldosterone secretion on steroidogenic acute regulatory phosphorylation

The steroidogenic acute regulatory (StAR) protein mediates cholesterol transport within the mitochondria, and its phosphorylation is believed to be required for steroidogenesis. Increased extracellular potassium concentrations (K(+)), angiotensin II (AngII), and adrenocorticotropic hormone (ACTH) induce aldosterone secretion from bovine adrenal glomerulosa cells. We hypothesized that, although these agonists act via different signaling pathways, StAR phosphorylation should be common to their action. We studied the effects of K(+), AngII, and ACTH, at concentrations that yield comparable secretory responses, on StAR phosphorylation. All three agents induced significant increases in StAR phosphorylation although the response to ACTH was less than that of AngII and K(+). In cells stimulated with the protein kinase C (PKC) agonist 12-tetradecanoylphorbol 13-acetate (TPA), the Ca(2+) channel agonist BAY K8644, and the adenylate cyclase agonist forskolin, TPA caused a small but statistically significant increase in StAR phosphorylation while BAY K8644 and forskolin had no significant effect. Interestingly, the combination of TPA and BAY K8644 produced a larger increase in StAR phosphorylation than the agents alone. We conclude that in cultured bovine adrenal glomerulosa cells the PKC signaling pathway is most effective at inducing StAR phosphorylation but that there is no simple correlation between this event and aldosterone production.     

Effects of alpha-adrenoceptor agonists and antagonists on thyroid hormone secretion

The effects of various alpha-adrenoceptor agonists and antagonists on blood radioiodine levels were studied in mice pre-treated with 125I and thyroxine. The non-selective alpha-adrenoceptor agonist noradrenaline and the selective alpha 1-adrenoceptor agonist phenylephrine both enhanced blood radioiodine levels. Noradrenaline was more potent than phenylephrine. Contrary, the selective alpha 2-adrenoceptor agonist clonidine depressed basal levels of blood radioiodine. The non-selective alpha-adrenoceptor antagonist phentolamine and the selective alpha 1-adrenoceptor antagonist prazosin both inhibited the noradrenaline-induced elevation of radioiodine levels, whereas the alpha 2-adrenoceptor antagonist yohimbine had no such effect, except at a high dose level. All three alpha-adrenoceptor agonists, noradrenaline, phenylephrine and clonidine, inhibited the radioiodine response to TSH. In addition, TSH-induced increase in radioiodine levels was inhibited by prazosin, whereas yohimbine had no effect. Phentolamine inhibited the radioiodine response to TSH when given 2 h prior to TSH, whereas when given 15 min prior to TSH the response to TSH was potentiated by phentolamine. It is concluded, that under in vivo conditions in the mouse, alpha 1-adrenoceptor activation stimulates basal thyroid hormone secretion and inhibits TSH-induced thyroid hormone secretion. Further, alpha 2-adrenoceptor activation inhibits basal thyroid hormone secretion. In addition, TSH-induced thyroid hormone secretion is inhibited by alpha 1-adrenoceptor antagonism. Thus, alpha-adrenoceptors induce both stimulatory and inhibitory effects of thyroid function.