Hypothalamic peptides: central nervous system control of visceral functions

Thyrotropin-releasing factor (TRF), somatostatin, and bombesin-like peptide are present in the brain and may be involved in central nervous system (CNS) control of visceral functions. All three peptides exert potent actions to modify animal thermoregulation. TRF and somatostatin or somatostatin analogs act within the brain to influence parasympathetic and sympathetic outflow resulting in changes of adrenal epinephrine secretion, gastric acid secretion, heart rate, and blood pressure. Bombesin acts within the brain to increase adrenal epinephrine secretion and to inhibit gastric acid secretion without influencing other sympathetic or parasympathetic activities. These peptides and others may be important physiological regulators of CNS information processing related to a variety of visceral systems.     

Activation of angiotensin II receptors in brain potentiates the stimulating effect of endogenous opioid neurons on central sympathetic outflow

Endogenous opioid peptides appear to have neurotransmitter or neuromodulator functions in brain mediating a wide variety of effects. We have reported that intracisternal administration of synthetic human beta-endorphin increases plasma concentration of catecholamines, apparently by acting at unknown brain sites to increase sympathetic outflow to the adrenal medulla and sympathetic nerves. In the present study we examined the possibility that angiotensin II, acting in brain, modulates endorphin-induced catecholamine secretion. Simultaneous intracisternal administration of angiotensin II 1.0 nmol together with synthetic human beta-endorphin 1.45 nmol potentiated the plasma epinephrine, norepinephrine and dopamine responses to intracisternal beta-endorphin. In contrast, simultaneous intracisternal administration of the angiotensin II antagonist, [Sar1, Val5, Ala8]-angiotensin II (saralasin), 1.1 nmol together with beta-endorphin, blunted the plasma epinephrine, norepinephrine and dopamine responses to beta-endorphin. These data are consistent with the hypothesis that activation of angiotensin II receptors in brain potentiates the endorphin-induced stimulation of central sympathetic outflow. It remains to be demonstrated whether angiotensin II acting in brain to modulate activity of opioid neurons is synthesized in brain or is derived peripherally.     

The influence of alpha-fluoromethylhistidine and histamine receptor antagonists on the beta-endorphin-induced corticosterone response

Involvement of a central histaminergic mechanism in the stimulating effect of beta-endorphin (beta-End) on the pituitary-adrenocortical activity, measured indirectly through corticosterone secretion, was investigated in conscious rats. The rise in serum corticosterone levels, induced by beta-End injected intraventricularly (icv) was considerably impaired by pretreatment with naltrexone, an opioid receptor antagonist. The stimulating effect of beta-End was almost totally suppressed by a prior icv administration of mepyramine, a histamine H1-receptor antagonist, and also considerably reduced by pretreatment with cimetidine, an H2-receptor antagonist. The strongest suppression, by 83%; of the beta-End-induced corticosterone response was evoked by a prior administration of alpha-fluoromethylhistidine, an inhibitor of neuronal histamine synthesis in the brain. These results indicate that both the brain neuronal histamine and central histamine H1- and H2-receptors are considerably involved in the beta-endorphin-induced stimulation of the pituitary-adrenocortical activity.     

Cysteamine-induced depletion of somatostatin and prolactin

Cysteamine (2-aminoethanethiol [CSH], given in vivo or in vitro, rapidly but reversibly depletes immunoreactive somatostatin (irSS) in the central nervous system and gut as well as biological and immunological prolactin (PRL) activity in both the anterior pituitary and blood of the rat. This depletion of irSS and PRL is dose dependent and cannot be accounted for by release of either compound. Basal and potassium-stimulated SS release is reduced from hypothalamic tissue in vitro in CSH-treated animals. PRL secretion induced both pharmacologically and physiologically is abolished after CSH administration. Furthermore, CSH reduces cellular PRL content in a number of hyperprolactinemic states. The mechanism by which CSH reduces PRL levels is not clear, but it does not appear to act through the dopamine receptor nor does it alter the morphological structure of the lactotrope in normal animals. Most likely, CSH acts by interacting with the disulfide bonds of PRL, thus rendering the molecule both immunologically and biologically inactive.     

Histochemistry and function of bombesin-like peptides

Bombesin-like peptides are a group of brain-gut peptides found in several neuronal groups in the central nervous system and in peripheral intrinsic gut neurons and sensory neurons. The SIF cells (small intensely fluorescent cells) of the sympathetic ganglia also contain immunoreactivity for these peptides. These peptides are present in some pulmonary endocrine cells and tumors originating from these cells. Chromatographic studies suggest that several different peptides, possibly originating from at least two different precursors, are present in mammalian tissues. Authentic amphibian peptide bombesin does not appear to be found in mammalian tissues. Functional studies indicate that these peptides may be involved in many important functions, including sensory transmission, regulation of central autonomic pathways, thermoregulation, secretion of pituitary hormones, gastric and pancreatic secretion, food intake and satiety.     

革兰氏阴性菌IX型分泌系统的研究进展

IX型分泌系统(Type IX Secretion System,T9SS)是一种最新发现的存在于许多革兰氏阴性细菌中的分泌系统。T9SS参与细菌的毒力和滑行运动及复杂生物聚合物的降解过程。近年来,与T9SS相关的研究一直都是微生物学领域关注的热点。本文就T9SS的发现、组成与结构、分泌机制及调控机制等方面的研究进展进行综述,以期为进一步解析细菌的T9SS提供新的思路。     

Proopiomelanocortin (POMC) products in the central regulation of sympathetic and cardiovascular dynamics: studies on melanocortin and opioid interactions

The proopiomelanocortin (POMC)-derived peptides are important regulators in a number of central nervous system pathways especially as they relate to food intake as well as metabolic and autonomic responses. In this study, we investigated the sympathetic nervous and cardiovascular responses to intracerebroventricular (i.c.v.) administration of alpha melanocyte stimulating hormone (alphaMSH), beta-endorphin (beta-END) and adrenal corticotrophic hormone (ACTH) alone or in the presence of a melanocortin antagonist, or an opioid antagonist, in normal animals. The i.c.v. administration of alphaMSH and ACTH resulted in a significant increase in the lumbar sympathetic nerve activity (LSNA) that was accompanied by an increase in mean arterial pressure (MAP). On the other hand i.c.v. administration of beta-END decreased the LSNA and MAP. The pretreatment of animals with the melanocortin-4 (MC-4) receptor antagonist, agouti protein, significantly antagonized the response to alphaMSH and also, paradoxically, not only antagonized the response to beta-END but converted its inhibitory responses on both the LSNA and MAP to a sympathetic activated and pressor response. Pretreatment with the opioid antagonist, naloxone, significantly antagonized the sympathetic nervous and cardiovascular response to beta-END. It partially but significantly antagonized the MAP response to alphaMSH, but the sympathetic response was unaffected. Neither agouti protein nor naloxone altered the sympathetic nervous and cardiovascular response to ACTH. From these studies, we conclude that i.c.v. administration of alphaMSH and ACTH increases the LSNA and cardiovascular dynamics, whereas beta-END decreases it. And, the MC-4 receptor antagonist reverses the endorphin response and the opioid antagonist attenuates the alphaMSH response suggesting possible receptor or central neural pathway interactions between MC-4 and the opioid receptor mediated effects.     

雨蛙肽中枢促胃酸分泌作用机制的初步分析

利用特异的受体阻断剂能够拮抗相应的受体激动剂的效应的原理,分析雨蛙肽中枢促胃酸分泌作用的受体机制。向大鼠侧脑室内注射微量雨蛙肽(67ng/鼠),可引起急性灌流大鼠胃酸分泌明显增加。预先向大鼠侧脑室内注射肾上腺素受体阻断剂酚妥拉明或心得安,20min后再向侧脑室内注射雨蛙肽,预处理对雨蛙肽的促胃酸分泌作用影响不大。但事先向侧脑室内注射乙酰胆碱受体阻断剂阿托品或胆囊收缩素(CCK)受体阻断剂二丁酰环化-磷酸鸟苷(Bt_2 cGMP)则可有效地阻断雨蛙肽的作用。以上结果提示,脑内雨蛙肽促胃酸分泌机制中,可能有 CCK 受体和胆碱能受体参与,而与肾上腺素能系统关系不大。     

Plasma dopamine: regulation and significance

Dopamine (DA) normally circulates in plasma. The plasma concentration of the free form of DA is approximately equivalent to that of epinephrine (E) and 20% that of norepinephrine (NE). The free form constitutes less than 2% of total plasma DA, and the remainder exists predominantly as sulfate or glucuronide conjugates. DA is found in adrenal medulla and cortex, peripheral nerves, sympathetic ganglia, carotid body, and kidney, but quantitatively the origin of circulating DA remains poorly understood. Plasma concentrations of free DA increase in association with events that increase sympathetic tone, although to a much lesser degree than seen for NE or E. Thus, upright posture, bicycle exercise, a variety of emotional and physical stresses, and hypoglycemia may be associated with increases in plasma free DA. Plasma DA decreases during the course of dietary sodium depletion in humans, in contrast to the plasma NE response, and consistent with a physiological role for DA in the regulation of aldosterone secretion. Plasma DA increases after administration of its precursor L-dihydroxyphenylalanine, together with the decarboxylase inhibitor carbidopa. Plasma NE and (in some studies) plasma DA decrease after administration of the DA receptor agonist bromocriptine. In contrast, plasma DA and one of its major metabolites, homovanillic acid, increase after administration of the DA receptor antagonist haloperidol. Administration of the endogenous opioid peptide beta-endorphin into the brain increases central sympathetic outflow, thus increasing plasma DA concentration, although to a lesser extent than for NE or E. Disordered basal concentrations of DA in plasma or disordered responses of plasma DA have been reported in a number of disease states. Clear understanding of physiological roles of DA in plasma and of its pathophysiology awaits definition.     

Receptor sites for atrial natriuretic factors in brain and associated structures: an overview

1. Recent data have clearly shown the existence of specific receptor binding sites for atrial natriuretic factors (ANF) or polypeptides in mammalian brain tissues. 2. Ligand selectivity pattern and coupling to cGMP production suggest that brain ANF sites are similar to high-affinity/low-capacity sites found in various peripheral tissues (kidney, adrenal gland, blood vessels). These brain ANF sites possibly are of the B-ANP subtype. 3. High densities of ANF binding sites are found especially in areas of the central nervous system associated with the control of various cardiovascular parameters (such as the subfornical organ and area postrema). However, high densities of sites are also present in other regions such as the hippocampus, cerebellum, and thalamus in the brain of certain mammalian species, suggesting that brain ANF could act as a neuromodulator of noncardiovascular functions. 4. The density of brain ANF binding sites is modified in certain animal models of cardiovascular disorders and during postnatal ontogeny, demonstrating the plasticity of these sites in the central nervous system (CNS). 5. Specific ANF binding sites are also found in various other CNS-associated tissues such as the eye, pituitary gland, and adrenal medulla. In these tissues ANF appears to act as a modulator of fluid production and hormone release. 6. Thus, ANF-like peptides and ANF receptor sites are present in brain and various peripheral tissues, demonstrating the existence of a family of brain/heart peptides.     

Central interaction of the brain atrial natriuretic polypeptide (ANP) system and the brain renin-angiotensin system in ANP secretion from heart--evidence for possible brain-heart axis

To elucidate the involvement of the brain renin-angiotensin system and the brain atrial natriuretic polypeptide (ANP) system in the regulation of ANP secretion from the heart, the effects of intracerebroventricular administration of angiotensin II and ANP on the plasma ANP level were examined in conscious unrestrained rats. The intracerebroventricular administration of angiotensin II at doses of 100 ng and 1 microgram significantly enhanced ANP secretion induced by volume-loading with 3-mL saline infusion (peak values of the plasma ANP level: control, 220 +/- 57 pg/mL; 100 ng angiotensin II, 1110 +/- 320 pg/mL, p less than 0.01; 1 microgram angiotensin II, 1055 +/- 60 pg/mL, p less than 0.01). The intracerebroventricular injection of angiotensin II at the same doses alone had no significant effect on the basal plasma ANP level. The enhancing effect of central angiotensin II on ANP secretion induced by volume-loading was significantly attenuated by pretreatment with the intravenous administration of the V1-receptor antagonist of vasopressin or with the intracerebroventricular administration of phentolamine. The intracerebroventricular administration of alpha-rANP(4-28) (5 micrograms) had no significant influence on the basal plasma ANP level; however, it significantly attenuated central angiotensin II potentiating effect of volume-loading induced ANP secretion. These results indicate that the brain renin-angiotensin system regulates ANP secretion via the stimulation of vasopressin secretion and (or) via the activation of the central alpha-adrenergic neural pathway, and that the brain ANP system interacts with the brain renin-angiotensin system in the central modulation of ANP secretion from the heart.(ABSTRACT TRUNCATED AT 250 WORDS)     

Neuropeptide FF receptors antagonist, RF9, attenuates opioid-evoked hypothermia in mice

The present study used the endpoint of hypothermia to investigate opioid and neuropeptide FF (NPFF) interactions in conscious animals. Both opioid and NPFF systems played important roles in thermoregulation, which suggested a link between opioid receptors and NPFF receptors in the production of hypothermia. Therefore, we designed a study to investigate the relationship between opioid and NPFF in control of thermoregulation in mice. The selective NPFF receptors antagonist RF9 (30nmol) injected into the third ventricle failed to induce significant effect, but it completely antagonized the hypothermia of NPFF (45 nmol) after cerebral administration in mice. In addition, RF9 (30 nmol) co-injected i.c.v. in the third ventricle reduced the hypothermia induced by morphine (5nmol,) or nociceptin/orphanin FQ (N/OFQ) (2 nmol). Neither the classical opioid receptors antagonist naloxone (10 nmol) nor NOP receptor antagonist [Nphe(1)]NC(1-13)NH(2) (7.5 nmol) reduced the hypothermia induced by the central injection of NPFF at dose of 45 nmol. Co-injected with a low dose of NPFF (5 nmol), the hypothermia of morphine (5 nmol) or N/OFQ (2 nmol) was not modified. These results suggest that NPFF receptors activation is required for opioid to produce hypothermia. In contrast, NPFF-induced hypothermia is mainly mediated by its own receptors, independent of opioid receptors in the mouse brain. This interaction, quantitated in the present study, is the first evidence that NPFF receptors mediate opioid-induced hypothermia in conscious animals.     

Effect of 3beta-hydroxysteroid dehydrogenase inhibition by trilostane on blood pressure in the Dahl salt-sensitive rat

The brains of rats and humans express the enzymes required for the synthesis of aldosterone from cholesterol, including the 3beta-steroid dehydrogenase that catalyzes the conversion of pregnenolone to progesterone in the pathway of adrenal steroid synthesis. Salt-induced hypertension in the Dahl inbred salt-sensitive (SS/jr) rat is associated with normal to low levels of circulating aldosterone, yet it is abrogated by the central infusion of mineralocorticoid receptor antagonists. To test the hypothesis that de novo synthesis of aldosterone in the brain has a pathophysiological role in the salt-induced hypertension of the SS rat, the 3beta-steroid dehydrogenase antagonist trilostane was infused continuously intracerebroventricularly or subcutaneously in two different cohorts of Dahl SS/jr rats, one female, the other male, during and after the development of salt-induced hypertension. The doses of trilostane used had no effect on blood pressure when infused subcutaneously. Animals receiving vehicle intracerebroventricularly experienced a 30- to 45-mmHg increase in systolic blood pressure measured by tail cuff. The intracerebroventricular, but not subcutaneous, infusion of 0.3 microg/h trilostane effectively blocked the increase in systolic blood pressure and reversed the hypertension produced by drinking 0.9% saline. Trilostane was equally effective in female and male rats. Weight gain, serum aldosterone and corticosterone concentrations, and behavior assessed subjectively and by elevated plus maze were unchanged by the trilostane treatment. These studies suggest that the synthesis in the brain of a mineralocorticoid receptor agonist, probably aldosterone, is responsible in part for the salt-induced hypertension of the inbred Dahl SS/jr rat.     

Unexpected effects of nalmefene, a new opiate antagonist, on the hypothalamic-pituitary-gonadal axis in the male rat

In order to gain additional information on the role of brain opioid peptides in the regulation of the hypothalamic-pituitary-gonadal axis, we studied the effects of nalmefene, a new opiate antagonist, on gonadotropin and testosterone secretion in male rats. The results were compared with those obtained with naloxone, a well-studied antagonist. Acute injections of either nalmefene or naloxone (2 mg/kg) produced 4-fold increases in LH and testosterone secretion. In castrated male rats treated with testosterone propionate (TP), nalmefene (10 mg/kg) reversed the androgen negative feedback on LH secretion; surprisingly, when higher doses (25 and 50 mg/kg) were injected, the compound lost its ability to antagonize the testosterone-induced inhibition of LH levels. In contrast, naloxone was able to increase LH levels in TP-treated castrated rats even at the highest dose tested (50 mg/kg). Chronic administration of these antagonists resulted in suppression of the acute release of LH and T secretion in nalmefene-treated but not in naloxone-injected animals. These data are consistent with previous observations suggesting that opioid peptides a) exert a tonic inhibitory effect on LH and testosterone production and b) participate in the negative androgen-induced feedback control of LH secretion. Our results also show that the antagonistic action of nalmefene, but not naloxone, is reversed when higher doses are used or following chronic administration.     

Histidyl-proline diketopiperazine: its biological role as a regulatory peptide

Summary Histidyl-proline diketopiperazine [cyclo(His-Pro)] is a metabolic of thyrotropin releasing hormone (TRH). This review summarizes the literature concerning cyclo (His-Pro) and, in addition, some studies dealing with TRH and other peptides that are considered of interest. The enzymes concerned with the metabolism of TRH are discussed. Distribution studies of peptides by immunological methods show that, while TRH is concentrated in synaptosomes, cyclo (His-Pro) is not, suggesting that cyclo (His-Pro) is not a classical neurotransmitter. Rat brain contains approximately three times as much cyclo (His-Pro) as TRH, mainly localized in the pituitary and hypothalamus. While the TRH is found in a free form, the cyclo (His-Pro) is bound to a carrier of molecular weight approximately 70 000. While specific membrane receptors for TRH have been detected in pituitary cells, no such receptors for cyclo (His-Pro) have yet been found in brain or pituitary; however, there is a specific binding of cyclo (His-Pro) to adrenal cortex membranes, Both TRH and cyclo (His-Pro) have effects in the central nervous system or pituitary. These include effects on prolactin release, thermoregulation, CNS depression, stereotypic behavior and cyclic nucleotide levels. Possible mechanisms and interrelations of these effects are discussed.     

Effects of orexin on cultured porcine adrenal medullary and cortex cells

New orexigenic peptides called orexins have recently been described in the neurons of the lateral hypothalamus and perifornical area. No orexins have been found in the adipose tissues or visceral organs, including the adrenal gland. However, expression of the orexin receptor (OXR) in the rat adrenal gland has been reported. With regard to the effects of orexins on peripheral organs, we previously reported that orexins suppress catecholamine synthesis and secretion in the rat pheochromocytoma cell line PC12. To further clarify the pharmacological effects of orexins on peripheral organs, we examined the effects of orexin-A on catecholamine, cortisol, and aldosterone secretion, using cultured porcine adrenal glands. We initially confirmed the expression of the orexin receptor (OXR-1) in cultured porcine adrenal medulla and cortex. Orexin-A (1000 nM) significantly increased the release of both epinephrine (E) and norepinephrine (NE) from porcine adrenal medullary cells. Similarly, orexin-A (> or = 100 nM) significantly increased the release of both cortisol and aldosterone from porcine adrenal cortex cells. Orexin-A (100 nM) significantly inhibited basal and the PACAP-induced increase in cAMP levels in adrenal medullary cells. Conversely, orexin-A (>o = 100 nM) significantly increased the cAMP level in adrenal cortex cells. These results indicate that orexin-A induces the release of catecholamine from porcine adrenal medullary cells, and aldosterone and cortisol from the cortex cells and has opposite effects on cAMP levels in adrenal medulla and cortex.     

Anti-stress and anti-anxiety effects of centrally acting angiotensin II AT1 receptor antagonists

The brain and the peripheral (hormonal) angiotensin II systems are stimulated during stress. Activation of brain angiotensin II AT(1) receptors is required for the stress-induced hormone secretion, including CRH, ACTH, corticoids and vasopressin, and for stimulation of the central sympathetic activity. Long-term peripheral administration of the angiotensin II AT(1) antagonist candesartan blocks not only peripheral but also brain AT(1) receptors, prevents the hormonal and sympathoadrenal response to isolation stress and prevents the formation of stress-induced gastric ulcers. The mechanisms responsible for the prevention of stress-induced ulcers by the AT(1) receptor antagonist include protection from the stress-induced ischemia and inflammation (neutrophil infiltration and increase in ICAM-1 and TNF-alpha) in the gastric mucosa and a partial blockade of the stress-induced sympathoadrenal stimulation, while the protective effect of the glucocorticoid release during stress is maintained. AT(1) receptor antagonism prevents the stress-induced decrease in cortical CRH(1) and benzodiazepine binding and is anxiolytic. Blockade of brain angiotensin II AT(1) receptors offers a novel therapeutic opportunity for the treatment of anxiety and other stress-related disorders.     

Dual effects of dopamine in rat adrenal glomerulosa cells

The effects of dopamine (DA) on cAMP production and aldosterone secretion were compared in freshly isolated cells and in primary cultures of rat adrenal glomerulosa cells. Under isolated conditions, glomerulosa cells exhibited dopamine receptors from DA-1 and DA-2 subclass, whereas in cultured conditions, where cells are very sensitive to their known stimuli, cells only exhibited dopamine receptors from the DA-1 subclass. Moreover, unlike freshly isolated cells, dopamine stimulated both cAMP production and aldosterone secretion in 3-day cultured preparations. These effects were receptor specific since they were completely suppressed by Scherring 23390 (a specific DA-1 antagonist) and were unaffected by a beta-adrenergic antagonist. As in vivo rat adrenal cortex contains DA, we discuss a possible involvement of this neurotransmitter in the regulation of aldosterone secretion.     

Modulation of testicular functions by testicular opioid peptides.

The possible physiological role of testicular opioid peptides in the control of testicular functions has been studied. In neonatal rats intratesticular administration of opiate receptor antagonists (naloxone, nalmefene) stimulates Sertoli cell proliferation and secretion. Both in adult and neonatal rats local injection of the testis with opiate receptor antagonists or with beta-endorphin antiserum results in a decrease in steroidogenesis in long-term studies. Treatment of neonatal testis with an enkephalin analogue induces a short-term suppression of testosterone secretion. Further studies were carried out to investigate whether the above described local effects of opiate agonist or antagonist on testicular function are under the regulatory control of testicular nerves. Partial denervation of the testis was performed by testicular injection of 6-hydroxydopamine (a neurotoxin degenerating sympathetic neural structures) or by vasectomy (cutting the inferior spermatic nerve). If testicular administration of opioid agonist or antagonist was combined with partial denervation of the testis, the effects of pharmacological agents influencing testicular opioid level were not evident. The data indicate that opioid peptides synthesized in the testis are components of the intratesticular regulatory system and that local opioid actions are modulated by testicular nerves.     

Peptide E and other proenkephalin-derived peptides are potent kappa opiate receptor agonists

Various proenkephalin-derived peptides such as peptide E and the bovine adrenal medulla peptides BAM-12P and BAM-22P are potent competitors on mu and kappa binding sites in guinea pig brain sections. Moreover, they are all potent agonists in the rabbit vas deferens, a specific kappa opiate receptor bioassay. As described before, dynorphin and some of its fragments are also potent kappa agonists. Our results suggest that not only prodynorphin-derived peptides could act as endogenous kappa ligands but also some proenkephalin-derived peptides such as peptide E.