Nitric oxide mediates leptin-induced preovulatory luteinizing hormone and prolactin surges in rats

The objective of this study was to investigate whether nitric oxide (NO) plays a significant role in mediating the facilitatory action of leptin on the reproductive system. The covariate of reproductive function we used for evaluation was preovulatory surges of luteinizing hormone (LH) and prolactin (PRL), which were simulated by priming ovariectomized rats with estradiol and progesterone. A systemic treatment of normally-fed rats with an NO synthase inhibitor (N(W)-nitro-L-arginine methyl ester) significantly decreased the magnitude of both LH and PRL surges. Three-day-fasted rats did not show a significant surge of either LH or PRL. An intracerebroventricular administration of leptin to fasted rats led to a significant recovery of these hormonal surges, but a simultaneous administration of both the NO synthase inhibitor and leptin significantly abrogated the effects of leptin. This is the first report to demonstrate a significant intermediary role of NO in leptin-induced preovulatory LH and PRL surges in rats.     

Photoperiodic regulation of prolactin release in male hamsters with hypothalamic knife cuts

Horizontal knife cuts placed dorsal to the paraventricular nucleus (PVN) of the hypothalamus prevent testicular regression in hamsters kept in short days. We examined the effects of these cuts on the photoperiodic modulation of the postcastration rise in gonadotropins, as well as on the release of prolactin in castrated and gonadally intact animals. The cuts blocked the inhibitory effects of short daylengths on the postcastration rise in circulating levels of gonadotropins. However, the cuts did not prevent the reduction in prolactin levels induced by short daylengths in castrated and gonadally intact animals. We conclude that dorsal connections of the PVN are not required for transduction of photoperiodic information used to regulate prolactin release. The knife cuts may remove tonic inhibitory influences on the release of follicle-stimulating hormone and luteinizing hormone, and thus produce elevated gonadotropin levels that mask the effects of nonstimulatory photoperiods on testicular size.     

A significant participation of orexin-A, a potent orexigenic peptide, in the preovulatory luteinizing hormone and prolactin surges in the rat

Orexins are novel hypothalamic peptides which stimulate food intake. In view of the well-known tight connection between the nutritional state and the reproductive function, in this study we examined a possible role of orexin-A in the generation of ovarian steroid-induced luteinizing hormone (LH) and prolactin (PRL) surges in ovariectomized rats. Experiments were performed on both normally-fed and 3-day-fasted rats. Although fasting led to abolition of both LH and PRL surges, intracerebroventricular administration of orexin-A (0.3 and 3.0 nmol) resulted in a dose-dependent recovery of the hormonal surges. In addition, anti-orexin-A antisera given to normally-fed rats completely abrogated the surges of both hormones. These results demonstrate for the first time a significant participation of orexin-A in the preovulatory LH and PRL surges in the rat.     

Role of the septum on LH, FSH and prolactin secretion in male rats

Serum concentrations of luteinizing hormone (LH) follicle-stimulating hormone (FSH), prolactin (PRL) and testosterone were measured by radioimmunoassay in male Wistar rats:

1. (a) Four days after a septal lesion (n = 19) and

2. (b) Just following electrical stimulation of the septum (n = 15). Septal lesions induced a significant decrease in serum LH (16.37 ± 2.01 vs. 30.27 ± 2.08 ng/ml; p < 0.001) and testosterone concentrations (0.53 ± 0.05 vs. 1.01 ± 0.14 ng/ml; p < 0.02). No significant changes were observed for FSH or PRL levels. Electrical septal stimulation induced an increase in serum levels of LH (211.5 ± 46.4 vs. 29.6 ± 11.5 ng/ml; p < 0.01) and FSH (703 ± 83 vs. 378 ± 57 ng/ml;p < 0.01), without changes in PRL or testosterone concentrations. From these data we conclude that in male rats the septum may play a role in the mechanisms controlling gonadotropins release by the anterior pituitary gland.

Involvement of serotonin 5HT1 and 5HT2 receptors and nitric oxide synthase in the medial preoptic area on gonadotropin secretion

Due to the stimulatory action of serotonin (5HT) and nitric oxide (NO) on the secretion of gonadotropins and PRL, this work aimed at investigating the participation of serotoninergic receptors 5HT(1) and 5HT(2) of the medial preoptic area (MPOA) in the control of luteinizing hormone (LH), follicle stimulating hormone (FSH) and prolactin (PRL) secretion and the possible modulation by ovarian steroids as well as the possible participation of NO as a mediator of the stimulatory effects of serotonin in the MPOA on LH secretion. Microinjections of three different doses (0.02, 0.2, and 2 ug) of methiothepin, a serotoninergic 5HT(1) antagonist or ketanserin, a seretoninergic 5HT(2) antagonist, were carried out into the MPOA in ovariectomized rats treated or not with estrogen or estrogen plus progesterone. Other groups of ovariectomized rats treated with estrogen, estrogen plus progesterone or vehicle were prepared to evaluate NOS activity in the MPOA. Plasma LH, FSH, and PRL in ovariectomized rats were not altered by the microinjection of methiothepin or ketanserin in the MPOA. Methiothepin microinjection in the MPOA reduced LH but did not change plasma FSH and PRL in ovariectomized rats treated with estrogen or estrogen plus progesterone. On the other hand, ketanserin microinjection in the MPOA reduced plasma LH and FSH but did not change plasma PRL in the animals submitted to the same steroidal treatment. NOS activity in the MPOA was significantly reduced by methiothepin or ketanserin in ovariectomized rats treated with estrogen or estrogen plus progesterone. In conclusion, this work showed that in the studied conditions, serotonin in the MPOA: (1) does not work in the control of PRL secretion through 5HT(1) and 5HT(2) receptors; (2) integrates the control of FSH secretion by 5HT(2) receptors, but not 5HT(1); (3) in the presence of estrogen, stimulates LH secretion by 5HT(1) and 5HT(2) receptors, which can be differentially modulated by progesterone; (4) at least partly, stimulates LH secretion by nitric oxide activity.     

Immediate prolactin release after pericommissural deafferentation in behaving male rats

Adult male rats received a chronic midline implant of Halász-type knife placed at the level of the anterior commissure. A chronically implanted heart cannula allowed for sequential blood sampling in unrestrained conditions. Anterior knife rotation of 180 degrees induced a significant increase of plasma prolactin concentration in 30 min. Plasma LH levels remained within control levels. It is suggested that neural projections dorsally entering the preoptic-suprachiasmatic region are significantly involved in the control of prolactin release in male rats.     

Evidence for the involvement of nitric oxide and nitric oxide synthase in the modulation of opioid-induced antinociception and the inhibitory effects of exposure to 60-Hz magnetic fields in the land snail

The attenuation of opioid peptide-mediated antinociception is a well-established effect of extremely low frequency (ELF) electromagnetic fields with alterations in calcium channel function and/or calcium ion flux and protein kinase C activity being implicated in the mediation of these effects. The present study was designed to examine the effects of nitric oxide (NO) and calcium ion/calmodulin-dependent nitric oxide synthase (NOS) on opioid-induced antinociception and their involvement in mediating the inhibitory effects of exposure to ELF magnetic fields. We observed that enkephalinase (SCH 34826)-induced, and likely enkephalin-mediated, antinociception in the land snail, Cepaea nemoralis, as measured by the enhanced latency of a foot withdrawal response to a thermal (40°C) stimulus, was reduced by the NO releasing agent, S-nitro-N-acetylpenicillamide (SNP), and enhanced by the NO synthase inhibitor, N^G-nitro- -arginine methyl ester ( -NAME). Exposure of snails to an ELF magnetic field (15 min, 60 Hz, 141 μT peak) also reduced the enkephalinase-induced antinociception. The inhibitory effects of the 60-Hz magnetic field were significantly reduced by the NO synthase inhibitor, -NAME, and significantly enhanced by the NO releasing agent, SNP, at dosages which by themselves had no evident effects on nociceptive sensitivity. These results suggest that: (1) NO and NO synthase have antagonistic effects on opioid-induced analgesia in the snail, Cepaea and (2) the inhibitory effects of ELF magnetic fields on opioid analgesia involve alteration in NO and NO synthase activity.     

Medial preoptic-anterior hypothalamic area involvement in the suppression of pulsatile LH release by a mu-opioid agonist in the ovariectomized rat

The objective of this study was to examine whether specific activation of mu-opioid receptors at the level of the medial preoptic-anterior hypothalamic area (MPOA-AHA) could suppress pulsatile LH release. The experiments were done using rats that had been ovariectomized (OVX) 24 hr before on diestrus 2, animals in which we have previously demonstrated an active endogenous opioid peptide suppression of pulsatile LH release (2). DAGO, DPDPE, or U50488H, specific agonists of mu-, delta- and kappa-opioid receptors, respectively, were continuously applied directly to the MPOA-AHA by means of push-pull perfusion. Perfusion of the MPOA-AHA with 0.5 micrograms DAGO/hr suppressed LH pulse amplitude. This effect of DAGO was not due to spread to the third ventricle and subsequent diffusion via the CSF to another CNS site, since push-pull perfusion with this dose of DAGO in the region just dorsal to or in the posterior hypothalamus was ineffective in altering LH pulse amplitude. The response to DAGO was dose-dependent since a higher dose (4.8 micrograms/hr) markedly suppressed both LH pulse amplitude and frequency. The same doses of DPDPE and U50488H (0.5 and 4.8 micrograms/hr) had no effect on pulsatile LH secretion, providing support for mu receptor involvement in the DAGO-induced suppressive action. These data demonstrate MPOA-AHA involvement in the suppression of pulsatile LH release by a mu-opioid agonist in the OVX rat.     

Enhanced prolactin release by injection of glycine in the medial preoptic area (mPOA) of the rat1

Injection of glycine into the medial preoptic area (mPOA) in doses of 12.5, 25 and 50 micrograms produced a marked increase in prolactin release in freely-moving male rats. Neither taurine nor beta-alanine had effect on prolactin. These amino acids were unable to modify the resting plasma LH levels. The present studies show that the mPOA is a target site for the prolactin releasing action of glycine. Furthermore, they suggest a participation of this amino acid in the mPOA mechanism for control of prolactin secretion in the rat.     

Effects of nitric oxide (NO) synthesis inhibition on the development of supersensitivity to stereotypy and locomotion stimulating effects of methamphetamine

The present study examined the effects of nitric oxide (NO) synthase inhibitor, Nω-nitro-l-arginine methyl ester (LNAME; 30 and 60 mg/kg, i.p.) on the development of supersensitivity to stereotypy as well as locomotion stimulating effects of methamphetamine (MA) (3.22 and 0.805 mg free base/kg, s.c., respectively). Rats treated with MA for 10 days showed enhancement in MA-induced stereotypy and locomotor activity. Rats pretreated with LNAME prior to MA also showed enhancement in the two types of behavior, also they showed significantly reduced stereotypy scores compared to those treated with MA alone. The results suggest that NO synthesis is not critically involved in the development of behavioral supersensitivity to stereotypy stimulating as well as locomotion stimulating effect of MA. However, NO synthesis may have a modulatory role in behavioral sensitization in stereotypy.     

一氧化氮和一氧化氮合酶在鼠脑内形成吗啡依赖的作用研究

目的：研究一氧化氮（NO）和一氧化氮合酶（NOS）在吗啡依赖形成中的作用。方法;对吗啡依赖和戒断大鼠脑内NO含量和NOS活力进行测定。结果：未发现吗啡依赖和戒断大鼠脑内NO含量和NOS活力有改变。结论：对NO／NOS与吗啡依赖的关系还有待进一步研究。     

Social stress inhibits the nitric oxide effect on the corticotropin-releasing hormone- but not vasopressin-induced pituitary–adrenocortical responsiveness

Putative involvement of endogenous nitric oxide (NO) in the corticotropin-releasing hormone (CRH, 1 μg/kg i.p.)- and vasopressin (AVP, 5 μg/kg i.p.)-induced ACTH and corticosterone secretion was investigated in both non-stressed and crowded rats. The NO synthase blocker Nω-nitro--arginine (-NNA, 2 mg/kg i.p.) significantly augmented the AVP-induced ACTH and corticosterone secretion in control and stressed rats, but it increased the CRH-induced ACTH response only in control rats. Crowding stress did not affect the -NNA evoked increase in AVP-induced hormone responses, but it abolished the CRH-induced ACTH response.     

癫癎患者血清一氧化氮和一氧化氮合酶活性水平的研究

目的　探讨一氧化氮 (NK)和一氧化氮合酶 (NOS)在癫患者中血清活性水平及意义。方法　采用化学比色法对 10 0例癫患者血清中NO和NOS活性水平进行检测。结果　癫患者间歇期血清中NO和NOS活性水平显著高于对照组 (P <0 0 1)。结论　NO和NOS在癫病理过程中起重要作用。     

海人酸致痫动物模型脑内一氧化氮,一氧化氮合酶的变化

目的探讨一氧化氮（ＮＯ）、一氧化氮合酶（ＮＯＳ）在癫痫发生中的作用及ＮＯＳ抑制剂的作用。方法采用海人酸致痫大鼠模型并应用ＮＯＳ抑制剂Ｌ－硝基精氨酸甲酯（Ｌ－ＮＡＭＥ）,分别在致痫后３０分钟、６０分钟取海马组织,匀浆后测定ＮＯ及ＮＯＳ水平。结果致痫３０分钟后海马ＮＯ含量显著升高,至６０分钟恢复正常;ＮＯＳ活性水平增高＞５０％;Ｌ－ＮＡＭＥ明显抑制大鼠的痫性发作,应用ＮＯＳ抑制剂组大鼠海马ＮＯ、ＮＯＳ含量明显下降。结论癫痫发作后脑内ＮＯ、ＮＯＳ活性增强,ＮＯＳ抑制剂通过抑制酶活性使ＮＯ生成降低,并完全抑制痫性发作。ＮＯＳ活性受抑制＞４８％即可产生明显效果。提示ＮＯ可能有内源性致痫作用。     

儿童癫癎患者血清一氧化氮及一氧化氮合酶活性水平的研究

目的　探讨一氧化氮 (NO)及一氧化氮合酶 (NOS)在儿童癫患者中血清活性水平及意义。方法　采用化学比色法对12 4例儿童癫患者血清中NO及NOS活性水平进行检测。结果　儿童癫患者发作期及间歇期血清中NO及NOS活性水平均显著高于对照组 (P <0 0 1) ,发作期血清中NO及NOS活性水平均高于间歇期 (P <0 0 5 )。结论　NO及NOS在儿童癫病理过程中起重要作用     

Neonatal exposure to estradiol prevents the expression of ovarian hormone-induced luteinizing hormone and prolactin surges in adulthood but not antecedent changes in neuropeptide Y or adrenergic transmitter activity: Implications for sexual differentiation of gonadotropin secretion

Sex differences in adult patterns of mating behavior and gonadotropin secretion in rats are determined in part by the presence or absence of gonadal steroids during a perinatal critical period. For example, male rats and female rats exposed neonatally to androgen do not exhibit LH surge patterns when treated appropriately with ovarian hormones in adulthood, and there is evidence that this may be due to a failure of ovarian hormones to activate the hypothalamic neuronal systems that stimulate LH secretion in such animals. Because considerable evidence suggests that estradiol formed centrally from testosterone is responsible for the permanent defeminization of mating behavior and gonadotropin secretion, the present studies compared normal females with normal males and with females treated neonatally with estradiol on the ability of ovarian hormones to induce several important neurochemical changes antecedent to the LH surge, including changes in neuropeptide Y (NPY) and LH-releasing hormone (LHRH) concentrations in the median eminence, as well as changes in turnover rates for catecholamine transmitters in the medial basal hypothalamus and medial preoptic area. Normal ovariectomized female rats responded to sequential treatment with estradiol followed by progesterone with afternoon LH and prolactin (PRL) surges, and with sequential accumulation followed by decline in concentrations of LHRH and NPY in the median eminence prior to the LH surge. In addition, administration of progesterone increased the turnover rates of norepinephrine (NE) and epinephrine (EPI) in the arcuate-median eminence region of normal females. Gonadectomized male rats receiving the same ovarian hormone treatment failed to exhibit LH or PRL surges and displayed none of the changes in neurotransmitter turnover or peptide concentrations characteristically seen in the normal female. Unexpectedly however, when females that were treated with estradiol benzoate on days 1–3 postpartum were ovariectomized and treated with ovarian hormones in adulthood, they showed the same accumulation/decline in median eminence NPY concentrations and the same activation of NE and EPI turnover in the arcuate-median eminence region as normal females, even though they showed no LH or PRL surges or changes in median eminence LHRH concentrations. These results suggest that estradiol may not mediate all of the defeminizing actions of androgen exerted during the early neonatal period, and particularly those actions that result in a lack of responsiveness in central noradrenergic, adrenergic and NPY systems in adulthood. However, an action of neonatal estradiol may result in uncoupling of the LHRH neurosecretory system from normal excitatory neurochemical influences.     

一氧化氮及一氧化氮合酶抑制剂在大鼠局灶性脑缺血时作用研究

目的：观察一氧化氮及一氧化氮合酶抑制剂在大鼠局灶性脑缺血时的作用方法;民凝大鼠大脑中动脉制成脑缺血模型,选择脑缺血３０ｍｉｎ,６０ｍｉｎ,１２０ｍｉｎ,１８０ｍｉｎ为研究时点,观察各时点用选择性,非选择性一氧化氮合酶抑制剂亚硝酸盐含量测定,缺血脑组织坏死体积测定及损伤海马ＣＡ１电镜观察。     

Activation of epileptic foci by transcranial magnetic stimulation: effects on secretion of prolactin and luteinizing hormone

Summary Transient elevation of serum levels of prolactin has been observed following several types of epileptic seizures and after electrical stimulation of limbic temporal lobe structures via implanted electrodes. Transcranial magnetic stimulation has been found to selectively induce epileptiform afterdischarges in the epileptic focus of candidates for epilepsy surgery who suffered from temporal lobe epilepsy. Lateralized serial transcranial magnetic stimulation was therefore used and serum levels of prolactin or luteinizing hormone were measured to find if it could be used as a non-invasive diagnostic tool. The investigation was performed on six patients and five healthy volunteers. In the patients the induction of epileptiform potentials was continuously monitored via subdural electrodes. A transient surge of prolactin and luteinizing hormone was found in only one patient, in whom a complex partial seizure was induced. Thus, transcranial magnetic stimulation appeared not to be helpful for the lateralization of the (primary) epileptic focus during presurgical evaluation.     

Assessment of the effects of a synthetic gonadotropin-releasing hormone associated peptide on hormone release from the in situ and ectopic pituitaries in adult male rats

The in vivo effects of synthetic human gonadotropin-releasing hormone associated peptide (GAP) were evaluated in adult male rats. In normal rats, intracerebroventricular (III ventricle) injection of 5 ng GAP significantly increased plasma LH levels after 60 minutes. Intracerebroventricular administration of 5, 25 or 125 ng of GAP elevated circulating LH levels also at 120 minutes of injection but did not alter plasma FSH, prolactin or testosterone concentrations. In hypophysectomized-pituitary-grafted rats injection of 125 ng GAP directly into the ectopic pituitary induced no changes in peripheral hormone levels. However, intrapituitary graft injection of 25 ng of GnRH significantly elevated circulating levels of LH and testosterone. These results indicate that the ectopic pituitary graft can respond to acute exogenous GnRH stimulation and that the commercially available synthetic GAP fails to inhibit prolactin release in adult male rats.     

迟发性运动障碍患者血浆超氧化物歧化酶和一氧化氮及一氧化氮合酶的变化

目的 探讨血浆超氧化物歧化酶(SOD)、一氧化氮(NO)及NO合酶(NOS)的变化与抗精神病药所敛的迟发性运动障碍(TD)的关系。方法 对42例长期使用抗精神病药治疗伴有TD的男性精神分裂症患者的血浆锰SOD(MnSOD)、铜-锌SOD(CuZnSOD)、NO及NOS的活性进行测定,以59例不伴有TD男性精神分裂症患者和50例健康男性作对照组,使用异常不自主运动量表(AIMS)进行临床评估。结果 TD组MnSOD、CuZnSOD和NO分别高于非TD组(P<0.05)或正常对照组(P<0.05),TD组NOS明显低于正常对照组(P<0.05)、略高于非TD组(p<0.05)。TD组MnSOD浓度越高则TD的症状越严重、NOS则相反(P<0.01),且在TD组MnSOD与NO呈显著的负相关(p<0.05)、在非TD组或正常对照组却呈正相关(前者P<0.01)。分层后发现TD组MnSOD浓度在NO较低时显著高于非TD组(P<0.01),而在NO浓度较高时则略低于非TD组(P>0.05)。结论 抗精神病药所致的TD,可能与患者血浆SOD尤其是MnSOD活性增高以及血浆NO浓度升高密切相关,两者可能来源于不同病理过程,但均提示自由基活动异常。