Prostaglandins of the E Series Stimulate Cyclic AMP Accumulation and N-Acetylation of Serotonin in Chick Pineal Cells

We investigated the effects of prostaglandins on cyclic AMP (cAMP) levels and on the activity of the rate-limiting enzyme of melatonin biosynthesis, arylalkylamine-N-acetyltransferase (NAT). The study was performed on primary cultures of dispersed chick pineal cells. Prostaglandin E, (PGE,) increased cAMP levels 2-fold and this stimulation went up to 4-fold in the presence of a phosphodiesterase inhibitor. The PGE,- evoked increase in cAMP levels did not desensitize over 6 h. The potency order of a series of prostaglandins to increase cAMP levels (PGE₁ PGE₁>PGA2>PGD₂?PGF₂α) agreed with the pharmacological profile of the adenylate cyclase-coupled prostaglandin receptor. Inhibition of endogenous prostaglandin synthesis by two cyclooxygenase inhibitors (indomethacin and aspirin) caused a 30% decrease in cAMP levels. This effect was completely reversed by the addition of exogenous PGE₁ or PGE₂. Indomethacin and aspirin also caused a 50% decrease in NAT activity. Prostaglandins of the E series increased NAT activity up to 2-fold above basal level and restored NAT activity after inhibition by indomethacin or aspirin. These results are the first illustration of a role for prostaglandins in chick pineal cells. The correlations observed between cAMP levels and NAT activity suggest that the regulation of NAT activity by prostaglandins of the E series might be mediated by changes in cAMP concentration.     

Cerebrospinal fluid cyclic AMP and acid monoamine metabolites following probenecid: Studies in psychiatric patients

At probenecid levels greater than 10 g/ml, CSF cAMP was independent of CSF probenecid concentration. At these levels of probenecid, cAMP transport out of CSF is probably maximally blocked and cAMP levels reflect cAMP release into CSF. CSF cAMP was significantly higher in RDC-diagnosed schizophrenics than in other psychotics or depressives. A significant decrease in CSF cAMP was found in psychotic patients treated with chlorpromazine. No changes in CSF cAMP were observed in patients treated with tricyclic antidepressants or lithium.     

Single-dose tolerance to the behavioral effects of dibutyryl cyclic AMP in mice

The behavioral effects of varying doses of intraperitoneally administered dibutyryl cyclic AMP, cyclic AMP, adenosine, 5-AMP, and butyric acid were studied in male ICR mice. Behavioral parameters 25 min following treatment included measurement of spontaneous locomotor activity (SLMA) and rotarod performance, the latter providing an indication of neuromuscular coordination. Dibutyryl cyclic AMP produced a dose-related inhibition of SLMA with the largest dose, 75 mg/kg, decreasing activity by 89%. Adenosine and 5-AMP produced maximal inhibition of approximately 50–80% of SLMA at doses ranging from 75–250 mg/kg, while cyclic AMP decreased SLMA by 58% at only the highest dose, 250 mg/kg. Butyric acid failed to produce alterations in SLMA at doses ranging from 25–250 mg/kg. No compound altered neuromuscular coordination. Single-dose tolerance to the inhibitory effect of dibutyryl cyclic AMP on SLMA developed within 3 h and lasted at least 7 days. Adenosine failed to produce tolerance while cyclic AMP and 5-AMP exhibited only a slightly reduced effect following a second injection at intervals of 4 and 24 h. These results suggest that exogenous administration of dibutyryl cyclic AMP and its metabolites exert centrally mediated behavioral effects with selective development of single-dose tolerance to the dibutyryl derivative.     

Responses of fetal rat bone cells and bone organ cultures to the ionophore,A23187

The ionophore A23187 produced a rapid transient increase in the rate of calcium uptake by isolated fetal rat bone cells. There was no effect on calcium efflux or total cellular calcium. The magnitude of the effect on influx was amplified when the cell were incubated at 4°C. Cellular metabolic functions and resorption of cultured fetal rat bones (release of⁴⁵Ca from pre-labeled long bone) were affected by A23187 in a biphasic manner: cell cyclic AMP (cAMP) was increased by 0.1 and 0.3 g/ml of the ionophore, whereas 10 g/ml was either ineffective or lowered the cAMP levels. The high A23187 concentration abolished the stimulatory effects of parathyroid hormone and methylisobutylxanthine. Concentrations of 0.1 and 0.3 g/ml A23187 stimulated bone resorption. The effect was abolished by calcitonin. Ionophore concentrations above 1 g/ml produced less bone resorption. These higher concentrations antagonized the bone-resorbing effect of parathyroid hormone and 1,25-dihydroxyvitamin D₃. A23187 at 5 and 10 g/ml decreased bone cell lactate and ATP. Thus at low concentrations, A23187 produced effects on bone similar to those of parathyroid hormone, suggesting that calcium is the primary initiator of PTH-induced bone resorption. At the higher concentrations A23187 may have a general inhibitory effect on cell metabolism.     

Alterations of dopaminergic neurotransmission after chronic morphine treatment: Pre- and postjunctional studies in striatal tissue

Summary Repeated morphine administration reversed the acute effects of morphine in rats, e.g. catalepsy and akinesia, and induced symptoms suggesting an activation of dopaminergic mechanisms. In morphinewithdrawn rats, the potency or intrinsic activity of dopamine in stimulating the synthesis of cyclic AMP in striatal homogenates was not significantly altered. However, the K⁺-induced release of¹⁴C-dopamine from striatal slices of morphine-withdrawn rats was significantly increased, compared with that from striatal slices of saline-treated controls. The results suggest that chronic morphine administration to rats increases the dopaminergic neurotransmission in brain by a pre-synaptic (prejunctional) mechanism, probably reflecting some kind of adaptation to the acute morphine action, which decreases the dopaminergic neurotransmission. The nigro-striatal dopaminergic system, therefore, seems to be a good model to study acute morphine actions and mechanisms of morphine dependence at the cellular level.Some of these results were presented at the Symposium on Acute Effects of Narcotic Analgesics in Nokkala, Espoo, Finland, July 18–20, 1975, and at the Vth Congress of the Polish Pharmacological Society, Szczecin, Sept. 24–27, 1975     

肿瘤坏死因子-β抗肿瘤及作用机制的研究

目的 :探讨肿瘤坏死因子 -β(tu mornecrosisfactor β ,TNF β)对 3种人癌细胞的增殖抑制作用及其细胞分子机制。方法 :采用多种体外及体内实验方法 ,从多侧面证实TNF β的抗肿瘤作用。并采用细胞内游离钙浓度测定、12 5I cAMP放免检测法检测cAMP含量。结果 :不同浓度TNF β对肿瘤细胞系均有增殖抑制作用 ,且呈剂量依赖性。当TNF β与顺铂和多柔比星合用 ,JF3 0 5细胞死亡百分比分别达到 ( 68 6±9 0 ) %和 ( 76 5± 7 9) %。TNF β实验组细胞内cAMP浓度明显增加 ,JF3 0 5细胞由( 0 0 5 72± 0 0 176)上升到 ( 0 2 896±0 0 784) pmol/10 6个细胞。此外细胞内钙浓度上升并且凋亡。结论 :TNF β具有体内、外抗肿瘤作用 ,其部分机制是通过增加cAMP含量及诱导细胞凋亡     

Tyrosine kinase effects on adrenoceptor-stimulated cyclic AMP accumulation in preoptic area and hypothalamus of female rats: modulation by estradiol

These studies examined the functional interactions between adrenergic G-protein coupled receptors and protein tyrosine kinases in the preoptic area and hypothalamus, brain regions that regulate reproductive function in female rats, and evaluated whether in vivo treatment with estradiol for 2 days modulates the cross-talk between these two signaling pathways. In hypothalamic slices genistein, a general tyrosine kinase inhibitor, enhances norepinephrine-stimulated cAMP synthesis independent of estradiol treatment. Genistein appears to act by increasing beta-adrenoceptor signaling. At high norepinephrine concentrations, estradiol potentiates genistein enhancement of the cAMP response in hypothalamic slices. This interaction between estradiol and genistein appears to involve modification of alpha(2)-adrenoceptor signaling mechanisms. In preoptic area slices, genistein enhancement of norepinephrine-stimulated cAMP synthesis is only observed in estradiol-treated rats. In this brain region, genistein enhances cAMP accumulation by modifying alpha(1)- and/or alpha(2)-adrenoceptor rather than beta-adrenoceptor signaling. Genistein amplification of norepinephrine-stimulated cAMP synthesis is not mediated by interactions with estrogen receptors, or by regulation of adenylyl cyclase or phosphodiesterase activities. At the concentration used, genistein inhibits tyrosine phosphorylation in slices from both brain regions. Daidzein, an inactive analogue of genistein, fails to enhance the norepinephrine-stimulated cAMP response in either brain region independent of hormone treatment. These results suggest that protein tyrosine kinases regulate adrenergic responses in the hypothalamus and preoptic area. Moreover, the functional interaction between adrenergic G-protein coupled receptor signaling and protein tyrosine kinases is modified in a brain region and receptor subtype specific manner by estradiol.     

胸水ADA与LDH检测在鉴别恶性与结核性渗出性胸水中的作用

目的:评价胸腔积液腺苷脱氨酶(ADA)、乳酸脱氢酶(LDH)在支气管肺癌胸水及结核性胸水的诊断价值。方法:对119例患者(支气管肺癌54例,结核性65例),每例均检测患者胸水ADA和LDH。结果:肺癌患者胸水LDH水平显著高于结核组(P<0.001),而其ADA显著低于结核患者(P<0.001)。胸水ADA与LDH联合检测,对肺癌所致胸水判别正确率为96.3%。结论:高PLDH和低PADA水平提示恶性胸水,仅有高水平PADA是结核性胸水的特征。     

穴位埋线对慢性胃炎患者环核苷酸及胃肠激素的影响

目的:观察穴位埋线治疗慢性胃炎的临床疗效.方法:将70例慢性胃炎患者随机分为埋线组(36例)与针刺组(34例).主穴均为胃俞、中脘、足三里,分别进行埋线或针刺治疗,并观察血浆环磷酸腺苷(cAMP)、环磷酸鸟苷(cGMP)含量及胃泌素(Gas)、P物质(SP)含量的改变.结果:埋线组总有效率为88.89%优于针刺组76.47%(P＜0.05);两组各自治疗前后比较,血浆cAMP、cGMP、Gas、SP含量的改变差异具有非常显著性意义(P＜0.01);埋线组各项指标的改善程度均优于针刺组(P＜0.05).结论:穴位埋线治疗慢性胃炎有肯定疗效,通过调节环核苷酸和胃肠激素含量,从而改善了神经-内分泌-免疫调节功能.     

β-Adrenoceptor activates endothelium-dependent release of nitric oxide in rat aorta

AIM:To examine the possible role of agents elevating cAMP to release NO from aortic en-dothelial cells. METHODS:NG-nitro-L-arg inine methylester (L-NAME) , an inhibitor of NO synthase, partially inhibited endothelium-dependent relaxation evoked in phenylephrine-precontracted rings by isoproterenol and abolished relaxation mediated by forskolin 0. 2 umol L-1.RESULTS: In rings without en-dothelium, isoproterenol and forskolin were less effective relaxants and L-NAME had no effect on the responses. In methylene blue-treated rings isoproterenol- and forskolin-induced relaxation were prevented in both en-dothelium-intact and -denuded rings, but the inhibitory effects of methylene blue were significantly more in rings with endothelium than in those without. On the other hand, relaxation induced by sodium nitroprusside was not inhibited by L-NAME, but was inhibited by methylene blue in both the endothelium-intact and -denuded rings. The concentration relaxation curves to sodium nitroprusside after methylene bl