血小板内皮聚集受体1及其介导的信号通路在血小板和内皮细胞中的作用研究进展

血小板内皮聚集受体1(platelet endothelial aggregation receptor 1, PEAR1)是2005年被发现的一种跨膜受体,主要在血小板和内皮细胞上表达。PEAR1是血小板与血小板间相互接触的受体蛋白,在血小板活化和聚集过程中起着重要作用。内皮细胞在维持血管张力和血管修复方面发挥重要作用,PEAR1通过影响其增殖和相关新生血管的形成,调控肿瘤的发生、发展过程。近年来,PEAR1逐渐被公认为是抗血栓药物的潜在靶点。本综述主要阐明血小板内皮聚集受体1在血小板和内皮细胞中的作用机制以及相关信号通路,为肿瘤相关血栓的药物治疗研究提供新思路。     

低氧大鼠肺组织eNOS、NO和cGMP的变化

为探讨低氧大鼠肺组织eNOS、NO和cGMP的变化,将雄性Wistar大鼠18只随机分为常氧（N）组、急性低氧（AH）组和慢性低氧（CH）组,每组6只。AH组急性低氧30 min;CH组慢性低氧2周、8 h/d;N组吸入空气。低氧结束后测定大鼠mPAP、肺小血管肌化程度和红细胞比容（Hct）,并行肺组织eNOS Western blot检测和cGMP、NO含量测定。结果显示：①N组eNOS蛋白含量明显高于AH组（P〈0.01）,明显低于CH组（P〈0.01）;②AH和CH组NO含量明显低于N组（P〈0.05）;③AH组cGMP含量明显低于N组（P〈0.05）,N组和CH组差异无统计学意义（P〉0.05）;④AH和CH组大鼠mPAP明显高于N组（P〈0.01）;⑤CH组肺小血管肌化程度和Hct明显高于N组（P〈0.01）,AH组与N组差异无统计学意义（P〉0.05）。结论：急性低氧可抑制大鼠肺组织eNOS表达,减少NO/cGMP产量;慢性低氧可上调大鼠肺组织eNOS表达,但存在功能缺陷。慢性低氧大鼠肺组织cGMP含量虽与正常大鼠无明显区别,但不足以阻止肺动脉高压的发病。     

通过环磷酸腺苷信号通路治疗焦虑症的研究进展

目的:综述近年来国内外通过第二信使环磷酸腺苷(c AMP)信号通路治疗焦虑症的相关研究进展,寻找治疗焦虑症新的潜在靶点。方法:以AnxietyCyclic adenosine monophosphateAdenylate cyclasePhosphodiesteraseProtein kinase A等组合作为关键词,查阅2000-2014年Pub Med、Science Direct、Springer等数据库,检索药物通过作用第二信使c AMP通路治疗焦虑症的研究文献,对其相关研究进展进行汇总分析。结果与结论:共检索到相关文献236篇,其中有效文献33篇。c AMP信号通路治疗抑郁症的潜在靶点可能位于腺苷酸环化酶(AC)、磷酸二酯酶(PDE)和c AMP依赖的蛋白激酶A(PKA)。通过敲除Ca2+调节的AC基因、抑制或激活相关G蛋白偶联受体、抑制AC活性、降低细胞内c AMP水平可产生一定的抗焦虑样作用;而PDE抑制剂和PKA激动药则可通过增加特定脑区内的c AMP水平产生抗焦虑样作用,但其治疗焦虑症的作用机制有待更深入的研究。     

第二信使cAMP、cGMP信号通路调节骨形成的研究进展

骨形成过程受多种因素的调节,包括激素、细胞因子、生长因子等。其调控方式是由复杂的信号分子及其相连的信号通路实现的,因此,信号通路在其中的作用是当前研究的热点,该文综述了cAMP、cGMP信号通路调节骨形成的研究进展。     

NO-cGMP信号通路舒张甲亢性高血压大鼠胸主动脉的特性

目的探讨NO-cGMP信号通路舒张甲亢性高血压大鼠胸主动脉的特性。方法大鼠皮下每天注射甲状腺素(T4)0.5 mg.kg-1的剂量或等体积的生理盐水连续16 d,制备甲亢性高血压大鼠模型组和对照组。采用两组大鼠的离体胸主动脉环标本,观察NO供体SNAP对胸主动脉环的影响;利用可溶性鸟苷酸环化酶(sGC)激活剂BAY 41-2272(BAY)、sGC阻断剂ODQ和能透过细胞膜进入胞内而激活蛋白激酶G(PKG)的8-Br-cGMP,观察NO-cGMP信号通路对甲亢性高血压大鼠胸主动脉的舒张作用的影响。结果与对照组相比,甲亢性高血压大鼠体重明显下降而心率、脉压差和收缩压明显升高;SNAP对两组大鼠的胸主动脉环均有明显的舒张作用,但在甲亢性高血压大鼠中的舒张作用明显弱于对照大鼠;用ODQ预处理后,SNAP对两组大鼠胸主动脉环的舒张作用均被阻断;BAY和8-Br-cGMP对两组大鼠的血管环均有明显的舒张作用,但在甲亢性高血压大鼠中的舒张作用明显弱于对照大鼠。结论甲亢性高血压的病理状态下,NO-cGMP信号通路对胸主动脉的舒张作用减弱,且此效应可能与sGC和PKG功能下调有着密切关系。     

腺苷酸环化酶及蛋白激酶A在a受体激动增加eNOS活性信号通路中的作用

目的 阐明a受体激动增加内皮型一氧化氮合酶(eNOS)活性信号通路中腺苷酸环化酶(AC)及蛋白激酶A(PKA)的作用.方法 体外培养人脐静脉内皮细胞;运用同位素两步色谱法([3H]-L-精氨酸转化法)检测eNOS活性.本研究设置空白对照组、AC组和PKA组,每组因素下再分ISO及BSS两个干预因素组,观察AC特异性阻断剂SQ-2256(5×10-5 mol/L)及PKA特异性阻断剂H-89(1×10-7 mol/L)分别与人脐静脉内皮细胞孵育10 min,再与异丙肾上腺素(ISO)孵育30 min后eNOS活性变化.结果 ISO明显增加eNOS活性(30 7±3 9)%,P<0 01;分别阻断AC、PKA,ISO诱导的eNOS活性增加均受到抑制(12 1±3 53)%、(4 73±2 19)%,P<0 01.结论 ISO激活eNOS活性的信号通路上,AC和PKA均有参与.     

益肾补骨汤对骨质疏松症大鼠骨形成和一氧化氮-环磷酸鸟苷信号通路的影响

目的：探究益肾补骨汤对骨质疏松症大鼠骨形成及一氧化氮-环磷酸鸟苷(NO-cGMP)信号通路的影响。方法：采用摘除双侧卵巢法建立绝经后骨质疏松症(PMOP)SD大鼠模型,将大鼠按照随机数字表法分为假手术组(sham组)、PMOP大鼠模型组(PMOP组),益肾补骨汤L组、M组和H组(分别给予益肾补骨汤2、4和8 mL/kg灌胃干预),以及阳性对照组(给予戊酸雌二醇灌胃干预)。比较各组大鼠术前和术后体重,观察各组大鼠一般状态,采用酶联免疫吸附试验检测血清中总碱性磷酸酶(TALP)、血清抗酒石酸酸性磷酸酶(TRAP)含量,双能X线检测大鼠骨密度,苏木精-伊红染色检测大鼠股骨组织形态学变化,分别用分光光度计法和放射免疫法检测大鼠股骨组织中NO、cGMP含量;采用蛋白质印迹法检测股骨组织中Wnt3a、β-catenin蛋白表达。结果：与sham组相比,PMOP组大鼠体重明显降低(P<0.05);与PMOP组相比,益肾补骨汤L组、M组和H组大鼠体重明显升高(P<0.05),差异均有统计学意义。PMOP组大鼠血清TALP含量和股骨BMD低于sham组,血清TRAP含量高于sham组(P&l...     

腺苷酸环化酶及蛋白激酶A在β受体激动增加eNOS活性信号通路中的作用

目的阐明β受体激动增加内皮型一氧化氮合酶(eNOS)活性信号通路中腺苷酸环化酶(AC)及蛋白激酶A(PKA)的作用。方法体外培养人脐静脉内皮细胞;运用同位素两步色谱法([3H]-L-精氨酸转化法)检测eNOS活性。本研究设置空白对照组、AC组和PKA组,每组因素下再分ISO及BSS两个干预因素组,观察AC特异性阻断剂SQ-2256(5×10-5mol/L)及PKA特异性阻断剂H-89(1×10-7mol/L)分别与人脐静脉内皮细胞孵育10min,再与异丙肾上腺素(ISO)孵育30min后eNOS活性变化。结果ISO明显增加eNOS活性(30.7±3.9)%,P<0.01;分别阻断AC、PKA,ISO诱导的eNOS活性增加均受到抑制(12.1±3.53)%、(4.73±2.19)%,P<0.01。结论ISO激活eNOS活性的信号通路上,AC和PKA均有参与。     

甲基蓝对阿片类物质产生耐受和依赖的阻断作用

目的：探讨鸟苷酸环化酶(sGC)抑制剂甲基蓝(MB)对阿片耐受和依赖的阻断作用。方法：体外培养iNOS稳定表达的神经细胞做为模型,竞争性蛋白结合法、放免法和³H-Arg转化³H-Cit法检测胞内cAMP,cGMP水平和NOS活性, 激光共聚焦扫描技术测定胞内Ca²⁺浓度。观察MB对δ-阿片激动剂DPDPE和吗啡预处理细胞48 h及纳洛酮戒断,对胞内cGMP,cAMP含量、［Ca²⁺］i 和NOS活性的影响。结果：MB可明显抑制阿片激动剂长时程所致cGMP含量增加（P<0.01）,对cAMP含量、［Ca²⁺］i和NOS活性的变化无影响。结论：MB通过抑制sGC活性,使NO-cGMP通路下调,减缓阿片耐受和依赖的发生。     

中药干预高脂血症相关信号通路的研究进展

高脂血症是因多种原因导致脂质代谢紊乱的一种病理状态,可引起动脉粥样硬化等多种疾病的发生,严重影响患者的生活质量。目前化学药治疗存在不良反应大、耐药等缺点。而中药用于治疗高脂血症的历史悠久,临床经验丰富,且以不良反应少、用药依从性好的优点成为近几年研究的热点。通过查阅分析国内外有关中药干预高脂血症信号通路的文献,归纳总结出6条中药干预高脂血症相关信号通路,分别为过氧化物酶体增殖物激活受体（PPAR）信号通路、腺苷酸激活蛋白激酶（AMPK）信号通路、环磷酸腺苷（cAMP）信号通路、脂肪细胞因子（Adipocytokine）信号通路、法尼酯衍生物X受体（FXR）-小异二聚体伴侣（SHP）信号通路及磷脂酰肌醇-3-激酶（PI3K）-丝氨酸/蛋白激酶B（Akt）信号通路,以期为治疗高脂血症的药物研发提供参考。     

杏仁核中一氧化氮对睡眠-觉醒的影响

目的研究杏仁核中一氧化氮（ＮＯ）对大鼠睡眠 觉醒的影响,并分析其作用机制。方法多导睡眠描记和杏仁核微量注射。结果一氧化氮合酶抑制剂Ｌ 硝基精氨酸（Ｌ ＮＮＡ）可增加慢波睡眠（ＳＷＳ）和减少觉醒（Ｗ）,而一氧化氮（ＮＯ）供体硝普钠（ＳＮＰ）可增加Ｗ、减少ＳＷＳ,并可对抗Ｌ ＮＮＡ的促睡眠效应;ＮＯ前体Ｌ 精氨酸（Ｌ Ａｒｇ）对睡眠 觉醒无直接影响,但可对抗Ｌ ＮＮＡ的促睡眠效应。环磷酸鸟苷（ｃＧＭＰ）具有明显的增加Ｗ和减少ＳＷＳ效应,而鸟苷酸环化酶抑制剂亚甲蓝（ＭＢ）增加睡眠、减少觉醒,并可阻断ＳＮＰ的促睡眠效应。结论杏仁核参与睡眠 觉醒调节,杏仁核中ＮＯ具有促进Ｗ、抑制ＳＷＳ效应,这一作用是通过激活鸟苷酸环化酶使ｃＧＭＰ增多实现的。     

Involvement of nitric oxide/cyclic GMP signaling pathway in the regulation of fatty acid metabolism in rat hepatocytes

The role of nitric oxide (NO)/guanosine 3',5'-cyclic monophosphate (cGMP) signaling pathway in the regulation of fatty acid metabolism was investigated in rat hepatocytes. Treatment with NO donors, which are known to activate soluble guanylyl cyclase, inhibited in parallel fatty acid synthesis de novo and acetyl-CoA carboxylase activity. This effect was mimicked by 8-Br-cGMP and abolished by KT5823, a selective inhibitor of cGMP-dependent protein kinase (PKG). Furthermore, specific and hydrolysis-resistant activators of PKG, and inhibitors of Ca2+ release from endoplasmic reticulum, were also effective in inhibiting both fatty acid-synthesizing activities. These results suggest that this biological action of NO is regulated by a signaling cascade involving soluble guanylyl cyclase, cGMP, and PKG, and may be mediated, at least in part, by inhibition of Ca2+ release from endoplasmic reticulum. In addition, 8-Br-cGMP was able to stimulate fatty acid oxidation by two different mechanisms: the relieving of malonyl-CoA-dependent inhibition by lowering levels of this product of acetyl-CoA carboxylase, and a malonyl-CoA-independent stimulation of carnitine palmitoyltransferase I. Taken together, results of this study suggest that NO/cGMP signaling pathway is endowed with regulatory properties in fatty acid metabolism, and may have a physiological role in the control of this metabolism in liver.     

Effects of local anesthetics on calmodulin-dependent guanylate cyclase in the plasma membrane of Tetrahymena pyriformis

A highly purified preparation of Tetrahymena calmodulin activated a membrane-bound guanylate cyclase by more than 40-fold. This activation of guanylate cyclase by calmodulin was inhibited completely by local anesthetics such as dibucaine, tetracaine, lidocaine and procaine at concentrations that had no appreciable effect on the activities of basal guanylate cyclase (without calmodulin) and adenylate cyclase. The inhibition by dibucaine of calmodulin-mediated activation of the enzyme activity was not reversed by calcium but was partially overcome by increasing the concentration of calmodulin. Kinetic analysis of local anesthetic-induced inhibition of activation of guanylate cyclase demonstrated a mixed type of antagonism. These results suggest the possibility that the inhibition of calmodulin-dependent guanylate cyclase resulted, in part, from interaction of the drugs with calmodulin.     

Endothelium-dependent and -independent relaxation and VASP serines 157/239 phosphorylation by cyclic nucleotide-elevating vasodilators in rat aorta

Endothelium-dependent vasodilation is thought to be mediated primarily by the NO/cGMP signaling pathway whereas cAMP-elevating vasodilators are considered to act independent of the endothelial cell layer. However, recent functional data suggest that cAMP-elevating vasodilators such as beta-receptor agonists, adenosine or forskolin may also be endothelium-dependent. Here we used functional and biochemical assays to analyze endothelium-dependent, cGMP- and cAMP-mediated signaling in rat aorta. Acetylcholine and sodium nitroprusside (SNP) induced a concentration-dependent relaxation of phenylephrine-precontracted aorta. This response was reflected by the phosphorylation of the vasodilator-stimulated phosphoprotein (VASP), a validated substrate of cGMP- and cAMP-dependent protein kinases (cGK, cAK), on Ser(157) and Ser(239). As expected, the effects of acetylcholine were endothelium-dependent. However, relaxation induced by the beta-receptor agonist isoproterenol was also almost completely impaired after endothelial denudation. At the biochemical level, acetylcholine- and isoproterenol-evoked cGK and cAK activation, respectively, as measured by VASP Ser(239) and Ser(157) phosphorylation, was strongly diminished. Furthermore, the effects of isoproterenol were repressed by eNOS inhibition when endothelium was present. We also observed that the relaxing and biochemical effects of forskolin were at least partially endothelium-dependent. We conclude that cAMP-elevating vasodilators, i.e. isoproterenol and to a lesser extent also forskolin, induce vasodilation and concomitant cyclic nucleotide protein kinase activation in the vessel wall in an endothelium-dependent way.     

Beneficial effect of the oligomerized polyphenol oligonol on high glucose-induced changes in eNOS phosphorylation and dephosphorylation in endothelial cells

Background and purpose:

Hyperglycaemia is known to reduce nitric oxide (NO) bioavailability by modulating endothelial NO synthase (eNOS) activity, and polyphenols are believed to have cardiovascular benefit. One possible mechanism could be through interaction with eNOS.

Experimental approach:

The effects of the oligomerized polyphenol oligonol on eNOS phosphorylation status and activity were examined in porcine aortic endothelial cells cultured in high glucose concentrations.

Key results:

Exposure to high glucose concentrations strongly inhibited eNOS phosphorylation at Ser-1177 and dephosphorylation at Thr-495 in bradykinin (BK)-stimulated cells. These inhibitory effects of high glucose were significantly prevented by treatment with oligonol. Akt and p38 mitogen-activated protein kinase (MAPK) were activated in BK-stimulated cells. High glucose inhibited Akt activation but enhanced p38 MAPK activation, both of which were reversed by oligonol treatment. The phosphatidylinositol 3-kinase inhibitor wortmannin blocked the reversal by oligonol of phosphorylation at Ser-1177, but not dephosphorylation at Thr-495, in BK-stimulated cells exposed to high glucose. The effect of oligonol on BK dephosphorylation under high glucose was mimicked by protein kinase C (PKC) ε-neutralizing peptides. These data suggest that the effects of oligonol on high glucose-induced attenuation of eNOS Ser-1177 phosphorylation and Thr-495 dephosphorylation may be regulated by Akt activation and PKCε inhibition respectively. Oligonol also prevented high glucose-induced attenuation of BK-stimulated NO production.

Conclusions and implications:

Oligonol prevented the impairment of eNOS activity induced by high glucose through reversing altered eNOS phosphorylation status. This mechanism may underlie the beneficial cardiovascular health effects of this oligomerized polyphenol.     

S-甲基异硫脲抑制梗塞兔心肌诱导型一氧化氮合酶的表达

目的　研究S 甲基异硫脲 (SMT)对梗塞兔心肌组织内诱导型一氧化氮合酶 (iNOS)活性的抑制作用。方法　对左房心耳和心尖中间弯曲的冠状动脉前外侧枝进行结扎 ,建立心肌梗塞模型。应用L 精氨酸转换为L 胍氨酸法测定家兔心肌梗塞区和非梗塞区诱导型一氧化氮合酶的活性 ,同时观察S 甲基异硫脲和NW 硝基 L 精氨酸 (L NNA)对诱导型一氧化氮合酶活性的抑制作用。结果　冠状动脉结扎后 48h、72h和 96h ,心肌梗塞区诱导型一氧化氮合酶活性比非手术组显著增加 (P <0 0 1) ,并在 72h达到峰值 ;梗塞后 72h左室壁cGMP含量也明显增加 (P <0 0 1) ;同时SMT能明显降低梗塞区心肌诱导型一氧化氮合酶的活性 (P<0 0 1)。结论　SMT能明显抑制梗塞兔心肌iNOS的活性 ,提示SMT对改善心脏功能和治疗急性心肌梗塞具有一定的临床效果。     

Effects of phenothiazines on the membrane-bound guanylate and adenylate cyclase in tetrahymena pyriformis

The particulate-bound guanylate cyclase activity of Tetrahymena pyriformis was shown previously to be Ca²⁺-dependent and to be activated by an endogenous calmodulin-like protein (Tetrahymena Ca²⁺-binding protein, TCBP) [S. Nagao, Y. Suzuki, Y. Watanabe and Y. Nozawa, Biochem. biophys. Res. Commum.90, 261 (1979)]. Phenothiazine derivatives, such as chlorpromazine and trifluoperazine, that interact with calmodulin were found to inhibit the Ca²⁺-dependent guanylate cyclase activity and the TCBP-induced activation of the guanylate cyclase activity. Ethylene glycol-bis (β-aminoethyl ether)-N, N'-tetraacetic acid (EGTA), a Ca²⁺ chelator, also inhibited the activation of guanylate cyclase. However, the mechanisms by which EGTA and trifluoperazine act were different. The EGTA-induced inhibition could not be overcome by increasing the concentration of TCBP, whereas the trifluoperazine-induced inhibition could be overcome by increasing the concentration of TCBP, but not by increasing the concentration of Ca²⁺. These findings suggest that the mechanism by which trifluoperazine inhibits the activation of guanylate cyclase involves competition with TCBP.     

金粉蕨素拮抗氧化损伤所抑制的内皮细胞增殖的作用及其机制

目的　探讨金粉蕨素拮抗Menadione氧化损伤所抑制的内皮细胞增殖的作用及其机制。方法　以Menadione(O- 2 )损伤人脐静脉内皮细胞作为氧化损伤模型 ,采用MTT法和细胞计数法 ,观察不同浓度金粉蕨素对Menadione损伤内皮细胞生长抑制率的影响 ;利用硝酸还原酶法测定培养液中NO含量 ;以Westernblot检测细胞eNOS活性及磷酸化ERK1 / 2的表达。结果　金粉蕨素保护组与损伤组相比 ,内皮细胞的生长抑制率明显降低 ,培养液中NO含量增高 ,eNOS活性增强 ,磷酸化ERK1 / 2表达上调。结论　NO和ERK1 / 2通路可能介导了金粉蕨素拮抗Menadione氧化损伤所抑制内皮细胞增殖的保护作用     

Cyclic GMP and protein kinase-G in myocardial ischaemia-reperfusion: opportunities and obstacles for survival signaling

It is clear that multiple signalling pathways regulate the critical balance between cell death and survival in myocardial ischaemia-reperfusion. Recent attention has focused on the activation of survival or salvage kinases, particularly during reperfusion, as a common mechanism of many cardioprotective interventions. The phosphatidyl inositol 3'-hydroxy kinase/Akt complex (PI3K/Akt) and p42/p44 mitogen-activated protein kinase cascades have been widely promoted in this respect but the cyclic guanosine 3',5'-monophosphate/cGMP-dependent protein kinase (cGMP/PKG) signal transduction cassette has been less systematically investigated as a survival cascade. We propose that activation of the cGMP/PKG signalling pathway, following activation of soluble or particulate guanylate cyclases, may play a pivotal role in survival signalling in ischaemia-reperfusion, especially in the classical preconditioning, delayed preconditioning and postconditioning paradigms. The resurgence of interest in reperfusion injury, largely as a result of postconditioning-related research, has confirmed that the cGMP/PKG pathway is a pivotal salvage mechanism in reperfusion. Numerous studies suggest that the infarct-limiting effects of preconditioning and postconditioning, exogenously donated nitric oxide (NO), natriuretic peptides, phosphodiesterase inhibitors, and other diverse drugs and mediators such as HMG co-A reductase inhibitors (statins), Rho-kinase inhibitors and adrenomedullin, whether given before and during ischaemia, or specifically at the onset of reperfusion, may be mediated by activation or enhancement of the cGMP pathway, either directly or indirectly via endogenous NO generation downstream of PI3K/Akt. Putative mechanisms of protection include PKG regulation of Ca(2+) homeostasis through the modification of sarcoplasmic reticulum Ca(2+) uptake mechanisms, and PKG-induced opening of ATP-sensitive K(+) channels during ischaemia and/or reperfusion. At present, significant technical obstacles in defining the precise roles played by cGMP/PKG signalling include the heavy reliance on pharmacological PKG inhibitors of uncertain selectivity, difficulties in determining PKG activity in intact tissue, and the growing recognition that intracellular compartmentalisation of the cGMP pool may contribute markedly to the nucleotide's biological actions and biochemical determination. Overall, the body of experimental evidence suggests that cGMP/PKG survival signalling ameliorates irreversible injury associated with ischaemia-reperfusion and may be a tractable therapeutic target.     

Phosphodiesterase in the liver fluke, Fasciola hepatica.

Phosphodiesterase was found in homogenates of the liver fluke, Fasciola hepatica, and was distributed between a supernatant and particulate fraction after centrifugation at 2000 g. Mg²⁺ was necessary for enzyme activity; Ca²⁺ in the presence of Mg²⁺ did not affect enzyme activity. Enzyme kinetics followed the Michaelis-Menten model with a K_m of 8 μM for cAMP and 300 μM for cGMP as the substrate. The most potent inhibitor tested was 1-ethyl-4-(isopropylidenehydrazino)-1 H-pyrazolo- (3,4-b)-pyridine-5-carboxylic acid, ethyl ester, HC1 (SQ 20009) which had a K_i of 26 μM. The K_i for isobutyl methyl xanthine (IBMX) was 45 μM; for 6,7 dimethyl-4 ethylquinazoline (Quazodine) 75 μM; papaverine. 100 μM; theophylline, 550 μM; and for caffeine or D-lysergic acid diethylamide (LSD), 800 μM. The effects on fluke motility of these phosphodiesterase inhibitors were tested. All phosphodiesterase inhibitors except caffeine stimulated the rhythmical movement of the flukes. None of the inhibitors tested significantly increased the endogenous cAMP concentrations of fluke heads. IBMX potentiated the rise in endogenous cAMP caused by 5-hydroxytryptamine (5-HT) but SQ 20009, LSD, and papaverine prevented it. The latter results could not be explained on the basis of phosphodies-terase inhibition, but might be attributed to interference with the stimulation of adenylate cyclase by 5-HT.