多沙唑嗪对映体对大鼠离体心脏心肌活力的作用

目的观察多沙唑嗪(Dox)对映体对大鼠离体心房肌和心室肌功能的作用。方法制备大鼠离体左心房、右心房和右心室肌条标本。左右心房均分别累积给予Dox对映体3,10和30μmol·L-1。右心室非累积给予Dox对映体3,10和30μmol·L-1。测定心率和心肌收缩力。结果右旋Dox(R-Dox)3～10μmol·L-1,使28%的右心房(含窦房结)发生停搏反应,消旋Dox(rac-Dox)3～10μmol·L-1使7%的右心房(含窦房结)发生停博反应,左旋Dox(S-Dox)3～10μmol·L-1未诱发右心房(含窦房结)停搏反应。R-Dox3～30μmol·L-1随浓度增加,减慢大鼠离体右心房心率作用有增强趋势。rac-Dox 10和30μmol·L-1显著减慢大鼠离体右心房心率(P<0.01)。S-Dox 3～30μmol·L-1对大鼠离体右心房心率无影响。S-Dox 3～30μmol·L-1增强大鼠离体左心房心肌收缩。相反,R-Dox 3～30μmol·L-1浓度依赖性地抑制左心房心肌收缩(P<0.01)。rac-Dox 3～30μmol·L-1亦浓度依赖性地抑制左心房心肌收缩。S-Dox 3～30μmol·L-1对大鼠右心室肌收缩力无显著影响。R-Dox和rac-Dox 3～30μmol·L-1浓度依赖性地抑制右心室肌收缩(P<0.01)。结论 rac-Dox 3～10μmol·L-1可诱发大鼠离体心脏停搏,并显著抑制大鼠心室肌的收缩;rac-Dox对心脏的作用与R-Dox有关;同浓度的S-Dox对大鼠离体右心房心率无影响,对大鼠心室肌的收缩无作用。     

多沙唑嗪对映体对兔离体膀胱逼尿肌的作用及机制

目的观察多沙唑嗪(rac-DOX)及其对映体(S-DOX、R-DOX)对兔离体膀胱逼尿肌的作用并分析其机制。方法制备兔背侧和腹侧膀胱逼尿肌标本,记录药物或神经刺激诱发的膀胱平滑肌收缩反应。结果在兔背侧和腹侧膀胱逼尿肌标本,卡巴胆碱产生浓度依赖性收缩反应,两种标本的收缩反应差异无显著性(P>0·05)。在背侧膀胱逼尿肌标本,苯肾上腺素产生浓度依赖性收缩反应;但是,苯肾上腺素对腹侧膀胱逼尿肌无作用。S-DOX、R-DOX和rac-DOX在1μmol·L-1时,均可竞争性拮抗苯肾上腺素诱发的兔背侧膀胱逼尿肌收缩反应,其pKB值分别为7·44±0·19、7·39±0·14和7·38±0·30,三者的pKB值相同。电场刺激诱发兔背侧和腹侧膀胱逼尿肌产生稳定的收缩反应,该收缩反应被0·3μmol·L-1浓度的河豚毒素完全阻断。S-DOX、R-DOX和rac-DOX均抑制电场刺激诱发的背侧膀胱逼尿肌收缩反应(P<0·01),且三者的抑制作用强度差异无显著性(P>0·05);但是,它们对电场刺激诱发的腹侧膀胱逼尿肌收缩反应无影响。结论在兔离体膀胱背侧逼尿肌,S-DOX拮抗苯肾上腺素诱发收缩反应的pKB值与rac-DOX和R-DOX相同,三者尚能抑制电场刺激诱发的神经源性收缩反应。     

多沙唑嗪对映体对兔离体前列腺收缩反应的影响

目的观察多沙唑嗪[(±)Dox]及其对映体[(-)Dox和(+)Dox]对兔离体前列腺平滑肌收缩反应的影响。方法制备兔离体前列腺标本,记录药物诱发的前列腺肌条收缩反应。结果苯肾上腺素浓度依赖性诱发兔前列腺平滑肌收缩反应。(-)Dox、(+)Dox或(±)Dox拮抗苯肾上腺素诱发前列腺收缩反应的pKB值分别为8.14±0.17、8.12±0.14和8.11±0.21,三者之间差异无统计学意义(P>0.05)。(-)Dox、(+)Dox和(±)Dox均可显著性抑制电场刺激诱发的前列腺神经源性收缩反应(P<0.01),且三者的抑制作用强度差异无统计学意义(P>0.05)。结论多沙唑嗪对映体可抑制苯肾上腺素或电场刺激诱发的兔离体前列腺收缩反应,三者的抑制作用相同。     

多沙唑嗪以及阿夫唑嗪对映体对小鼠离体心房心率和收缩力的影响

目的分析多沙唑嗪以及阿夫唑嗪的光学异构体及其外消旋体与药物调节小鼠离体心房心率和心肌收缩力效应的关系。方法制备小鼠离体左心房和离体右心房标本,观察消旋多沙唑嗪[(±)DOX]、左旋多沙唑嗪[(-)DOX]、右旋多沙唑嗪[(+)DOX]、消旋阿夫唑嗪[(±)ALF]、左旋阿夫唑嗪[(-)ALF]以及右旋阿夫唑嗪[(+)ALF]对小鼠离体右心房心率及左心房心肌收缩力的影响。结果 (+)DOX组的16例标本中,加入30μmol·L-1药物后,5例(31.3%)发生停搏;(±)DOX组、(-)DOX组各有1例发生停搏;其他各组标本未出现停搏反应。(+)DOX和(±)DOX各浓度均减慢小鼠右心房心率(P<0.01),并具有浓度依赖关系;(+)DOX减慢心率的作用强于同浓度(±)DOX(P<0.01)。10和30μmol·L-1浓度的(-)DOX减慢心率(P<0.01),其作用弱于同浓度(+)DOX(P<0.01)。(-)ALF、(+)ALF及(±)ALF在10和30μmol·L-1浓度时均轻度减慢小鼠右心房心率(P<0.05)。在小鼠离体左心房标本,(+)DOX(10和30μmol·L-1)抑制心肌收缩力(P<0.05);而(-)DOX(3～30μmol·L-1)增强心肌收缩力(P<0.05),其增强作用强于同浓度(±)DOX(P<0.05)。(±)ALF及其对映体(3～30μmol·L-1)对小鼠离体左心房心肌收缩力无影响。结论 DOX对小鼠离体心房的心率和心肌收缩力具有明显的影响,高浓度尚可诱发心脏停博反应;DOX的手性结构对其上述活性具有明显的影响。相反,ALF仅影响小鼠心率,ALF的手性结构对其心脏效应无明显影响。     

多沙唑嗪对映体对麻醉猫心血管功能的选择性作用

目的研究多沙唑嗪对映体对麻醉猫心血管功能的影响。方法采用八道生理仪记录麻醉猫股动脉血压、心率以及左心室收缩压、左心室舒张末期压和左心室内压最大变化率(±dp/dtmax)。结果十二指肠给予右旋多沙唑嗪[(+)doxazosin,(+)DOX]0.03～1.0 mg.kg-1剂量依赖性降低麻醉猫收缩压、舒张压、平均动脉压和左心室收缩压(P<0.05)。十二指肠给予同等剂量的左旋多沙唑嗪[(-)doxazosin,(-)DOX]和消旋多沙唑嗪[(±)doxazosin,(±)DOX]对麻醉猫收缩压、舒张压、平均动脉压和左心室收缩压无影响(P>0.05)。3种药物对左心室舒张末期压、左心室-dp/dt、左心室+dp/dt和心率无影响(P>0.05)。结论麻醉猫十二指肠给药时,(+)DOX降低动脉血压并抑制心室收缩功能,相同剂量的(-)DOX无作用;提示DOX的手性结构对药物的心血管效应具有明显的影响。     

多沙唑嗪对映体对大鼠血压和排尿功能的影响

目的观察十二指肠给予多沙唑嗪(rac-DOX)及其对映体(S-DOX、R-DOX)对麻醉大鼠血压和膀胱排尿功能的影响。方法采用八道生理仪记录麻醉大鼠颈总动脉血压、心率以及膀胱排尿压、排尿间隔,并测量排尿量。结果十二指肠给予S-DOX、R-DOX和rac-DOX均可剂量依赖性降低颈总动脉收缩压、舒张压和平均动脉压,1.0mg.kg-1时3者对平均动脉压的降低幅度分别达到23.5%±4.6%、38.5%±8.9%和42.6%±7.5%,3者降低平均动脉压的ED30值依次为(2.0±0.8)、(0.6±0.7)、(0.6±0.5)mg.kg-1。S-DOX降低收缩压、舒张压和平均动脉压的作用均弱于rac-DOX和R-DOX(P<0.05),rac-DOX与R-DOX的降压作用差异无显著性(P>0.05)。rac-DOX在0.1～3.0mg.kg-1剂量范围内剂量依赖性抑制麻醉大鼠心率,而S-DOX和R-DOX仅在3.0mg.kg-1剂量时对心率有抑制作用。十二指肠给予S-DOX、R-DOX和rac-DOX均剂量依赖性降低麻醉大鼠膀胱排尿压,3种药物对排尿压的最大降低幅度分别为13.4%±5.7%、14.5%±11.0%和10.9%±7.6%,3者降低排尿压的作用差异无显著性(P>0.05)。与S-DOX相比,R-DOX可缩短排尿间隔并减少排尿量(P<0.05),而S-DOX和rac-DOX对排尿间隔和排尿量无影响。结论与R-DOX和rac-DOX相比,S-DOX保留了对麻醉大鼠膀胱排尿压的有利作用,减轻了对血压、心率和膀胱排尿间隔的不良影响。     

多沙唑嗪对映体对老年小鼠前列腺增生的影响

目的观察多沙唑嗪[(±)Dox]及其对映体[(-)Dox和(+)Dox]对老年小鼠前列腺体积、湿重、细胞增殖周期与凋亡百分率的影响。方法取13月龄♂小鼠,灌胃给予(±)Dox及其对映体(-)Dox和(+)Dox连续12周,采用流式细胞技术观察药物对小鼠前列腺增生的影响。结果与青年对照组相比,老年组小鼠前列腺湿重明显增加(P<0.05);与青年对照组相比,老年组小鼠前列腺体积指数差异无显著性,而(-)Dox 6.0 mg.kg-1组、(+)Dox 6.0 mg.kg-1组和(+)Dox 0.6 mg.kg-1组以及(±)Dox 6.0 mg.kg-1组小鼠前列腺体积指数明显减小(P<0.05)。与青年对照组相比,老年组小鼠前叶前列腺G0/G1期细胞周期百分率显著降低(P<0.01),G2/M期细胞周期百分率和增殖指数均显著增高(P<0.01);老年组小鼠前列腺细胞凋亡率无明显改变。与老年组相比,(±)Dox及其对映体(-)Dox和(+)Dox对老年小鼠前列腺细胞的增殖指数和细胞周期无明显影响。结论长期(12周)灌胃给予(±)Dox及其对映体(-)Dox和(+)Dox,可轻度降低老年小鼠前列腺细胞体积指数。     

多沙唑嗪对映体诱发大鼠心房肌收缩力变化的作用机制

目的分析多沙唑嗪对映体的手性结构诱发大鼠离体心房肌收缩力变化的作用机制。方法建立(-)DOX诱发的大鼠离体左心房正性肌力模型以及(+)DOX诱发的大鼠离体左心房负性肌力模型,探讨DOX对映体诱发大鼠心房肌正性肌力作用或负性肌力作用的机制。结果在维拉帕米预处理标本,3μmol·L-1浓度(-)DOX的正性肌力作用由对照组的(245.71±44.29)mg降低至(172.50±43.34)mg(P<0.05)。在亚甲蓝预处理标本,3μmol·L-1浓度(-)DOX的正性肌力作用由对照组的(245.71±44.29)mg增强至(303.33±45.90)mg(P<0.05)。在H-89预处理标本,3、10和30μmol·L-1(-)DOX诱发的正性肌力作用由对照组的(245.71±44.29)mg、(314.29±90.34)mg和(357.14±68.49)mg增强至(338.57±96.86)mg、(471.43±107.61)mg和(520.00±103.44)mg(P<0.05或0.01)。酚苄明、阿托品、普萘洛尔、吲哚美辛预处理标本时,多沙唑嗪对映体的未见明显改变。结论 (-)DOX增强大鼠心房肌收缩力的作用,可能与心肌α受体、M胆碱受体、β受体以及环氧合酶无关;L型Ca2+通道以及细胞内cGMP可能在某种程度上参与了(-)DOX在大鼠左心房的正性肌力作用。但是,心肌α受体、M胆碱受体、β受体、Ca2+通道、环氧合酶、cGMP及PKA,可能未参与(+)DOX对大鼠左心房的负性肌力作用。     

硝普钠在豚鼠离体气管螺旋条中的舒张作用

目的研究硝普钠(SNP)在豚鼠离体气管螺旋条中舒张作用的机制.方法在浴槽内加入硝普钠从10-7M至10-3M,观察气管螺旋条张力的变化,并检测浴槽中NO,气管螺旋条组织cAMP、cGMP的变化.结果加入硝普钠气管螺旋条张力下降,浴槽内NO增加,气管螺旋条组织cAMP、cGMP增加.结论硝普钠有舒张气管螺旋条的作用,推测是通过NO-cGMP系统发挥作用.     

硝普钠在豚鼠离体气管螺旋条中的舒张作用

目的:研究硝普钠(SNP) 在豚鼠离体气管螺旋条中舒张作用的机制.方法:在浴槽内加入硝普钠从10-7M至10-3M,观察气管螺旋条张力的变化,并检测浴槽中NO,气管螺旋条组织cAMP、cGMP的变化.结果:加入硝普钠气管螺旋条张力下降,浴槽内NO增加,气管螺旋条组织cAMP、cGMP增加.结论:硝普钠有舒张气管螺旋条的作用,推测是通过NO-cGMP系统发挥作用.     

腺苷受体激动剂在豚鼠离体气管螺旋条中的作用

腺苷在心血管已有广泛研究,其在气道中的作用已有报道[1]。腺苷受体激动剂Ｒ苯异丙基腺苷(Ｒｐｈｅｎｙｌｉｓｏｐｒｏｐｙｌａｄｅｎｏｓｉｎｅ,ＲＰＩＡ)在气道中作用如何呢?我们通过观察ＲＰＩＡ在豚鼠离体气管条中的作用,旨在了解ＲＰＩＡ对气道上皮及平滑肌的影响。1　材料与方法1.1　动物选择与处理　取Ｈａｒｔｌｅｙ豚鼠20只,♀♂不拘,体重(250±50)ｇ。用断头术击毙豚鼠,取整条气管,在Ｋｒｅｂｓ营养液内分离干净外面包绕的组织,分成长度相等的两段,随机取一段,用直径与之相似的毛玻璃棒去掉上皮,剪成螺旋条。另一段不去上皮,直接…     

鸭嘴花碱对豚鼠离体气管平滑肌收缩功能的影响

目的：研究鸭嘴花碱对组胺和乙酰胆碱所致气管收缩的抑制作用。方法：离体豚鼠气管条。结果：鸭嘴花碱能抑制氯化钾、乙酰胆碱、磷酸组胺所致气管平滑肌收缩，而且能使磷酸组胺、乙酰胆碱收缩气管平滑肌的量效曲线右移，并抑制最大效应，其作用为剂量依赖性。结论：鸭嘴花碱对气管平滑肌具有显著舒张作用。     

薯蓣皂苷元衍生物的制备及对豚鼠离体气管平滑肌的作用

目的 研究薯蓣皂苷元及其衍生物的制备及对豚鼠离体气管平滑肌的作用.方法 采用酰化和还原的方法合成衍生物;药理学实验在豚鼠离体气管模型上进行.结果 合成了11个薯蓣皂苷元衍生物(化合物Ⅰ～Ⅺ);薯蓣皂苷元及其衍生物对豚鼠离体气管平滑肌都有不同程度的舒张作用.结论 经1HNMR、13CNMR鉴定了所合成衍生物的结构;首次发现薯蓣皂苷元对离体豚鼠气管条有舒张作用,其3位的结构修饰可以提高其活性.     

Mechanisms of relaxant action of luteolin in isolated guinea pig trachea

We have investigated the mechanisms of action of luteolin, a flavone found in Perilla frutescens, a Chinese herbal medicine for treating asthma. In fact, luteolin occurs mostly as a glycoside in many plant species. The tension changes of tracheal segments were isometrically recorded on a polygraph. Luteolin concentration-dependently relaxed histamine (30 microM)-, carbachol (0.2 microM)- and KCl (30 mM)-induced precontractions, and inhibited cumulative histamine- and carbachol-induced contractions in a non-competitive manner. Luteolin also concentration-dependently and non-competitively inhibited cumulative Ca2+-induced contractions in depolarized (K+, 60 mM) guinea-pig trachealis. The nifedipine (10 microM)-remaining tension of histamine (30 microM)-induced precontractions was further relaxed by luteolin, suggesting that no matter whether VDCCs were blocked or not, luteolin may have other mechanisms of relaxant action. The relaxant effect of luteolin was unaffected by the removal of epithelium or by the presence of propranolol (1 microM), 2',5'-dideoxyadenosine (10 microM), methylene blue (25 microM), glibenclamide (10 microM), Nomega-nitro-L-arginine (20 microM), or alpha-chymotrypsin (1 U/mL). However, luteolin (10-20 microM) produced parallel and leftward shifts of the concentration-response curve of forskolin or nitroprusside. Luteolin or IBMX at various concentrations (10-300 microM) concentration-dependently and significantly inhibited cAMP- and cGMP-PDE activities of the trachealis. The IC50 values of luteolin were estimated to be 32.4 and 34.6 microM, respectively. IBMX at various concentrations (10-300 microM) selectively inhibited neither cAMP-, nor cGMP-PDE activity. In contrast to IBMX, luteolin at 100 and 300 microM more potently (P < 0.05) inhibited cGMP-, than cAMP-PDE activity. The above results indicate that the mechanisms of relaxant action of luteolin may be due to its inhibitory effects on both PDE activities and its reduction on [Ca2+]i of the trachealis.     

Relaxant effects of aflatoxins on isolated guinea pig trachea.

Dyspnea is one of the symptoms of acute aflatoxicosis. Contrary to expectations, we observed that naturally occurring aflatoxins (AF) AFB(1), AFB(2), AFG(1), and AFG(2) and their major metabolites AFM(1), AFM(2), AFP(1), AFQ(1), and AFG(2a) relaxed carbachol (C) precontracted guinea pig trachea to different degrees. The efficacies but not the potencies of AFB(1), AFB(2), AFG(1), and AFG(2) were similar to that of the beta-agonist, isoprenaline, whose activity was potentiated by the AF. Their mechanism of action is not clearly understood but several mechanistic indications were obtained with AFB(1): 1) its effect was not influenced by the beta-blocker, timolol, indicating that a direct interaction with beta(2)-adrenergic receptors was not involved. 2) AFB(1) potentiated PGE(1) and PGE(2), two relaxant prostaglandins, and its activity was reduced by indomethacin. 3) The cAMP level in the guinea pig trachea relaxed by AFB(1) increased, possibly due to inhibition of phosphodiesterase; direct interaction with PG receptors; and/or interaction with A(2) adenosinic receptors, suggested by the inhibitory activity of XAC, a specific antagonist. 4) Finally, since tetrodotoxin reduced the relaxant activity of AFB(1), it is speculated that this mycotoxin could stimulate inhibitory nonadrenergic, noncholinergic nerves (i-NANC). In conclusion, the symptoms of acute aflatoxicosis do not seem to be due to a direct activity on the tracheal muscle, but rather, to the well-known pro-inflammatory activity of the aflatoxins, which are capable of releasing arachidonic acid from cell membranes.     

Actions of 5'-methylthioadenosine in isolated guinea pig tracheal rings

The effects of 5'-methylthioadenosine (MTA) on smooth muscle were investigated using isolated guinea pig tracheal rings. MTA, at high concentrations caused the relaxation of isolated guinea pig tracheal rings in a concentration-dependent manner. These actions were pronounced in the tracheal rings contracted by histamine or leukotriene D4. The tracheal contractions induced by varying doses of histamine or leukotriene D4 were also suppressed by pretreatment of relatively low doses of MTA in a dose-dependent manner. Pretreatment of the tracheal rings with propranolol, tetrodotoxin, indomethacin and dipyridamole did not block the actions of MTA. In contrast, theophylline blocked the effects of MTA. These results suggested that MTA action on tracheal smooth muscle cells may be mediated by direct action on adenosine receptors.     

Effects of S 9977-2 on the guinea pig isolated trachea and the human isolated bronchus

The effects of S 9977-2, a new compound which belongs to the trimethylxanthine family and has shown in vivo promnesic activity and in vitro acetylcholinesterase activities inhibition, were studied on the guinea pig isolated trachea and on human isolated bronchi. On the guinea pig isolated trachea, S 9977-2 in concentrations of 10^?7–10^?4 M potentiated the contractile effect of acetylcholine. The potency of acetylcholine was increased 3.39, 4.26, 9.54, and 13.18 fold with concentrations of 10^?7, 10^?6, 10^?5, and 10^?4M, respectively. The maximum effect of acetylcholine was not modified. S 9977-2 did not potentiate the effects of carbachol or pilocarpine. Under similar conditions, eserine (10^?8 and 10^?6M) and tacrine (10^?8–10^?6M) also potentiated the effects of acetylcholine. The potentiating effect of these two substances was stronger than that of S 9977-2, with a 44.7 fold increase for eserine (10^?7M) and a 64.6 fold increase for tacrine (10^?6M). However, both eserine and tacrine had a contractile effect of their own on the guinea pig isolated trachea, whereas S 9977-2 had no such effect. On the human isolated bronchus, S 9977-2 at a concentration of 10^?5M produced a 19.1 fold increase of acetylcholine effects. On the guinea pig isolated trachea, the effects of S 9977-2 vs. acetylcholine were not modified by epithelium removal. They were increased by pretreatment with indomethacin 10^?6M. In very high concentrations (10^?4 and/or 10^?3M), S 9977-2 reduced the effects of histamine and those of serotonin on the guinea pig isolated trachea. S 9977-2 had no effect on the contractile action of potassium chloride or on the relaxant action of adenosine. The results suggest that in the airway smooth muscle S 9977-2 partially inhibits acetylcholinesterase and/or pseudocholinesterase activity. © 1992 Wiley-Liss, Inc.     

Mechanisms of relaxant action of 3-O-methylquercetin in isolated guinea pig trachea

We investigated the mechanisms of action of 3-O-methylquercetin (3-MQ), isolated from Rhamnus nakaharai (Hayata) Hayata (Rhamnaceae) which is used as a folk medicine for treating constipation, inflammation, tumors and asthma in Taiwan. The tension changes of tracheal segments were isometrically recorded on a polygraph. 3-MQ concentration-dependently relaxed histamine (30 microM)-, carbachol (0.2 microM)- and KCl (30 mM)-induced precontractions, and inhibited cumulative histamine-, and carbachol-induced contractions in a non-competitive manner. 3-MQ also concentration-dependently and non-competitively inhibited cumulative Ca(2+)-induced contractions in depolarized (K(+), 60 mM) guinea-pig trachealis. The nifedipine (10 microM)-remaining tension of histamine (30 microM)-induced precontraction was further relaxed by 3-MQ, suggesting that no matter whether VDCCs were blocked or not, 3-MQ may have other mechanisms of relaxant action. The relaxant effect of 3-MQ was unaffected by the removal of epithelium or by the presence of propranolol (1 microM), 2',5'-dideoxyadenosine (10 microM), methylene blue (25 microM), glibenclamide (10 microM), N(omega)-nitro-L-arginine (20 microM), or alpha-chymotrypsin (1 U/ml). However, 3-MQ (7.5 - 15 microM) and IBMX (3 - 6 microM), a positive control, produced parallel and leftward shifts of the concentration-response curve of forskoline (0.01 - 3 microM) or nitroprusside (0.01 - 30 microM). 3-MQ or IBMX at various concentrations (10 - 300 microM) concentration-dependently and significantly inhibited cAMP- and cGMP-PDE activities of the trachealis. The IC50 values of 3-MQ were estimated to be 13.8 and 14.3 microM, respectively. The inhibitory effects of 3-MQ on both enzyme activities were not significantly different from those of IBMX, a non-selective PDE inhibitor. The above results reveal that the mechanisms of relaxant action of 3-MQ may be due to its inhibitory effects on both PDE activities and its subsequent reducing effect on [Ca(2+)]i of the trachealis.3-MQ:3-O-methylquercetinIBMX:3-isobutyl-1-methylxanthineVDCCs:voltage dependent calcium channelscAMP:adenosine 3',5'-cyclic monophosphatecGMP:guanosine 3',5'-cyclic monophosphatePDE:phosphodiesteraseWe investigated the mechanisms of action of 3-O-methylquercetin (3-MQ), isolated from Rhamnus nakaharai (Hayata) Hayata (Rhamnaceae) which is used as a folk medicine for treating constipation, inflammation, tumors and asthma in Taiwan. The tension changes of tracheal segments were isometrically recorded on a polygraph. 3-MQ concentration-dependently relaxed histamine (30 microM)-, carbachol (0.2 microM)- and KCl (30 mM)-induced precontractions, and inhibited cumulative histamine-, and carbachol-induced contractions in a non-competitive manner. 3-MQ also concentration-dependently and non-competitively inhibited cumulative Ca(2+)-induced contractions in depolarized (K(+), 60 mM) guinea-pig trachealis. The nifedipine (10 microM)-remaining tension of histamine (30 microM)-induced precontraction was further relaxed by 3-MQ, suggesting that no matter whether VDCCs were blocked or not, 3-MQ may have other mechanisms of relaxant action. The relaxant effect of 3-MQ was unaffected by the removal of epithelium or by the presence of propranolol (1 microM), 2',5'-dideoxyadenosine (10 microM), methylene blue (25 microM), glibenclamide (10 microM), N(omega)-nitro-L-arginine (20 microM), or alpha-chymotrypsin (1 U/ml). However, 3-MQ (7.5 - 15 microM) and IBMX (3 - 6 microM), a positive control, produced parallel and leftward shifts of the concentration-response curve of forskoline (0.01 - 3 microM) or nitroprusside (0.01 - 30 microM). 3-MQ or IBMX at various concentrations (10 - 300 microM) concentration-dependently and significantly inhibited cAMP- and cGMP-PDE activities of the trachealis. The IC50 values of 3-MQ were estimated to be 13.8 and 14.3 microM, respectively. The inhibitory effects of 3-MQ on both enzyme activities were not significantly different from those of IBMX, a non-selective PDE inhibitor. The above results reveal that the mechanisms of relaxant action of 3-MQ may be due to its inhibitory effects on both PDE activities and its subsequent reducing effect on [Ca(2+)]i of the trachealis.3-MQ:3-O-methylquercetinIBMX:3-isobutyl-1-methylxanthineVDCCs:voltage dependent calcium channelscAMP:adenosine 3',5'-cyclic monophosphatecGMP:guanosine 3',5'-cyclic monophosphatePDE:phosphodiesterase