钩藤碱对大鼠离体子宫收缩反应的影响

本文观察到Rhy对催产素和高K~+去极化后Ca~(2+)引起的大鼠离体子宫收缩均有抑制作用,前一作用可被Ca~(2+)所对抗。CaCl_2量效曲线显示,Rhy对其呈非竞争性拮抗。在无Ca~(2+)高K~+液中,Rhy10μM抑制催产素依赖细胞内Ca~(2+)引起的收缩,而Rhy 40μM除加强这一作用外,对催产素依赖细胞外Ca~(2+)的收缩亦有抑制作用。     

Influence of hormonal treatment on the response of the rat isolated uterus to histamine and histamine receptor agonists.

The response of the isolated uterus to histamine and histamine agonists was investigated in progesterone- and oestrogen-treated rats. The uterine inhibitory responses to histamine and 4-methylhistamine (a histamine H2 receptor agonist) were similar in KCl-contracted uteri from progesterone- and oestrogen-treated rats. The histamine H1 receptor agonist, 2-pyridyl-ethylamine, produced a relaxant response only in progesterone dominant uterus. This was inhibited by the histamine H1 receptor antagonist. In the rat isolated uterus which was not preconstricted by KCl, neither histamine, 4-methylhistamine, nor 2-pyridyl-ethylamine produced any effect in the presence or absence of ranitidine. Ranitidine competitively antagonized the histamine-relaxant uterine response in oestrogen-treated rats (pA2 = 7.21 (6.83-7.58)), but not in progesterone-treated rats, except in the presence of clemizole (10(-7) M) when the pA2 value of ranitidine against histamine was similar to that obtained in oestrogen-treated rats (pA2 = 6.74 (6.64-6.85)). These results indicate that treatment with ovarian steroids influences responses mediated by the histamine receptors of the isolated rat uterus. Both histamine H2 and H1 receptors contribute to the uterine inhibitory effect of histamine in progesterone-treated rats.     

Relaxant effect of dopamine on the isolated rat uterus

Summary The effect of dopamine was studied on the isolated uterus of diethylstilboestrol-treated rats. Dopamine, at concentrations (10⁷–10^–4 M) produced a concentration-dependent relaxation in the K⁺-depolarized rat uterus. On a molar basis, dopamine was about 500 times less potent than adrenaline in relaxing the uterus, the maximum degree of relaxation obtained with both drugs was the same. Pretreatment of the rats with reserpine (5 mg/kg) did not produce any modification of the dose-response curve to dopamine. Similarly, cocaine (3 × 10^–6 M) failed to modify the relaxant effect of dopamine. The dopamine induced relaxation was inhibited by propranolol (10^–9–10^–7 M) in a dose-dependent manner. Prazosin (10^–7 M), SCH 23390 (10^–7 M) and sulpiride (10^–7 M) did not affect the dopamine dose-response curve. In the isolated rat uterus which was not preconstricted by KCl neither dopamine nor adrenaline produced any effect when added to the organ bath. This lack of response to both catecholamines was present even in tissues pretreated with propranolol or sulpiride. It is concluded that dopamine produced a concentration-dependent relaxation of the uterus from diethylstilboestrol-treated rats by direct activation of beta-adrenoceptors. There was no evidence for indirect action (catecholamine release and neuronal uptake mechanisms) and specific dopamine receptor mediated relaxation and alpha-adrenoceptor mediated contractions have not been found in this preparation. Send offprint requests to F. J. Morales-Olivas at the above address     

Estrogen and antiestrogen non-genomic effect in rat uterus contraction in calcium-free solution

1. The effects of estrogens estradiol (E₂, 10^-6-10^-4M) and diethylstilbestrol (DES, 10^-6-10^-4M) and the antiestrogens nafoxidine (N, 10^-6-10^-4M), tamoxifen (T, 10^-6-6 × 10^-4M), tamoxifen ethyl bromide (TEB, 10^-4M) and ICI 164,384 (ICI, 10^-5M) on tonic contractions induced by oxytocin (2 × 10^-8M) or vanadate (3 × 10^-4M) in rat uterus incubated in calcium-free EDTA treated solution have been assayed.2. E₂ and DES relaxed the tonic contraction induced by oxytocin in a dose dependent way (EC₅₀: 1.11 ± 0.01 × 10^-4M and 1.5 ± 0.07 × 10^-5M). The vanadate-induced contraction only was relaxed with DES (57.62 ± 2.38% at 10^-3M).3. The effect of DES on oxytocin contraction was unmodified by the protein synthesis inhibitor cycloheximide (10 μg/ml) and by the cycloxygenase inhibitor indomethacin (3 × 10^-6M), but enhanced by the intracellular calcium release inhibitor TMB-8 (10^-5M). The antiestrogen tamoxifen (3 × 10^-5M) promotes the relaxing effect of DES.4. The antiestrogens N, and T, but not ICI, relaxed the oxytocin-induced contraction (EC₅₀: 4.51 ± 0.43 × 10^-5M and 2.27 ± 0.05 × 10^-4M). TEB (10^-4M) produces a relaxation of 74.5 ± 2.11%. The vanadate contraction is also relaxed by T (EC₅₀: 6.03 ± 0.04 × 10^-4M).5. The effect of T on oxytocin contraction was unmodified with cycloheximide or TMB-8 but decreased with indomethacin.     

Influence of albumin on isoprenaline and propranolol effects on isolated rat uterus

We investigated the effect of albumin (6%) on the (±)-isoprenaline-induced relaxation of strips of isolated rat uterus and its antagonism by (?)-propranoioi. The mean isoprenaline EC₅₀ in the presence of albumin was significantly less than that in the absence of albumin (geometric mean 1.94 ± 3.33 versus 3.21 ± 3.50 nM, respectively; n = 14; p = 0.006, paired t test). This indicates enhancement of isoprenaline activity by albumin which could not be explained by protein binding, as this would have reduced activity. Geometric mean control K_B values for inhibition of isoprenaline by propranolol at 26.8 and 500 nM were 0.835 ± 1.68(n = 10) and 0.889 ± 1.60 nM (n = 34), respectively. In the presence of 6% albumin, K_B for propranolol was increased significantly to 13.3 ± 1.8 nM (n = 27, p <0.001). Calculation of K_B in terms of the measured propranolol unbound concentration of 26.8 nM, after taking into account the lower isoprenaline EC₅₀ in the presence of albumin, yielded a mean value of 0.725 ± 1.86 nM, which was not significantly different from either control (p >0.05). Therefore, propranolol activity was as predicted by the unbound drug concentration in Contrast to isoprenaline activity. We conclude that albumin can alter in vitro drug activity by mechanisms in addition to the reduction of unbound drug concentration.     

The relaxant action of BRL 34915 in rat uterus.

1 BRL 34915 (0.04-1.3 microM) caused concentration-dependent inhibition of spontaneous phasic spasms of the isolated uterus of the term pregnant rat and this effect was not antagonized by propranolol. Spasms evoked by low concentrations of KCl (less than 20 mM) were inhibited by BRL 34915 but those evoked by higher concentrations (greater than 40 mM) were unaffected. 2 In experiments using extracellular electrical recording, BRL 34915 (10 microM) selectively inhibited oxytocin-induced phasic spasms and the associated spike activity but had little effect on the tonic component of the spasms. BRL 34915, as an inhibitor of phasic spasms to oxytocin (0.2 nM), was antagonized by procaine (0.3 and 1 mM). 3 BRL 34915 (10 microM) did not inhibit Ca2+-induced spasm of saponin-skinned thin myometrial strips. 4 Intracellular microelectrode recording from myometrial strips showed that BRL 34915 (10 microM) inhibited action potentials and phasic spasms in the presence of oxytocin (0.2 nM) and produced a hyperpolarization of 5 mV. 5 In single myometrial cells under current or voltage clamp, BRL 34915 (10 microM) had no effect on action potentials and inward current in Ca2+- or Ba2+-containing media in the presence of tetraethylammonium, 4-aminopyridine and caesium chloride. In the absence of these K+-channel inhibitors, BRL 34915 had no effect on resting membrane potential, membrane resistance, action potential, inward current or outward current. 6 BRL 34915 (1 or 10 microM) had no effect on 86Rb efflux from myometrial strips. 86Rb efflux was increased by oxytocin (0.2 and 20 nM). 7 The relaxant profile of BRL 34915 in the rat uterus is similar to that described for other smooth muscles where an action to open membrane K+-channels has been proposed. BRL 34915 inhibited spike production but produced only a small hyperpolarization without a detectable increase in 86Rb efflux. Membrane resistance and transmembrane currents were unaffected. These results suggest that in the uterus the effects of BRL 34915 may be restricted to K+-channels involved in the production of pacemaker activity.     

Effects of clenbuterol treatment on the relaxant response in rat uterus.

Prolonged treatment with the beta(2)-adrenergic agonist clenbuterol (0.25 mg kg(-1) s.c. once daily for 10 days) produced a reduction of the relaxant response and cAMP production mediated by stimulation of beta-adrenoceptors in oestrogen-treated rat uterus. Substantial decreases in the relaxant effect of isoproterenol is observed in uterine rings precontracted with 50 mM KCl from clenbuterol-treated rats. The recovery of the relaxant response was also studied and significant differences were seen between acute and prolonged treatment with clenbuterol (P<0.05 vs control). In contrast the relaxant effect of forskolin and 3-isobutyl-1-methylxanthine was similar in untreated or treated rats. Sodium fluoride also showed a relaxant response which was not affected by the treatment with clenbuterol. The radioligand studies showed a reduction in the number of beta-adrenoreceptors after acute and prolonged treatment with clenbuterol in rat uterus. These results suggest that prolonged treatment with clenbuterol caused a desensitization of the relaxant uterine response through beta(2)-adrenoceptors and also showed differences in the recovery of the relaxant response depending on the duration of treatment.     

Inhibitory effect of 3-carboethoxypyridine and 3-carbobutoxypyridine on isolated rat uterus

3-Carbomethoxypyridine (CMP) was isolated and characterized from the leaves of Pyrenacantha staudtii Hutch and Dalz, family Icacinaceae, in our earlier study and was found to possess an inhibitory activity on the isolated rat uterus. In order to study the structure - activity relationship, derivatives of CMP were obtained synthetically, purified and characterized by spectroscopic techniques such as infra red spectroscopy (IR), nuclear magnetic resonance (1H- and 13C-NMR) and mass spectrometry (MS). The synthesized compounds were subjected to pharmacological testing using isolated rat uterine preparation in oestrus suspended in an organ bath containing De Jalon physiological salt solution (PSS). The force of contraction was recorded via an isometric transducer connected to an Ugo Basile recorder. The effects of these two compounds were compared with salbutamol as a positive control. 3-Carboethoxypyridine (ECP) demonstrated very significant (p < 0.005) inhibitory activity on the uterus with a total elimination of the spontaneous contractility at a dose of 0.4 mg/mL. Carbobutoxypyridine (BCP) also demonstrated a marked reduction of oxytocin-induced contractions and elimination of spontaneous activity. The study lends support to the potential use of these agents as tocolytics.     

Influence of thyroid status on responses of rat isolated pulmonary artery, vas deferens and trachea to smooth muscle relaxant drugs.

1 Responses to relaxant drugs have been examined on isolated KCl-contracted smooth muscle preparations from rats in which thyroid status was changed by prior treatment with either thyroxine (T4) for 1 week (preparations of pulmonary artery, trachea and vas deferens) or methimazole for 10-12 weeks (pulmonary artery preparations). 2 On pulmonary artery preparations, T4 treatment caused a significant increase in the magnitude of the relaxant responses to noradrenaline and isoprenaline but not those to adrenaline. The potency of noradrenaline was increased 5.6 fold but that of isoprenaline and adrenaline was unchanged. This resulted in a change in the relative potencies from adrenaline greater than noradrenaline (controls) to noradrenaline = adrenaline (T4-treated). Methimazole treatment caused a significant reduction in the magnitude of the responses to noradrenaline and in its potency (2.8 fold). Isoprenaline and procaterol were unaffected. 3 On pulmonary artery preparations, T4 treatment did not affect the magnitude of the responses to forskolin, sodium nitrite or isobutylmethylxanthine (IBMX) or their potency. In vitro treatment with the monoamine oxidase (MAO) inhibitors, iproniazid or pargyline, did not potentiate responses to either noradrenaline or isoprenaline. Therefore, it was concluded that the T4-induced changes in the magnitude of the responses to noradrenaline and isoprenaline and in the potency of noradrenaline were unlikely to be due to reduced activity of cyclic nucleotide phosphodiesterase(s) or MAO. 4 On preparations of vas deferens and trachea, T4 treatment had no effect on the magnitude of the responses to noradrenaline, isoprenaline, adrenaline or procaterol.(ABSTRACT TRUNCATED AT 250 WORDS)     

1-(2,6二甲苯氧基)-2-(3,4二甲基苯乙胺基)丙烷酸盐(DDPH)对大鼠离体子宫平滑肌收缩性能的影响

目的研究DDPH对多种物质诱导大鼠离体子宫平滑肌收缩的抑制作用。方法离体子宫平滑肌实验方法。结果DDPH和维拉帕米对KCl,缩宫素,高K+除极化后CA2+诱导大鼠离体子宫平滑肌收缩均产生抑制作用,对CaCL2累积量效曲线均呈非竞争性拮抗效应,pD＇2值分别为4．32和7．43。DDPH和维拉帕米均能抑制缩宫素诱导依赖细胞内Ca2+收缩反映,对依赖细胞外Ca2+的收缩均无明显影响。结论DDPH对子宫平滑肌有较好的松弛作用。     

Influence of tracheal contraction on relaxant effects in vitro of theophylline and isoprenaline.

1 Relaxation by (-)-isoprenaline (Iso) and theophylline (Theo) was measured in guinea-pig isolated trachea, in the presence or absence of carbachol. 2 With basal tone or with carbachol at a concentration of 5.4 x 10(-7) M, causing 70% maximal contraction, Iso and Theo relaxed the trachea to the same extent. 3 With carbachol concentrations of 5.4 x 10(-6) M and 5.4 x 10(-5) M (96% and 100% maximal contractions) Iso caused no more than 63% and 34%, respectively, of the maximum relaxation to Theo. 4 When calculated at 25% of the maximum Theo relaxation, the Iso/Theo potency ratio was gradually reduced from 14,160 when evaluated at basal tone to 1,560 at the highest carbachol concentration. 5 In combination, at their maximally effective concentrations, Theo and Iso produced no larger a relaxation than did Theo alone. 6 At the two highest concentrations of carbachol, concentration-response curves to Theo were virtually superimposable whether determined in the absence or the presence of Iso at its maximally effective concentration. 7 It is concluded that Theo causes a greater relaxation of highly contracted tracheal muscle than Iso.     

Effect of diphenylhydantoin on drug and calcium induced contractions of isolated rat uterus: a comparative study with nifedipine

The sustained contractions induced by K+, acetylcholine (ACh) and oxytocin (Ot) were inhibited in a concentration-dependent fashion by diphenylhydantoin (DPH) and nifedipine (NIF) in the following order of sensitivity: K+ greater than ACh greater than Ot. Previous incubation of DPH and NIF produced a non-competitive antagonism towards ACh and Ot-induced contractions. Increasing of calcium (Ca2+) concentration (0.2-1.5 mM) completely reverse the inhibitory effect of DPH and NIF, suggesting a competitive type of antagonism, between Ca2+ and DPH. A clear difference between DPH and NIF actions was observed when the K+-depolarizing solution was used. In this condition, DPH caused a parallel and concentration-related rightward displacement of the dose-response curves of Ca2+ (pA2 = 4.91 +/- 0.1), while NIF produced a rightward displacement allied to a significant reduction of the Ca2+ maximal response. DPH, but not NIF, produced a concentration-dependent relaxation in sustained contraction induced by Ca2+ (1 mM) in depolarized tissue.     

吡那地尔和硝苯地平对大鼠离体血管的作用

吡那地尔和硝苯地平对大鼠离体血管的作用１汪海路新强张雁芳龙超良王家惠（军事医学科学院毒物药物研究所，北京１００８５０）吡那地尔（ｐｉｎａｃｉｄｉｌ，Ｐｉｎ）属ＡＴＰ敏感性钾通道激活剂类抗高血压药物，其抗高血压作用的强度，持续时间和反射性加快心率作用等...     

Reserpine non-selectively inhibits rat uterus contraction in vitro

1. Reserpine produced a direct in vitro non-selective inhibitory effect on smooth muscle contraction of endometrium-free rat uterus. 2. Reserpine uptake into uterine muscle and its antagonistic effect on contraction had a similar time course. 3. Reserpine had a relaxing effect similar to that of trifluoperazine and different from that of verapamil or papaverine, and also failed to exert any inhibitory effect on 45Ca uptake rate. 4. Both reserpine and trifluoperazine but not verapamil inhibited the acetylcholine-induced contraction when present during the Ca-release from intracellular stores. 5. It is hypothesized that reserpine exerts its inhibitory action intracellularly on the activation of smooth muscle contraction by sarcoplasmic Ca2+.     

Effect of methysergide and indomethacin on the anaphylactic contraction of the rat isolated uterus (Schultz-Dale response)

The anaphylactic contraction (Schultz-Dale response) of the isolated uterus from actively sensitized rats was partially suppressed by methysergide, 1.5 mug/ml. Although the inhibitory effect of indomethacin, 3.5 mug/ml, was only slight, the combination of indomethacin and methysergide abolished the response almost completely. These observations indicate that, although serotonin must be the primary mediator of tha anaphylactic uterine response, prostaglandin is also involved. Metiamide, a histamine H2-receptor antagonist, 10 mug/ml, did not affect the anaphylactic response, suggesting that histamine was not released in amounts sufficient to counteract the uterine contracting mediators.     

Modulatory effect of interleukin-1beta on rat isolated basilar artery contraction

An increased level of cytokine interleukin-1 (IL-1) has been detected around the site of stroke. However, the effect of IL-1beta on the basilar artery has received little attention. We evaluated the effects of IL-1beta on the contractile response of rat isolated basilar artery by measuring isometric tension change. IL-1beta (10 ng/ml) and phenylephrine (0.1 nM) markedly enhanced U46619 (30 and 100 nM)-induced basilar artery contraction. The IL-1beta-mediated potentiation was partly suppressed by zinc protoporphyrin (3 microM) and was abolished by tetrodotoxin (TTX, 100 nM), (-)-perillic acid (1 microM), PD98059 (0.3 microM), SB203580 (1 microM) and prazosin (1 microM). Our data suggest that IL-1beta (10 ng/ml) causes an enhancement of U46619-mediated basilar artery contraction that probably involves TTX-sensitive neuronal release of an alpha1-adrenoceptor agonist and activation of p42/p44 and p38 mitogen-activated protein kinases/p21(ras) pathways.     

Effects of optical isomers of clenbuterol on the relaxant response in rat uterus.

Previous works have shown that the administration of the racemic beta -adrenoceptor agent clenbuterol produces a desensitization of the relaxant response in rat uterus. The aim of this work was to study the effects of the optical isomers of clenbuterol on the relaxant response in rat uterus. The administration of (L)-clenbuterol (0.25 mg per kg per day) over 1 or 10 consecutive days, produced a reduction of the relaxant response to isoproterenol in uterine rings precontracted with 50 m m KCl from oestrogenic rats. The administration of (D)-clenbuterol (0.25 mg per kg per day) over 1 or 10 days did not affect the relaxant response of isoproterenol. (L)-clenbuterol also produced a concentration-dependent relaxant effect that was not observed with (D)-clenbuterol. These results show that the beta-adrenergic relaxant response and the desensitization of the relaxant effect to isoproterenol is due to the (L)-isomer and that the (D)-isomer is not involved in these effects.