静脉注射不同阿片肽拮抗物抗大鼠烫伤休克效果的比较

在大鼠20%体表面积Ⅲ°烫伤后,立即从静脉分别注射beta-内啡肽抗血清10μl,ICI_(174864) 0.2mg,TRH 2mg,或纳洛酮2mg,随后在1,2,3h再分别给予半量,观察心血管功能指标和存活时间。结果表明,beta-内啡肽抗血清、ICI_(174864)和纳洛酮,均可改善烫伤动物的心功能指标,延缓MAP下降和HR减慢,尤其beta-内啡肽抗血清可显著延长动物的存活时间。TRH在早期能增加烫伤动物的心率,延缓MAP的下降,晚期却加快了MAP的下降,对心功能指标几无改善。这提示beta-内啡肽抗血清、ICI_(174864)和纳洛酮,均有抗烫伤休克的作用;TRH如何适当地应用于抗烫伤休克,有待进一步探讨。     

The delta opioid receptor antagonist naltrindole attenuates both alcohol and saccharin intake in rats selectively bred for alcohol preference

This study demonstrates that the selective delta receptor antagonists ICI 174864 and naltrindole (NTI) attenuate alcohol intake in a dose-dependent manner, without altering water intake, in rats selectively bred for alcohol preference. ICI 174864 had a very limited duration of action, as evidenced by the fact that suppression of alcohol intake lasted for only an hour following ICI 174864 administration. NTI, when administered in a dose of 10 mg/kg, suppressed alcohol intake by 28%. Increasing the dose of NTI to 15 mg/kg produced a 44% suppression of alcohol intake, but a further increase to 20 mg/kg did not produce greater suppression than was seen with a dose of 15 mg/kg (46% versus 44%, respectively). This suggests that NTI is maximally effective in suppressing alcohol intake at a dose of 15.0 mg/kg. NTI displayed a long duration of action, as evidenced by attenuation of alcohol drinking that lasted for at least 8 h following drug treatment. Administering the maximally effective dose of NTI (15 mg/kg) in two parts, separated by 4 h, served to prolong the duration of action of NTI and produced an attenuation of alcohol intake, but not water intake, that lasted for at least 28 h. The effect of NTI on alcohol intake was not specific for alcohol, as evidenced by the fact that NTI reduced the intake of saccharin solutions with and without alcohol.     

大鼠脊髓不同类型阿片受体在介导下丘脑弓状核刺激镇痛中的作用

在轻度麻醉大鼠,电刺激下丘脑弓状核(ARH)大大延长了辐射热甩尾潜伏期,脊髓蛛网膜下腔注射(ith)κ阿片受体阻断剂nor-BNI对大鼠基础痛阈及ARH刺激引起的镇痛效应无明显影响,ithδ阿片受体阻断剂ICI 174864和不可逆的“阿片受体阻断剂β-FNA对基础痛阈仍无影响,但剂量依赖性地减弱了ARH刺激镇痛。结果提示,脊髓内的δ和μ受体参与了ARH对脊髓伤害性反射的下行性抑制。     

FUNCTION, CHARACTERIZATION AND AUTORADIOGRAPHIC LOCALIZATION AND QUANTITATION OF β-ADRENOCEPTORS IN CARDIAC TISSUES

1. This paper demonstrates the use of organ bath, radioligand binding and autoradiography to detect beta 1- and beta 2-adrenoceptors in human and guinea-pig cardiac tissues. 2. In organ bath experiments, non-selective and beta 1- and beta 2-adrenoceptor selective agonists produced concentration-dependent inotropic responses in human right atrial appendage. Both subtypes mediate inotropic responses. In guinea-pig right atria chronotropic responses were mediated predominantly through beta 1-adrenoceptors. 3. Receptor binding studies using (-)[125I]-cyanopindolol (CYP) and beta 1- and beta 2-adrenoceptor selective antagonists showed that beta 2-adrenoceptors comprised 25% of the total population of beta-adrenoceptors in guinea-pig right atria. In human right atria the proportion is higher (40%). 4. Quantitative autoradiography was used to determine the location and densities of beta 1- and beta 2-adrenoceptors in guinea-pig heart. Both beta 1- and beta 2-adrenoceptors were distributed on myocardium. The atrioventricular conducting system had a higher density of beta 2-adrenoceptors compared with myocardium.     

Pharmacological characterization of the receptors involved in the β-adrenoceptor-mediated stimulation of the L-type Ca2+ current in frog ventricular myocytes

1. The whole-cell patch-clamp was used for studying the effects of various β₁- and β₂-adrenoceptor agonists and antagonists on the L-type Ca current (I_Ca) in frog ventricular myocytes.
2. Dose-response curves for the effects of isoprenaline (non selective β-agonist), salbutamol (β₂-agonist), dobutamine (β₁-agonist) on I_Ca were obtained in the absence and presence of various concentrations of ICI 118551 (β₂-antagonist), metoprolol (β₁-antagonist) and xamoterol (partial β₁-agonist) to derive EC₅₀ (i.e. the concentration of β-agonist at which the response was 50% of the maximum) and E_max (the maximal response) values by use of a Michaelis equation. Schild regression analysis was performed to examine whether the antagonists were competitive and to determine the equilibrium dissociation constant (K_B) for the antagonist-receptor complex.
3. Isoprenaline increased I_Ca with an EC₅₀ of 20.0 nM and an E_max of 597%. ICI 118551 and metoprolol competitively antagonized the effect of isoprenaline with a K_B of 3.80 nM and 207 nM, respectively.
4. Salbutamol increased I_Ca with an EC₅₀ of 290 nM and an E_max of 512%. ICI 118551 and metoprolol competitively antagonized the effect of salbutamol with a K_B of 1.77 nM and 456 nM, respectively.
5. Dobutamine increased I_Ca with an EC₅₀ of 2.40 μM and an E_max of 265%. ICI 118551 and metoprolol competitively antagonized the effect of dobutamine with a K_B of 2.84 nM and 609 nM, respectively.
6. Xamoterol had no stimulating effect on I_Ca. However, xamoterol competitively antagonized the stimulating effects of isoprenaline, salbutamol and dobutamine on I_Ca with a K_B of 58–64 nM.
7. We conclude that a single population of receptors is involved in the β-adrenoceptor-mediated regulation of I_Ca in frog ventricular myocytes. The pharmacological pattern of the response of I_Ca to the different β-adrenoceptor agonists and antagonists tested suggests that these receptors are of the β₂-subtype.

     

The estrogen metabolites 2-methoxyestradiol and 2-hydroxyestradiol inhibit endometriotic cell proliferation in estrogen-receptor-independent manner

Endometriosis, a painful disorder associated with infertility, is estimated to occur in approximately 7–10% of reproductive age women. Although endometriosis is considered as an estrogen-dependent disease, the role of estrogen metabolites via receptor-independent mechanisms has not yet been comprehensively clarified. In the present study, growth studies were performed comparing the effect of estradiol (E2), estrogen metabolites, that is, 2-hydroxyestradiol (2-OHE2) and 2-methoxyestradiol (2-ME), as well as estrogen-receptor-independent mechanisms using the estrogen receptor antagonist fulvestrant, on cell proliferation of endometriotic cells. The estrogen metabolites 2-OHE2 and 2-ME inhibited cell growth in a dose-dependent manner in pharmacological doses. Lower concentrations of 2-OHE2 had a stimulating effect on cell proliferation while pharmacologic doses exerted an antimitogenic effect. The effects on cell growth were at least partially receptor-independent, as demonstrated by simultaneous receptor antagonization with fulvestrant. In conclusion, our results demonstrate that in pharmacological doses the estrogen metabolites 2-ME and 2-OHE2 show inhibiting effects on the proliferation of endometriotic cells and may be promising substances for the treatment of endometriosis.     

Evaluation of chemicals for immunomodulatory effects using an in vitro antibody-producing assay

Several chemicals were examined for immunomodulatory effects using the Mishell — Dutton in vitro antibody-producing assay. The chemicals studied were either of environmental concern and/or of special interest to the food industry. A number of these compounds have been shown by others to be immunosuppressive in whole animal exposure studies, at least in certain species and in relatively high doses. Azathioprine (Imuran) (0.5 μg/culture), gallic acid (7 μg/culture), dextran sulfate (100 μg/culture), methyl paraben (100 μg/culture), and vanillin (200 μg/culture) were all found to directly suppress the in vitro anti-sheep red blood cell (SRBC) antibody response at noncytotoxic doses. All of these chemicals appeared to interrupt an early phase of the immune response, and had no effect on the actual release of specific anti-SRBC antibody. The Mishell — Dutton in vitro antibody-producing assay was found to be a sensitive detection system for direct-acting immunosuppressive chemicals. Chemicals that require activation to immunosuppressive intermediates are not detectable in this assay.     

The development of tamoxifen for breast cancer therapy: A tribute to the late Arthur L. Walpole

Summary Tamoxifen, a nonsteroidal antiestrogen, is now the endocrine treatment most widely used in breast cancer, both in the adjuvant and advanced disease settings. Here we will trace the development of tamoxifen for advanced breast cancer in postmenopausal patients, consider the biological basis for the recent successful use of tamoxifen for long-term adjuvant therapy, and discuss the use of tamoxifen in premenopausal patients with advanced disease. In part, this will be a historical review offered as a tribute to the late Dr. Arthur L. Walpole, who must receive the chief credit for the discovery of tamoxifen and its subsequent application as an anticancer agent.     

Comparison of the new atypical antipsychotics olanzapine and ICI 204,636 with clozapine on behavioural responses to the selective “D1-like” dopamine receptor agonist A 68930 and selective “D2-like” agonist RU 24213

The effects of the putative atypical antipsychotics olanzapine and ICI 204,636 on behavioural responses to the selective D₂-like dopamine receptor agonist RU 24213 and to the selective D₁-like agonist A 68930 were compared with those of the prototype atypical antipsychotic clozapine, the selective D₁-like antagonist SCH 23390 and the selective D₂-like antagonist YM 09151-2. Olanzapine (0.4–2.0 mg/kg) and ICI 204,636 (4.0–36.0 mg/kg), like clozapine (4.0–36.0 mg/kg) and SCH 23390 (0.01–1.0 mg/kg), effected at best modest reduction in typical sniffing and locomotor responses and, with the exception of ICI 204,636, released episodes of atypical myoclonic jerking to RU 24213 (12.5 mg/kg); a high dose of olanzapine (10.0 mg/kg), like YM 09151-2 (0.005–0.5 mg/kg), blocked all responsivity to RU 24213. Conversely, olanzapine (0.4–2.0 mg/kg) and ICI 204,636 (4.0–36.0 mg/kg), like clozapine (4.0–12.0 mg/kg) and SCH 23390 (0.01–0.1 mg/kg), readily blocked typical grooming responses to A 68930 (0.5 mg/kg); YM 09151-2 failed to block grooming and exerted more variable effects. Olanzapine and, to a lesser extent, ICI 204,636 share with clozapine a preferential action to attenuate D₁-mediated function; given their lack of selective affinity for D₁-like receptors, this common effect may be exerted at an alternative level of synaptic function. The action of olanzapine and particularly ICI 204,636 to release additional episodes of atypical vacuous chewing to A 68930 indicates some deviation from a wholly clozapine-like profile, the clinical significance of which remains to be specified.