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31.
In the 12-day-old rat cochlea, the synthesis of inositol phosphates (IPs) can be activated via M3 cholinoceptors. This stimulation is blocked by ototoxins (mercury, ethacrynate, cisplatin, neomycin), drugs with side effects that lead to damage of hair cells and strial cells. As these toxic effects can be reversed in vivo by thiol molecules, we investigated whether modifications of thiol compounds could be involved in ototoxin-induced inhibition of the IP turnover in the cochlea. For this purpose, we assessed whether the sulphhydryl-modifying reagents N -ethylmaleimide and cadmium modify the carbachol-stimulated formation of IPs in the 12-day-old rat cochlea. Both molecules inhibit the carbachol effect on a dose-dependent way without altering the basal metabolism of IPs. As cadmium may block some calcium channels, the effect of verapamil, another calcium channel antagonist, was tested. Verapamil (1 –50 μM) does not alter carbachol-evoked IP formation, suggesting that the inhibitory effect of cadmium is not due to a calcium influx block. Binding experiments with the muscarinic ligand quinuclidinyl benzylate (QNB) showed that the sulphhydryl-modifying reagents do not displace QNB from binding sites. Combining ototoxins and reagents shows that N -ethylmaleimide acts synergistically with all ototoxins but ethacrynate while cadmium does so only with mercury. Both N -ethylmaleimide and cadmium have additive effects with ethacrynate. As a supplement, disulphide bond-modifying agents do not alter the carbachol-enhanced metabolism of IPs. These results suggest that molecules having thiol-modifying properties inhibit the carbachol-induced turnover of IPs without acting at the muscarinic sites. Since thiol modifiers and ethacrynate share similar features in both QNB binding and IP response it is hypothesized that they strike common targets, possibly G proteins. 相似文献
32.
Michiko Oka Y. Itoh Shigeru Tatsumi F.-H. Ma Yojiro Ukai Yoshiaki Yoshikuni Kiyoshi Kimura 《Naunyn-Schmiedeberg's archives of pharmacology》1997,356(2):189-196
The effect of (+)-5-oxo-D-prolinepiperidinamide monohydrate (NS-105), a novel cognition enhancer, on adenylate cyclase activity
was investigated in cultured neurons of the mouse cerebral cortex. NS-105 (10–7 and 10–6 M) inhibited forskolin-stimulated cyclic AMP formation, an action that was dependent on pertussis toxin-sensitive G proteins.
Conversely, in pertussis toxin-pretreated neurons, NS-105 (10–7 –10–5 M) significantly enhanced the forskolin-stimulated cyclic AMP formation, and this action was completely reversed by cholera
toxin. A metabotropic glutamate receptor agonist (1S, 3R)-1-aminocyclopentane-1, 3-dicarboxylic acid (1S, 3R-ACPD) produced
similar bi-directional actions on the cyclic AMP formation. Both of these inhibitory and facilitatory actions of NS-105 and
1S, 3R-ACPD were blocked by L(+)-2-amino-3-phosphopropinoic acid (L-AP3). NS-105 (10–6 M) and 1S, 3R-ACPD (10–4 M) significantly enhanced isoproterenol- and adenosine-stimulated cyclic AMP formation. The enhancement of such Gs-coupled
receptor agonists-stimulated cyclic AMP formation was also produced by quisqualate but not by L(+)-2-amino-4-phosphonobutanoate
(L-AP4). The phosphoinositides hydrolysis was enhanced by 1S, 3R-ACPD (10–4 M) but not by NS-105 (10–6 M), however, 1S, 3R-ACPD-induced increase in phosphoinositides turnover was attenuated by NS-105. These findings suggest
that NS-105 stimulates metabotropic glutamate receptor subclasses that are coupled both negatively and positively to adenylate
cyclase, but it acts as an antagonist at the receptor subclasses that are linked to phosphoinositides hydrolysis.
Received: 3 February 1997 / Accepted: 25 April 1997 相似文献
33.
Ryo Suzuki M.D. Shunsaku Kobayashi 《Documenta ophthalmologica. Advances in ophthalmology》1988,70(4):293-300
Using tension-recording methods, we compared the effects of acetylcholine (Ach) and carbachol on the bovine iris sphincter. The isolated muscle strips were mounted in a 0.2 ml organ bath, through which Krebs solution at 36 °C flowed continuously. There was a tenthousandfold difference in potency between carbachol and Ach in this tissue. Neostigmine or eserine, acetylcholinesterase (AchE) inhibitors, produced a larger contraction of the muscle than did Ach. Ach-induced contractions were potentiated by low doses of anti-AchEs and were inhibited by atropine.This in vitro study suggests that Ach and/or endogenous chemical agents may be spontaneously released from tissues and that AchE activities in this tissue strongly inhibit or mask the Ach action, probably in order to protect the nerve terminals from released Ach. 相似文献
34.
Jean-yves Gillon Pierre-Alain Vitte Francoise Lemonnier Gabor Kato 《Drug development research》1994,32(1):42-49
Medifoxamine, an antidepressant agent which has an original chemical structure, has been shown through in vitro studies, utilising radioligand binding in tissue homogenates, to bind with moderately high affinity to 5-HT1c and 5-HT2 receptor subtypes and to 5-HT uptake sites (IC50 950, 980, and 1,500 nM, respectively). It has been shown to bind in vivo to rat brain 5-HT2 receptors after acute treatment with high dose (50 mg/kg, i.e., 133.9 μmol/kg). After 14 days continuous treatment with low dose (20 mg/kg, 53.6 μmol/kg), a decrease in the capacity of [3H]-5-HT uptake and a dose-dependent down-regulation of 5-HT2 receptors in rat cerebral cortex were observed. These results indicate that medifoxamine, which has been shown previously to act through dopaminergic systems, interacts also with central serotonergic neurotransmission and particularly with the 5-HT2 receptors, which could contribute to its antidepressant effect. 相似文献
35.
Satomi Kitagawa Yu Yamaguchi Emiko Sameshima Masaru Kunitomo 《Clinical and experimental pharmacology & physiology》1994,21(12):963-970
1. Endothelium-dependent relaxation in response to acetylcholine (ACh) and the calcium ionophore A 23187 was examined in aorta, coronary, basilar and renal arteries isolated from Watanabe heritable hyperlipidaemic (WHHL) rabbits of 2, 6 and 12 months of age, with normolipidaemic heterozygous WHHL rabbits as controls. 2. In the rings of WHHL rabbit aortae and coronary arteries preconstricted with vasoconstrictors, endothelium-dependent relaxation in response to ACh was attenuated with age compared to the heterozygous WHHL rabbits. A significant negative correlation was found between the total cholesterol content and the relaxation response to ACh in the aortae or coronary arteries from 6 and 12 month old WHHL rabbits. 3. In the rings of basilar arteries, endothelium-dependent relaxations to ACh were not modified with age. Similarly, in the rings of renal arteries, the relaxation response to ACh was not changed with age, but in the 6 and 12 month preparations, after the age of 6 months, a contraction following the relaxation appeared at higher concentrations of ACh (10?7 to 10?6 mol/L). The contraction was endothelium-dependent and inhibited by indomethacin. 4. A 23187-induced endothelium-dependent relaxations were also markedly attenuated in the aorta and significantly in the coronary artery with age. 5. Endothelium-independent relaxation to sodium nitroprusside was not changed in all arteries from WHHL rabbits of different ages. 6. These findings indicate that in the aorta and coronary artery of the WHHL rabbit, the endothelium-dependent relaxation to ACh and A 23187 becomes impaired with increasing age (i.e., with the progression of cholesterol deposition in the arterial wall) but is preserved in the basilar and renal artery. 相似文献
36.
GABA RECEPTORS: AS COMPLEX AS ABC? 总被引:1,自引:0,他引:1
Graham A. R. Johnston 《Clinical and experimental pharmacology & physiology》1994,21(7):521-526
37.
38.
Activity at 5-HT1 and 5-HT2 receptor sites influences sexual behavior in male and female rats. 5-HT3 antagonists reportedly have no effect on copulatory activity in rats of either sex although they influence a variety of other behaviors. The effects of 5-HT3 agonists on sexual behavior are unknown. The following experiments were undertaken to assess the influence of the 5-HT3 agonists 1-phenylbiguanide (PBG) and 2-methyl-serotonin (2-Me-5-HT) on sexual behavior, when administered intracerebroventricularly. Consistent with earlier reports indicating that 5-HT1 and 5-HT2 receptor activity influences reproductive activity in a sex-dependent manner, PBG was found to facilitate male, but not female, rat sexual behavior. 2-Me-5-HT, however, failed to modify either female or male rat sexual activity. Evidence that PBG, but not 2-Me-5-HT, induces carrier-mediated dopamine release suggests that the effect of PBG in male rats is due to dopaminergic mediation. Overall, the present data indicate that 5-HT3 receptor activation has only slight effects on rat sexual behavior. 相似文献
39.
Hiroshi Ujike Kazuo Tsuchida Kazufumi Akiyama Yutaka Fujiwara Shigetoshi Kuroda 《Pharmacology, biochemistry, and behavior》1995,50(4):613-617
The ontogeny of the behavioral effects of acute cocaine administration and behavioral sensitization to cocaine in rat pups was investigated. Acute behavior stimulating effects of cocaine were observed in pups as young as 7 postnatal days (PND) old, although they needed a higher dose of cocaine than adult rats to evoke the same motor effects. An adult dose-response curve pattern of stereotypy and locomotion to acute cocaine treatment was observed at PND 21, and of rearing at PND 28. Rats aged PND 7, 14, 21, 28, and 56 received repeated injections of saline or cocaine (15 mg/kg) twice a day for 5 consecutive days. After a 3-week period of abstinence, sensitization to a challenge dose of cocaine was assessed. Cocaine-induced stereotyped behavior was enhanced significantly only in rats in which cocaine pretreatment was initiated on PND 21, 28, and 56, but not earlier on PND 7 and 14. Adult female rats given repeated cocaine injections on PND 56–60 showed significantly greater sensitization than males, but no such sex difference was observed in pups given cocaine repeatedly on PND 21–25 or 28–32. These results show clearly that cocaine-induced behavioral sensitization in rats occurred only when subchronic cocaine administration was commenced on PND 21 or later. 相似文献
40.
用辣根过氧化物酶标记的AcLDL2培养小白鼠腹腔巨噬细胞,直观地显示了巨噬细胞表面AcLDL受体的存在,此受体只特异性的识别修饰的LDL,其识别作用与配体分子荷大量负电荷有关。 相似文献