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71.
D. M. Jackson C. E. Wallsten E. Jerning P.-S. Hu A. M. Deveney 《Psychopharmacology》1998,139(4):300-310
The aim was to study firstly, the motor effects of a new 5-HT1A antagonist, NDL-249 [(R)-3-(N-cyclopentyl-N-propylamino)-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide hydrochloride] and of the reference 5-HT1A antagonist WAY-100 635 [N-(2-(1-(4-(2-methoxyphenyl)piperazinyl))ethyl)-N-(2-pyridinyl) cyclohexanecarboxamide trihydrochloride], in comparison to the 5-HT1A agonist (±)-8-OH-DPAT [(8-hydroxy-2-(di-N-propylamino) tetralin, hereafter 8-OH-DPAT], in rats acclimatised to the automated activity cages; secondly, to study whether
the behavioural effects of NDL-249 and 8-OH-DPAT are sensitive to the 5-HT depleting effects of p-chlorophenylalanine (PCPA); thirdly, to characterise the nature of the antagonist-induced activation seen in the automatic
activity cages with the aid of a behavioural observation analysis; fourthly, to examine the interaction between the 5-HT1Areceptors mediating the behavioural effects and dopamine (DA) receptors. NDL-249 was found to bind in vitro to rat hippocampal
5-HT1A receptors with high affinity and selectivity. In second messenger studies, it was devoid of agonist-like effects. In the
locomotor activity studies, each antagonist significantly increased the incidence of horizontal activity, peripheral activity
and rearing. 8-OH-DPAT, while significantly increasing peripheral and horizontal activities, decreased the incidence of rearing.
PCPA blocked the motor effects of NDL-249 but did not affect those of 8-OH-DPAT. Observational analyses indicated that NDL-249
induced significant increases at one or more doses in sniffing, rearing and locomotion together with a significant reduction
in stillness. WAY-100 635 significantly increased the incidence of rearing, intense grooming and vacuous chewing. The significant
increases in sniffing, grooming and intense grooming and the significant decrease in stillness induced by the DA D1 agonist, SK&F 38393 [(±)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol hydrochloride], were not altered by concomitant
pre-treatment with NDL-249. Pre-treatment of rats with either the DA D1 antagonist SCH-23390 (2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepin-7-ol) or the DA D2 antagonist, raclopride, blocked the reduced stillness and increased sniffing and rearing induced by NDL-249. In conclusion,
5-HT1A antagonists including the new selective antagonist, NDL-249, induce mild behavioural activation in rats, which is mediated
probably indirectly via DA systems.
Received: 3 April 1997/Final version: 23 February 1998 相似文献
72.
Peripheral and central injections of recombinant human interleukin-1β (IL-1β) have been shown to decrease social exploration and to induce body weight loss in rats. To characterize the receptor mechanisms of these effects, we used as a tool a specific antagonist of the receptors of IL-1, IL-1ra. Intraperitoneal (i.p.) administration of IL-1ra (8 mg/kg) blocked the effect of i.p. injection of IL-1β (4 μg/rat) on social behaviour but not on body weight. Central administration of IL-1ra (60 μg/rat, i.c.v.) abrogated the effects of centrally administered IL-1β (30 ngn/rat, i.c.v.) on both social behaviour and body weight. Central injection of IL-1ra (4 μg/rat, i.c.v.) also attenuated the effects of i.p. administered IL-1β (4 μg/rat) on social behaviour but not on body weight. These results suggest that the effects of IL-1β on social behavior are mediated centrally and that its effect on the loss of body weight involves different receptor mechanisms. 相似文献
73.
用小鼠热水缩尾法研究了高选择性的CCK-B受体拮抗剂PD134308的镇痛效应。PD134308在小鼠产生的镇痛有剂量依赖关系。阿片受体拮抗剂对抗其镇痛作用,表明阿片受体系统参与介导PD134308的镇痛。PD134308能加强吗啡的镇痛作用,但对α2受体激动剂可乐定的镇痛作用没有影响,表明CCK-B受体拮抗剂对阿片受体系统作用有选择性。脑啡肽酶抑制剂SCH32615加强PD134308的镇痛作用,说明PD134308可能是通过增加内源性阿片物质产生镇痛作用的。另外,PD134308还参与吗啡镇痛耐受性的形成。 相似文献
74.
本文对照研究了脑出血患者血浆及脑脊液(CSF)内皮素-1(ET-1)含量改变及其临床意义。发现脑出血患者血浆与CSF、ET-1含量均增高;单纯脑血肿者以血浆含量增高为主;脑实质出血伴有脑室系统或蛛网膜下腔出血(SAH)者血浆及CSF含量均显著升高;小量出血与中大量出血比较血浆含量无显著性,而大量出血者CSF、ET-1含量增高。提示脑出血者血浆ET-1增高可能与机体应激有关,而CSF、ET-1升高可能与血脑屏障(BBB)被破坏及损害或刺激室周组织、下丘脑、脉络丛脑膜,引起分泌释放增加有关。CSF、ET-1增高者应警惕迟发性脑血管痉挛。 相似文献
75.
76.
Angela J. Drake-Holland Mark I. M. Noble Sara Pugh Christopher Mills 《Cardiovascular drugs and therapy / sponsored by the International Society of Cardiovascular Pharmacotherapy》1988,2(2):239-243
Summary In this study any changes in action potential duration or Q-T interval due to acute doses of ketanserin were monitored. The effect of a bolus dose (10 or 20 mg) followed by an infusion (10 or 20 mg over 20 minutes) of ketanserin on the Q-T interval and action potential duration was studied in six patients undergoing routine cardiac catheterization. Action potential duration was measured with a silver-silver chloride electrode catheter while heart rate was kept constant by atrial pacing and reflex effects avoided by -adrenergic blockade. There were some prolongations of the action potential duration but they were not in excess of 40 msec and did not reach statistical significance (control 263±46.0 msec; bolus 269±52.1 msec; infusion 262±53.6 msec; nor were there any significant changes in Q-T interval. Thus acute intravenous doses of ketanserin, in the absence of hypokalaemia or other Q-T interval-prolonging drugs, have no consistent effect on Q-T interval or action potential duration; prolongation of the action potential, when it occurs, is small. 相似文献
77.
The effects of an intracellular calcium antagonist HA 1077 on delayed cerebral vasospasm in dogs 总被引:9,自引:0,他引:9
M. Shibuya Y. Suzuki M. Takayasu T. Asano T. Harada I. Ikegaki S. Satoh H. Hidaka 《Acta neurochirurgica》1988,90(1-2):53-59
Summary The effectiveness of calcium antagonists on a chronic cerebral vasospasm after an SAH is still under debate. Calcium channel blockers such as nimodipine, nefedipine etc. can dilate spastic arteries by intrathecal administration, but not by systemic (iv or po) use. HA 1077 is a novel and potent calcium antagonist vasodilator which is considered to act by employing different mechanisms from the usual calcium channel blockers since it inhibits 1. calcium ionophore A 23187 induced contraction in arterial strips and 2. phenylephrine induced contraction in calcium free media, suggesting that its site of action is in the intracellular space. HA 1077 is water soluble and relatively stable in light.In the present study, the efficacy of HA 1077 was evaluated on dogs by using the spiral arterial strips in vitro and by angiography in vivo. In the arterial strips from the control dogs, a 50% relaxation of KCl (15 mM) induced contraction was obtained by a 10–6 M HA 1077 for the intracranial basilar and middle cerebral arteries, while a 10–5 M was needed to obtain the same effect for the extracranial common carotid and vertebral arteries, indicating that HA 1077 is more effective for the intracranial arteries. A vasospasm was produced by the two haemorrhage model of Varsoset al. The average angiographic diameter of the basilar artery was reduced to 60% of the control on SAH day 7. Intravenous infusion of HA 1077 (0.5–3 mg/kg/30 min) significantly dilated the spastic basilar artery (up to 20–30%), for over 2 hours. A fall in the systemic BP remained less than 20% during this time. Such spasmolytic effects by intravenous administration could not have been obtained with the usual calcium channel blockers. HA 1077 may be suitable for the treatment of a vasospasm in humans as well. 相似文献
78.
The DEFIANT RESEARCH GROUP 《European heart journal》1992,13(11):1496-1505
A multicentre, randomized, double-blind, placebo-controlled,parallel-group trial was undertaken in 135 patients to determinewhether 4 weeks of treatment with long-acting nisoldipine coat-core(20 mg once a day) could alter diastolic function in patientswith a recent myocardial infarction and with mild left ventriculardysfunction as indicated by a left ventricular ejection fraction50%. The primary endpoint was the change in diastolic fillingparameters assessed by Doppler and two-dimensional echocardiography. The mean time of admission to the study was 20 days (range 735)after myocardial infarction. Mean left ventricular ejectionfraction was 41%. The drug increased early diastolic peak velocityat the tips of the mitral leaflet by 0·06 m . s1(95% confidence intervals (CI): 0·01, 0·11). Thetime velocity integral was increased by 1·2 cm (95% CI:0·16, 2·27). These findings are indicative ofincreased early diastolic flow across the mitral valve. An importantdeterminant appeared to be a reduced isovolumic relaxation time(by 14·7 ms, 95% CI: -22·5, -6·9). As therewas no change in heart rate, systolic and diastolic blood pressureor cardiac output, after load reduction appeared unlikely asan explanation. Peak workload on exercise was 12 watts higherin the group on nisoldipine (95% CI: 0·8, 23·3).Thus, nisoldipine was shown to improve indices of diastolicventricular function, as well as exercise capacity, in thisgroup of patients. The observed effects of nisoldipine may reflectan anti-ischaemic effect or be due to improved relaxation ofthe myocardium. 相似文献
79.
A. K. Mir H. Berthold G. E. Scholtysik J. R. Fozard 《Naunyn-Schmiedeberg's archives of pharmacology》1989,340(4):424-430
Summary The present experiments were carried out to investigate the cardiovascular effects of endothelin 1 (ET) in pithed spontaneously hypertensive (SH) rats and to evaluate its mechanism of action. The results show that ET (0.1 – 3 nmol/kg i.v.) is a powerful vasoconstrictor agent in the pithed rat. However, at a dose of 3 nmol/kg i.v. all the pithed animals died following a gradual decrease in mean arterial blood pressure and pulse pressure and changes in the form of the electrocardiogram (ECG). The predominant feature of the change in the ECG was a progressive decrease in the amplitude of the T wave resulting in a depression of the curve representing repolarization. Investigations in isolated perfused SH rat hearts showed that ET powerfully reduces coronary flow concentration-dependently (IC50 2.1 ±0.3 nM) an effect associated with sinus bradycardia and a decrease in coronary pressure amplitude. No overt ECG changes were seen. Control experiments with mechanical flow restriction suggest that bradycardia is a consequence of reduced coronary flow and that the ECG changes observed in vivo can be explained on the basis of coronary insufficiency and resulting myocardial hypoxia. Vasoconstrictor responses to angiotensin II (0.4 g/kg i.v.), phenylephrine (8 g/kg i.v.) and ET (0.5 nmol/kg i.v.) were antagonised by around 70% by isradipine (0.03 mg/kg i.a.). The results suggest that endothelin-induced vasoconstriction may involve receptor operated channel activation and opening of voltage sensitive Ca2+ channels.Send offprint requests to A. K. Mir at the above address 相似文献
80.
Spahn Hildegard Wellstein Anton Pflugmann Gabriele Mutschler Ernst Palm Dieter 《Pharmaceutical research》1989,6(2):152-155
Plasma concentrations of metoprolol after acute and repetitive administration of R/S-metoprolol to healthy volunteers were measured by a -adrenoceptor subtype-specific radioreceptor assay (RRA) and by an enantiospecific high-performance liquid chromatographic (HPLC) method. In the RRA, R/S-metoprolol showed a 20-fold 1-subtype selectivity: the S-( – )-enantiomer was 35-fold more potent than the R-( + )-enantiomer. A comparison between S-( – )-metoprolol concentrations detected in the plasma samples by HPLC and those detected by RRA yielded a 1/1 relationship, indicating that active metabolites are not present to a significant extent. These results were independent of the widely scattering metabolic clearance of metoprolol (with the potential of differences in the rate and extent of formation of active metabolites) in the volunteers. In general, HPLC methods can be validated by comparison with RRA in order to clarify whether active metabolites are present and—on the basis of the Ki value from RRA—whether the detection limit of the physicochemical procedure is sufficient to cover the therapeutically relevant range. 相似文献