摘要:

A topical application of 12-0-tetradecanoylphorbol-13-acetate (TPA) to mouse ear surface induces nonallergic inflammation, i.e. ear edema. Oral administration of 3-30 mg/kg of l-{[5’-(3”-methoxy-4”-ethoxycarbonyloxyphenyl)-2’,4’-pentadienoyl]aminoethyl}-4-diphenylmethoxypiperidine (TMK 688), a potent 5-lipoxygenase inhibitor with antihistamine activity, inhibited TPA-induced ear edema in a dose-dependent manner. TMK688 inhibited not only 5-lipoxygenase activity but also epidermal cyclooxygenase activity. 1 – {[ 5 ‘ (3 “ methoxy – 4”-hy droxyphenyl) – 2’, 4’- pentadienoyl] -aminoethyl}-4-diphenylmethoxypiperidine (TMK777), an active metabolite of TMK688, had more potent 5-lipoxygenase inhibitory activity but less potent cyclooxygenase inhibitory activity than TMK688. Oral administration of TMK688 (30 mg/kg) markedly inhibited TPA-stimulated LTB4 formation in mouse skin but TPA-stimulated PGE2 formation only slightly. Our experimental results suggest that both cyclooxygenase inhibitory activity and antihistamine activity of TMK688 are not essential to its anti-inflammatory action. The anti-inflammatory effect of orally administered TMK688 is due most probably to the anti-5-lipoxygenase activity of TMK688 and its

ISSN:0031-7012    

DOI:10.1159/000139190

出版商:S. Karger AG    

年代:1994

数据来源: Karger

摘要:

In ferrets, the highly selective 5-HT3 receptor antagonist, granisetron, abolished or reduced emesis induced by cisplatin (10 mg/kg i.v.) or whole body X-irradiation (50 Gy in 10.4 min) in a dose-dependent manner when administered by a variety of routes (intravenous, per os, subcutaneous, intramuscular). Complete protection from vomiting and retching was achieved with 0.5 mg/kg i.v. or p.o. granisetron. Granisetron (0.5 mg/kg i.v.) was also effective when given 6 h before cisplatin, completely protecting 50% of ferrets for a total of 10 h. Following repeat dosing, for either 4 days i.v. or 10 days p.o. before emetic challenge, granisetron (0.5 mg/kg) still retained its antiemetic activity on the 5th or 11th day. Prior treatment with cyclophosphamide (80 mg/kg i.v.) resulted in a significantly shorter time to the onset of vomiting after exposure to X-irradiation. Granisetron, but not saline, abolished vomiting and nausea when given as intervention after this combined emetic regimen. These results show that granisetron has potential flexibility for administraton via a variety of different routes and also a long duration of action when used as an antiemetic against a wide range of cytostatic agents.

ISSN:0031-7012    

DOI:10.1159/000139191

出版商:S. Karger AG    

年代:1994

数据来源: Karger

摘要:

The affinity of amitriptyline for muscarine M1 receptors was studied in the rat cerebral cortex and rabbit vas deferens utilizing binding studies as well as inhibition of carbachol-induced phosphoinositide hydrolysis in the cerebral cortex and blockade of the muscarinic prejunctional inhibition of sympathetic nerve stimulation in the rabbit vas deferens. The inhibition constants (K1) or dissociation constants (Kb) obtained were approximately 6- to 20-fold lower than those obtained at muscarine M2 receptors in rat atria (binding and negative inotropic response) indicating that amitriptyline exhibits a degree of muscarine M1 receptor selectivity.

ISSN:0031-7012    

DOI:10.1159/000139192

出版商:S. Karger AG    

年代:1994

数据来源: Karger

摘要:

We studied the effect of cilostazol, a cyclic nucleotide phosphodiesterase (PDE) III inhibitor, on a substance P (SP)-induced increase in lung resistance and in airway microvascular leakage in guinea pigs in vivo. Four minutes after intravenous (i.v.) administration of cilostazol (1.5 and 5 mg/ kg) or vehicle, Evans blue dye (20 mg/kg) was given i.v. One minute later, 30 nmol/kg SP was administered i.v. The SP-induced increase in lung resistance was measured for 6 min. Following the measurement of lung resistance, microvascular leakage at the trachea, main bronchi and intra-pulmonary airways was also examined. Cilostazol attenuated the SP-induced increase in lung resistance, with a significant inhibition at the concentration of 5 mg/kg. Five milligrams per kilogram cilostazol also significantly inhibited SP-induced Evans blue dye extravasation at the trachea and main bronchi. These results suggest that cilostazol might reduce airflow obstruction which is seen in diseases such as asthma through attenuation of bronchoconstriction and, possibly, airway edema resulting from airway microvascular leakage in man.

ISSN:0031-7012    

DOI:10.1159/000139193

出版商:S. Karger AG    

年代:1994

数据来源: Karger

摘要:

The effects of the specific bradycardic agent, zatebradine (UL·FS 49), on ventricular arrhythmias occurring during an acute ischemia were compared to those of verapamil. Anesthetized rabbits were submitted to a ligation of the left circumflex coronary artery for 20 min. Zatebradine (150 and 750 µg/kg, i.v.) dose-dependently reduced heart rate, but changed neither the left ventricular pressure nor the (+)dp/dtmax. In comparison, verapamil (150 and 750 µg/kg, i.v.) reduced heart rate, systemic blood pressure, left ventricular pressure and (+)dp/dtmax. The incidence of ventricular premature beats occurring during acute ischemia was changed neither by zatebradine nor by verapamil. Ventricular fibrillation, occurring in 36% of the saline-treated rabbits, was reduced to 18% in the presence of 750 µg/kg of zatebradine and 0% with verapamil (750 µg/kg, p < 0.05). The action of zatebradine on ischemia-induced ventricular fibrillation, albeit limited, was completely reversed by atrial pacing to the predrug heart rate. To further investigate the mechanisms involved in the antiarrhythmic potential of both zatebradine and verapamil, their electrophysiological actions were compared in canine Purkinje fibers. Both zatebradine and verapamil induced a dose-dependent increase in action potential duration (APD) measured at 90% repolarization. The APDs measured during the plateau level (APD30) and at 50% of the repolarization (APD50) were shortened by verapamil and increased by zatebradine showing that at the concentrations used, zatebradine did not exhibit any calcium antagonistic activity when compared to verapamil. The results of the present study suggest that the specific bradycardic agent zatebradine showed a beneficial action mainly because of its anti-ischemic properties. However, the present studies performed in anesthetized rabbits suggest that in this species pure reduction in heart rate is not sufficient to entirely prevent ischemic arrhyth

ISSN:0031-7012    

DOI:10.1159/000139194

出版商:S. Karger AG    

年代:1994

数据来源: Karger

摘要:

The main objective of the present investigation was to determine whether the uptake of [3H]-dopamine in human lymphocytes is mediated through a serotonin transporter. This was examined by studying the effects of various monoamine uptake inhibitors on the uptake of [3H]-dopamine in human lymphocytes. Among the compounds tested, indatraline, imipramine and fluoxetine, selective inhibitors of neuronal serotonin transporter, were the most potent inhibitors of [3H]-dopamine uptake in lymphocytes. The 50% inhibiting concentration (IC50) for these inhibitors was in the range of 3.5-17 nmol/l. Bupropion, GBR 12909, nomifensine and xylamine, selective inhibitors of dopamine and norepinephrine transporters, had low affinity for the dopamine uptake system in human lymphocytes with IC50 values ranging between 1,000 and 40,000 nmol/l. These findings provide supportive evidence for the participation of a serotonin transporter in the uptake of [3H]-dopamine in human lymphocytes. The existence of a high affinity transport system for dopamine and serotonin in human lymphocytes may serve as a readily accessible model to detect changes in the neuronal uptake of dopamine and serotonin in addictive and psychiatric disorders.

ISSN:0031-7012    

DOI:10.1159/000139195

出版商:S. Karger AG    

年代:1994

数据来源: Karger

摘要:

The contractile effect of dopamine in the rat isolated seminal vesicle was investigated to determine the nature of the receptors involved. Noradrenaline (NA; 10–8 to 10–4 mol/l), phenylephrine (PE; 10–7 to 10–4 and dopamine (DA; 10–5 to 10–2 mol/l) produced concentration-dependent contractions with no sign of tachyphylaxis. The relative potencies of NA:PE:DA derived from their EC50 values were 1:0.23:0.01. However, while NA and PE produced similar maximal contractions, the Emax obtained with DA was significantly less (intrinsic activity = 0.066). Depletion of tissue catecholamine stores by pretreating rats with reserpine did not significantly influence the responses of the seminal vesicle to DA or PE. Moreover, cocaine (10–5 mol/l) did not significantly affect the course of the concentration-response curve to DA. Prazosin (10–9 to 10–8 mol/l), phentolamine (10–7 to 10–6 mol/l), haloperidol (10–7 to 10–6 mol/l) and yohimbine (10–6 to 10–5 yohimbine. In addition, phenoxybenzamine (10–8 mol/l) produced a rightward shift of the concentration-response curves for both NA and DA. The displacement was greater in the case of DA, of which the maximum response was also reduced by 45%. Sulpiride (10–6 to 10–5 mol/l) had no effect on the concentration-response curves of either PE or DA. Similarly, apomorphine (10–6 mol/l) neither produced contraction on its own nor influenced those of PE or DA. These results taken together indicate that the contractile effect of DA in the rat isolated seminal vesicle is mediated through activation of postjunctional α1-adrenoceptors without involvement of specific DA

ISSN:0031-7012    

DOI:10.1159/000139196

出版商:S. Karger AG    

年代:1994

数据来源: Karger

摘要:

Pharmacologic and behavioral effects of alcohol on male sexual activity have long been controversial. Among the varied effects of alcohol, it has been described that ethanol reduces nitric oxide production. Appreciating the importance of nitric oxide-mediated regulation of corporal smooth muscle, this study was designed to investigate the in vitro pharmacologic effect of 1-5% ethanol on rabbit corpus cavernosum function. The results are summarized as follows. In isolated organ bath experiments, basal resting tension of corporal strips was significantly reduced with 3 and 5% ethanol exposure. Relaxation induced by field stimulation over a frequency range of 2-16 Hz was significantly decreased with 3 and 5% ethanol exposure. However, field-stimulated contraction at 32 Hz was reduced by 5% ethanol only. When corporal strips were prein-cubated with phenylephrine, 3 and 5% ethanol significantly inhibited field stimulated relaxation at all frequencies. Both phasic and tonic contraction induced by phenylephrine was significantly suppressed by 3 and 5% ethanol. KCl-induced contraction was decreased by 5% ethanol. ATP-induced relaxation was significantly enhanced by 1, 3 and 5% ethanol. Bethanechol-induced relaxation was significantly suppressed by 1, 3 and 5% ethanol. Direct nitroprusside-induced relaxation was not affected by any concentration of ethanol administration. These results demonstrated that ethanol had significant effects on both contraction and relaxation of rabbit corpus cavernosum. In general, corporal relaxation mediated through the acetylcholine-L-arginine-nitric oxide pathway was significantly more sensitive to ethanol than either ATP- or nitroprusside-induced relaxation.

ISSN:0031-7012    

DOI:10.1159/000139197

出版商:S. Karger AG    

年代:1994

数据来源: Karger