General pharmacology最新文献

1. Cerebrovascular permeability estimated as Evans blue extravasation significantly increased during insulin-induced hypoglycemia in both non-diabetic and diabetic rat groups. 2. Cerebrovascular permeability also increased significantly during 2-deoxy-glucose-induced intracellular glycopenia in both groups. 3. When a blood glucose level was fixed, cerebrovascular permeability showed no more significant change despite the hyperinsulinemic state in both groups. 4. Results suggest that hypoglycemia and/or intracellular glycopenia seems to be the major factor for increases in cerebrovascular permeability.

1. In the present study, the contractile effects of acetylcholine (Ach) were investigated in isolated tracheal strips obtained from insulin-dependent (ID) and non-insulin-dependent (NID) diabetic rats. 2. The maximum responses to Ach were significantly decreased in 5-6 week ID diabetic rat tracheal segments compared with those from controls but, the sensitivity (pD2 values) of ID diabetic tracheas to Ach were not significantly altered relative to corresponding controls. 3. Tracheas isolated from 11-12 week NID diabetic rats exhibited reduced maximal contractile effect of Ach and also sensitivity (pD2 values) of NID diabetic tracheas to Ach were significantly decreased when compared to control rat tracheas. 4. Insulin treatment of both group of diabetic rats for 10 days corrected the changes observed in diabetic tracheas.

1. In rat aorta, 2,3-dibenzylbutane-1,4-diol (DBB) inhibited noradrenaline (NA)-induced contraction in a concentration-dependent manner. The inhibitory effect of DBB was observed in verapamil-pretreated muscle, and did not differ from that in the high K+ solution containing verapamil (1.0 microM). 2. DBB inhibited not only contraction, but [Ca2+]i elevation induced by NA (10 microM) with the same potency. 3. The inhibitory effect of DBB on NA-induced contraction was reversed by methylene blue (3.2 microM) and enhanced by M&B 22,948 (10 microM). 4. DBB (100 microM) alone increased cyclic GMP levels. This effect was attenuated by methylene blue (3.2 microM) and augmented by M&B 22,948 (10 microM). 5. From these results, the inhibitory effects of DBB on NA-induced contraction in rat aorta may be caused by an increase of cyclic GMP levels.

1. In order to determine whether the degree of tolerance to and physical dependence on morphine induced by pellet implantation procedure in the rat depends on the dose used and the kinetic parameters, the effect of implantation of different number of pellets on tolerance-dependence and elimination kinetics of morphine from serum was determined. 2. Male Sprague-Dawley rats were implanted subcutaneously with pellets. Each pellet contained 75 mg of morphine free base. Three schedules of implantation were used. They included 2 pellets during a 3-day period (2/3), 4 pellets during a 3-day period (4/3) and 6 pellets during a 7-day period (6/7). Placebo pellets which did not contain morphine were implanted in rats which served as controls. 3. The degree of tolerance to and physical dependence on morphine increased as the number of morphine pellets implanted increased. 4. In separate groups of rats implanted with pellets, elimination kinetics of morphine was studied using radioimmunoassay. The kinetic parameters were: area under serum morphine concentration time curve (AUC0----infinity), serum concentration of morphine extrapolated to time zero (Cmax), half-life (t1/2), elimination rate constant (k), mean residence time (MRT) and total body clearance (Clt). 5. The AUC0----infinity and Cmax increased in proportion to the number of pellets implanted. The t1/2, k, MRT and Clt values for 2/3 and 4/3 schedules did not differ, but for 6/7 schedule were significantly different from the other two schedules. The degree of tolerance to and physical dependence on morphine was directly related to the AUC0----infinity and Cmax. The longer t1/2 and MRT and lower Clt and k values in 6/7 schedule may reflect a saturation of glucuronic acid transferase, the main enzyme metabolizing morphine in the liver, and may account for the greater degree of tolerance and physical dependence.

1. The catalepsy induced by dopamine antagonists has been tested and the possible dopamine subtypes involved in catalepsy was determined. 2. Dopamine antagonist fluphenazine, D-1 antagonist SCH 23390 or D-2 antagonist sulpiride induced catalepsy. The effect of fluphenazine and sulpiride was dose-dependent. Combination of SCH 23390 with sulpiride did not induce catalepsy potentiation. 3. D-1 agonist SKF 38393 or D-2 agonist quinpirole decreased the catalepsy induced by fluphenazine, SCH 23390 or sulpiride. 4. Combination of SKF 38393 with quinpirole did not cause potentiated inhibitory effect on catalepsy induced by dopamine antagonists. 5. The data may indicate that although D-2 receptor blockade is involved in catalepsy, the D-1 receptor may plan a role.

1. Comparisons were made between the doses required of aerosol and intraperitoneally administered morphine, dextromethorphan, codeine and the specific peripherally acting mu-receptor agonist DALDA (H-Tyr-D-Arg-Phe-Lys-NH2) to suppress citric acid-induced coughing in conscious guinea pigs. 2. Estimated ID50s for inhibition of numbers of coughs induced by an aerosol of 5% citric acid were 1.0 and 2.4 mg/kg for intraperitoneally administered morphine and dextromethorphan, respectively. 3. The estimated ID50s after inhalation of morphine and dextromethorphan as aerosols were approximately 2.2 and approximately 12 micrograms/kg, respectively. 4. Aerosilized codeine (approximately 72 micrograms/kg, n = 5) significantly inhibited coughing by 62 +/- 23% whereas 3 mg/kg, i.p. was required to significantly reduce coughing by a similar degree (60 +/- 6%, n = 7). 5. Inhalation of DALDA (approximately 7.2 micrograms/kg, n = 7) also significantly inhibited coughing. 6. The antitussive effect of inhaled morphine (approximately 7.2 micrograms/kg, n = 11) was inhibited after administration of 3 mg/kg of either naloxone hydrochloride or naloxone methylbromide intraperitoneally. 7. The results support the hypothesis that effects at a peripheral site can make a major contribution to the antitussive actions of these drugs.

1. The binding activity of 5-HT1 receptors was studied in membrane fractions from the cerebral cortex and hippocampus of male Wistar rats treated orally for 13 days with the Ca(2+)-antagonists nifedipine (20 mg/kg), verapamil (50 mg/kg) and flunarizine (10 mg/kg) and with the calmodulin antagonist trifluoperazine (3 mg/kg). 2. The binding capacity and affinity of the 5-HT1 receptors in the cerebral cortex were significantly decreased after the treatment with the Ca(2+)-antagonists nifedipine, verapamil and flunarizine. The dissociation constant (Kd) was increased after the treatment with the calmodulin antagonist trifluoperazine. 3. In the hippocampus the 5-HT1 receptor affinity and number of binding sites were significantly reduced after the treatment with all four antagonists tested--nifedipine, verapamil, flunarizine and trifluoperazine, the Kd value being increased insignificantly after the flunarizine treatment. 4. The results obtained afford the suggestion that the reduction of 5-HT1 receptor activity is at least one of the results of the well known Ca(2+)-ions mediated automodulation of 5-HT release. The data confirm the view about the great importance of Ca(2+)-ions for the regulation of membrane neurotransmitter receptor activities.