Pentobarbital-like discriminative stimulus effects of direct GABA agonists in rats

The discriminative stimulus effects of direct and indirect-acting GABAergic drugs were investigated in rats trained to discriminate 5 mg/kg pentobarbital (PB) from saline under a two-lever fixed ratio (FR) 32 schedule of food reinforcement. PB and diazepam produced dose-dependent substitution for the training dose of PB with response rate reduction only at doses above those producing full substitution. Muscimol, thiomuscimol and 4,5,6,7-tetrahydroisoxazolo [5,4-c]-pyridin-3-ol (THIP) produced intermediate levels of pentobarbital-lever responding (40–60%), accompanied by dose-dependent decreases in rates of responding following THIP and muscimol administration. The GABA_A agonist progabide and its metabolite 4-{[(4-chlorophenyl) (5-fluoro-2-hydroxyphenyl)methylene]amino}] butyric acid (SL 75102) also partially substituted for PB, producing means of 39–73% PB-lever responding. The GABA_B agonist, baclofen, completely failed to substitute for PB even at doses that decreased rates of responding. These results show that the discriminative stimulus effects of indirect GABA_A agonists, PB and diazepam, although similar to one another, differ from those of direct GABA_A receptor agonists, which produced only partial substitution for PB. The GABA_B agonist, baclofen, can be distinguished by lacking any ability to substitute for PB. These results contribute to a further understanding of the similarities and differences in the behavioral effects of different types of GABA agonists.     

慢性阻塞性肺疾病急性加重与呼吸道病毒感染的研究进展

慢性阻塞性肺疾病(COPD)是一种呼吸道常见的炎症性疾病,是全世界发病率和病死率较高的疾病之一。慢性阻塞性肺疾病急性加重(AECOPD)是其过程中的重要事件,常导致患者生活质量下降,病死率升高。呼吸道病毒感染与AECOPD密切相关。AECOPD的患者病毒感染具有多样性、季节性及地域性等特点。呼吸道病毒感染可通过活化炎症细胞及介质,参与免疫反应使COPD加重。各种各样的病毒感染对AECOPD的影响及机制可能不同,需要进一步研究。     

Triiodothyronine-induced changes in function,metabolism and weight of the rat heart: Effects of α- and β-adrenergic blockade

Summary The involvement of α- and β-adrenergic receptors in the triiodothyronine (T₃)-induced hemodynamic and metabolic alterations and in the development of cardiac hypertrophy was analyzed in time-course studies. Female Sprague-Dawley rats received daily injections of T₃ (200 μg/kg s.c) and a continuous i.v. infusion of 0.9% NaCl or α- or β-receptor blocking agents. NaCl-injected animals served as controls. Eighteen hours after T₃ administration, heart rate and LV dP/dt_max were considerably elevated. Cardiac output (CO) was not significantly changed. These alterations were abolished by simultaneous infusion of the β-adrenergic blocker metoprolol. After 48 h, CO as well as the cardiac RNA concentration were markedly elevated. The rise in LV dP/dt_max and heart rate was similar to the 18-h-value and was prevented by metoprolol. However, metoprolol did not influence the increase in CO and RNA concentration. Likewise, after 72h, metoprolol antagonized the T₃-induced increase in heart rate and LV dP/dt_max, but had no effect on the elevation of CO and RNA concentration, the enhancement of adenine nucleotide synthesis and cardiac hypertrophy. Like metoprolol, the α-adrenergic blocker prazosin did not influence the T₃-evoked cardiac hypertrophy. Thus, the development of cardiac hypertrophy in this model can occur independently of α- and β-adrenergic stimulation.     

白三烯拮抗剂ONO-1078对小鼠局灶性脑缺血的保护作用

AIM　To determine whether ONO-1078 {pranlukast, 4-oxo-8-［p-(4-phenylbutyloxy) benzoyl-amino]-2-(tetrazol-5-yl)-4H-1-benzopyran hemihydrate}, a potent leukotriene antagonist, has protective effect on focal cerebral ischemia in mice. METHODS　Focal cerebral ischemia was induced by permanent middle cerebral artery (MCA) occlusion in mice. ONO-1078 (0.01, 0.05, 0.10 mg·kg^-1), dexamethasone (0.5 mg·kg^-1), nimodipine (0.2 mg·kg^-1) or saline (control) were injected ip once daily for 3 days, and 30 min before MCA occlusion. Twenty-four hours after cerebral ischemia, the neurological scores were evaluated, infarct volumes and areas of the right and left cerebral hemispheres were measured by computer imaging analysis. RESULTS　ONO-1078, dexamethasone and nimodipine reduced the neurological scores. ONO-1078 and dexamethasone reduced the ratio of right/left hemisphere area, indicating inhibition of brain edema, while nimodipine showed no effect. ONO-1078 dose-dependently reduced infarct size, and dexamethasone and nimodipine showed the same effect. CONCLUSION　ONO-1078 showed protective effect on focal cerebral ischemia. This may represent a novel approach to the treatment of acute cerebral ischemia.     

Effect of epidural clonidine on minimum local anesthetic concentration (ED50) of levobupivacaine for caudal block in children

Background: Clonidine has the potential to significantly prolong the duration of caudal epidural anesthesia. We investigated the effect of the addition of clonidine to the MLAC of levobupivacaine in a randomized controlled dose–response trial. Methods: A group of 120 children aged <6 years of age received caudal anesthesia with levobupivacaine and 1, 2, or 3 μg·kg^?1 of clonidine. The MLAC was determined according to a Dixon‐Massey protocol. The primary outcome was effective surgical anesthesia. Secondary outcomes were the duration of postoperative analgesia, postoperative pain scores, clonidine side effects, and time to hospital discharge. Results: The MLAC of caudal levobupivacaine was 0.106%, 0.077%, and 0.035% with 1, 2, and 3 μg·kg^?1 of clonidine, respectively. There were significant dose‐dependent increases in median duration of analgesia. The incidence of delayed discharge, somnolence, and PONV was significantly increased in the 3 μg·kg^?1 of clonidine group. Conclusions: Clonidine produces a local anesthetic sparing effect with a dose‐dependent decrease in levobupivacaine MLAC for caudal anesthesia. In addition, there is a dose‐dependent prolongation of postoperative analgesia following lower abdominal surgery in children. A dose of 2 μg·kg^?1 of clonidine provides the optimum balance between improved analgesia and minimal side effects.     

Body cooling attenuates the decrease in maximal oxygen uptake associated with cardiovascular drift during heat stress

Previous research suggests cardiovascular drift (CV drift) is associated with decreased maximal oxygen uptake [Formula: see text] during heat stress, but more research manipulating CV drift with subsequent measurement of [Formula: see text] is needed to assess whether this relationship is causal. To assess causation, [Formula: see text] was measured during the same time interval that CV drift occurred (between 15 and 45 min of submaximal exercise under different conditions of body cooling intended to manipulate CV drift). Ten men completed a control graded exercise test (GXT) in 22 degrees C to measure [Formula: see text] then on separate occasions they cycled in 35 degrees C at 60% [Formula: see text] for 15 min (15 max), 45 min with no cooling (NC), and 45 min with fan airflow (FAN) beginning at approximately 18 min into exercise, and each bout was immediately followed by a GXT to measure [Formula: see text] In NC, [Formula: see text] decreased 18%, heart rate (HR) increased 16%, and stroke volume (SV) fell 12% (P < 0.05) from min 15 to min 45. In FAN, [Formula: see text] fell less (5.7%, P < 0.05) , HR rose less (4%, P < 0.05) and SV decreased less (3%, P < 0.05) from 15 to 45 min. The fall in [Formula: see text] associated with CV drift during exercise in a hot environment is attenuated with body cooling via fan airflow. The findings support the notion that a causal link exists between CV drift that occurs during prolonged exercise in a hot environment and a decrease in [Formula: see text].