Blood pressure and vascular reactivity to endothelin-1, phenylephrine, serotonin, KCl and acetylcholine following chronic alcohol consumption in vitro.

Ethanol has been reported to cause hypertension, the mechanism of which is unknown. Therefore, the effect of chronic ethanol consumption on vascular responsiveness and blood pressure was investigated. Systolic blood pressure was recorded weekly by tail-cuff method. Aortic rings from rats fed chow ad libitum or pair-fed liquid diets containing either ethanol (7.2% v/v) or isocaloric carbohydrate for 4 weeks were placed in organ chambers for isometric tension measurement. There was a mild but significant elevation of the systolic blood pressure in the alcohol-fed rats by week 1 compared to baseline measurements and this remained higher. No significant changes in reactivity of rat isolated aortas to phenylephrine, serotonin, endothelin-1 (ET-1) and KCl were seen in chronic ethanol consumption. In addition, the sensitivity (i.e. pD2) of alcohol-fed aortic rings to the vasoconstrictors was also unchanged compared to controls. Chronic ethanol consumption, however, increased relaxation to acetylcholine with increased pD2 values, but did not alter relaxation to sodium nitroprusside, a cyclic guanosine monophosphate (cGMP)-dependent direct smooth muscle dilator. The results indicate that chronic ethanol consumption significantly potentiates endothelium-dependent relaxations in aortic rings, probably through interference with the production and/or the release of nitric oxide (NO) or adaptive alterations in muscarinic receptors on the endothelial cells, and that increased vascular responsiveness to several vasoconstrictors is not a mechanism responsible for the blood pressure elevation in the chronic alcohol consumption in rats.

The effect of long-term ethanol feeding on Brucella melitensis infection of rats.

The adverse effects of ethanol on Brucella melitensis have not been studied previously. In this study, a new model of B. melitensis infection was used in the setting of chronic ethanol administration in rats. It was found that the chronically ethanol-receiving rats exposed to B. melitensis infection had significantly greater numbers of B. melitensis in their spleen and liver than the rats in the control group.

Antidepressant, anxiogenic, and antinociceptive properties of levofloxacin in rats and mice.

Levofloxacin, an optically active isomer of ofloxacin, is a fluorinated quinolone with a broad spectrum of antibacterial activity. Fluoroquinolones have been used for the treatment of bacterial infections for many years. Although they were considered as relatively safe drugs, various adverse effects have recently been reported along with increase in the usage of new-generation fluoroquinolones. In the present study, some of the central nervous system (CNS)-related side effects of levofloxacin were clarified in animals. Our results suggested that: levofloxacin (10-20-40 mg/kg i.p.) had no depression-like effect in the forced swimming test (FST) in rats; exerted anxiety-like effect in the elevated plus maze test in rats; did not alter the locomotor activity in rats; had no apparent effect on sleep latency but shortened the sleeping time on pentobarbital sleeping time in mice; and showed analgesic activity in acetic acid writhing and hot plate test in mice.

Antidepressant-like effect of 7-nitroindazole in the forced swimming test in rats.

RATIONALE: There is some strong evidence about the role of nitric oxide (NO) as an intercellular messenger in central physiological mechanisms. NO is synthesized from L-arginine by nitric oxide synthase (NOS), as a response to activation of N-methyl-D-aspartate (NMDA) receptors by excitatory amino acids. NMDA receptor antagonists also produce antidepressant-like actions in preclinical models. OBJECTIVE: In the present study, the involvement of NO in the mechanism of depression was investigated. 7-Nitroindazole (7-NI) (15, 30, 60, 90 mg/kg IP), a selective inhibitor of neuronal NOS was examined. METHODS: The Porsolt forced swimming test (FST) has been used as a test for screening new antidepressant agents. RESULTS: 7-NI dose-dependently decreased the immobility time in FST, but produced no significant change in locomotor activity in naive rats. Neither L-arginine, nor D-arginine (100 mg/kg) affected the immobility time in the FST or revealed any effect on locomotion. L-Arginine but not D-arginine, given 10 min before 7-NI, reversed the 7-NI-induced effect on immobility time. CONCLUSIONS: Our findings suggest that NO might be an important modulator of depression in rats.

Anxiolytic-like effects of 7-nitroindazole in the rat plus-maze test.

It is considered that nitric oxide (NO) is one of the most interesting research subjects. Because the actual role of NO in the mechanism of anxiety is still unclear, in this study, the involvement of NO in the mechanism of anxiety was investigated, using the plus-maze test. 7-Nitroindazole (7-NI) (15, 30, 60, 90, and 120 mg/kg), a new nitric oxide synthase (NOS) inhibitor was studied. The time spent on open arms and open-arm visits was evaluated. 7-NI, at 15-120 mg/kg doses potently increased the time spent on open arms and open-arm visits. However, at 120 mg/kg it attenuated the time spent on the open arms, compared to at 90 mg/kg. This effect was attributed to decreased locomotor activity in the higher dose group. Neither L-arginine, nor D-arginine (100 mg/kg) significantly affected any of the behavioral parameters measured in the rat elevated plus-maze test. Neither drugs revealed any effect on locomotion. L-Arginine but not D-arginine given 10 min before 7-NI, reversed the 7-NI induced anxiolytic-like effects. These data support an involvement of NO in the process of anxiety, and further suggest that the anxiolytic-like effect of 7-NI may be attributable to the inhibition of NO synthesis.

Dextromethorphan attenuates ethanol withdrawal syndrome in rats.

The effects of dextromethorphan (DM), a noncompetitive antagonist of the N-methyl-D-aspartate (NMDA) receptors, have been investigated on ethanol withdrawal signs in rats. Ethanol (7.2% v/v) was given to rats in a liquid diet for 16 days. DM (10, 20, and 40 mg/kg) and saline were injected intraperitoneally at the third hour of ethanol withdrawal. DM (40 mg/kg) and ethanol dependent saline were also administered to ethanol naive rats. DM (40 mg/kg) did not produce any significant change in locomotor activity in ethanol naive rats. The effects of DM on locomotor activity and total ethanol withdrawal score were evaluated at the fourth and sixth hours of ethanol withdrawal. DM inhibited locomotor hyperactivity at these periods. DM also reduced total ethanol withdrawal score from the fourth hour to the sixth hour, and it significantly decreased audiogenic seizures. Seizure susceptibility after chronic ethanol exposure may be dependent upon sensitization or upregulation of NMDA processes and NMDA receptors. Our results suggest that inhibition of NMDA receptors by DM alleviates signs of ethanol withdrawal.

Nitric oxide synthase inhibition attenuates signs of ethanol withdrawal in rats.

The effects of N(G)-nitro arginine methyl ester (L-NAME) and 7-nitroindazole (7-NI), nitric oxide synthase inhibitors, and L-arginine, a nitric oxide precursor, on ethanol withdrawal signs were investigated in rats. Ethanol (7.2% v/v) was given to rats by a liquid diet for 16 days. L-NAME (30 and 60 mg/kg), 7-NI (40 and 80 mg/kg), L-arginine (100 mg/kg), a combination of L-arginine (100 mg/kg) and 7-NI (40 mg/kg), and saline or vehicle were injected to rats intraperitoneally 30 min before ethanol withdrawal. A second series of injections was given at 6 hour after the first one, and subjects were then tested for audiogenic seizures. 7-NI (40 mg/kg), vehicle and saline were also administered to naive rats. 7-NI (40 mg/kg) did not produce any significant change in locomotor activity in naive rats. Both L-NAME and 7-NI significantly inhibited locomotor hyperactivity from the 2nd to the 6th hour of the withdrawal period. They also reduced the total ethanol withdrawal score from the 30th min to the 6th hour, and they significantly decreased audiogenic seizures. Neither drug increased locomotor activity nor total ethanol withdrawal score, which were increased significantly by L-arginine (100 mg/kg); however, L-arginine (100 mg/kg) prevented the inhibitory effects of 7-NI (40 mg/kg) on increased locomotor activity, total ethanol withdrawal score, and audiogenic seizure. Our results suggest that nitric oxide synthase inhibition by L-NAME and 7-NI alleviates the signs of ethanol withdrawal. The data also support the hypothesis that nitric oxide may take part in the neuroadaptation that develops during chronic ethanol ingestion in rats.

The effect of 7-nitro indazole on pentobarbital-induced sleep in mice.

The sleep-wakefulness continuity is sensitive to a wide range of agents with pharmacological activity. There is some strong evidence about the role of nitric oxide (NO) as an intercellular messenger in the central physiological mechanisms. The effects of 7-nitro indazole (7-NI 15, 30, 60 mg kg-1; intraperitoneal, i.p.), a selective inhibitor of neuronal nitric oxide synthase (NOS) and L-arginine (500, 1000 mg kg-1, i.p.), a NO precursor, on pentobarbital (35 mg kg-1, i.p.) sleep were examined in mice. Loss of the righting reflex was used to determine the start of sleep. Sleep latency and sleeping time were evaluated in each experiment. 7-Nitro indazole (7-NI 30 mg kg-1; i.p.), had no apparent effect on sleep latency but significantly increased sleeping time (P < 0.02) on pentobarbital sleep in mice. L-Arginine had no effect on both parameters. These findings suggest that NO might be an important modulator of sleep regulation and implicate that inhibition of release and/or synthesis of NO might lead to changes in the maintenance of sleep.