LPS-induced blood neutrophilia is inhibited by alpha 1-adrenoceptor antagonists: a role for catecholamines.

A role for catecholamines in the regulation of the blood neutrophilia induced by intravenous (i.v.) injection of lipopolysaccharide (LPS; 250 micrograms/kg) was examined in Wistar rats by means of surgical adrenalectomy or pretreatment with adrenergic and dopaminergic antagonists into naive animals. Treatment of animals with a single dose (250 micrograms/kg) of LPS caused a dramatic increase in the number of circulating neutrophils concomitant with a decrease in the number of these cells in the bone marrow. These effects were partially reversed when catecholamine stores were depleted with reserpine. It was found that neither adrenalectomy nor pretreatment with the dopaminergic antagonists, chlorpromazine and pimozide, affected the changes in neutrophil counts induced by LPS. The injection of the alpha 1/alpha 2-adrenoceptor antagonist, phentolamine, and the selective alpha 1-adrenoceptor antagonist, prazosin, significantly decreased blood neutrophilia induced by LPS. However, neither the selective alpha 2-adrenoceptor antagonist, yohimbine, nor the beta-adrenoceptor antagonist, propranolol, had any effect on LPS response. Taken together, these findings support the hypothesis that the catecholamine norepinephrine plays a role in the regulation of the LPS-induced neutrophilia through activation of alpha 1-adrenoceptors.

A role for adrenoceptors in the regulation of pleural neutrophilia induced by LPS.

The role of catecholamines in regulating pleural neutrophilia evoked by intrathoracic (i.t.) injection of lipopolysaccharide (LPS) was investigated in Wistar rats by means of surgical adrenalectomy, depletion of catecholamine stores or adrenoceptor blockade. Treatment of animals with a single dose of LPS evoked a dramatic increase in the number of pleural neutrophils concomitant with an increase in the number of these cells in blood at 4 h. Although blood neutrophilia was drastically reduced when catecholamine stores were depleted with intraperitoneal (i.p.) injection of reserpine, pleural neutrophilia was not modified. However, the i.t. injection of reserpine reduced the increase in pleural neutrophils after LPS stimulation. Adrenalectomy failed to inhibit the increase in neutrophil counts in the blood or pleural cavity after LPS challenge. Pretreatment with intravenous (i.v.) injection of prazosin, an alpha(1)/alpha(2B) antagonist, reduced LPS-induced blood but not pleural neutrophilia. On the other hand, although pleural neutrophilia was not affected by systemic pretreatment with the alpha(2)-adrenoceptor antagonist, yohimbine, the local treatment (i. t. injection) with this antagonist markedly reduced the increase in pleural neutrophil counts observed after stimulation by LPS. In contrast, pleural neutrophilia induced by i.t injection of formyl-methionyl-leucyl-phenylalanine (fMLP) was not modified by local treatment with yohimbine. Taken together, our results suggest that catecholamines, through activation of alpha(1) and alpha(2)-adrenoceptors, play a role in the regulation of blood and pleural neutrophilia observed during the inflammatory response evoked by LPS in the pleural cavity.

Adrenergic modulation of the blood neutrophilia induced by platelet activating factor in rats.

The involvement of catecholamines in blood neutrophilia observed after administration of platelet activating factor (PAF) to rats was studied. Intravenous (i.v.) injection of PAF (4 micrograms/kg) into naive rats more than doubled the number of neutrophils after 1 h. In contrast, PAF failed to induce neutrophilia in both adrenalectomized rats and those which had their catecholamine stores depleted by reserpine. PAF-induced neutrophilia was not inhibited by the selective antagonism of alpha 1- and alpha 2-adrenoceptors with prazosin and yohimbine, respectively. However, pretreatment with the beta-adrenoceptor antagonist, propranolol, significantly inhibited the phenomenon. Increase in the blood neutrophil counts was also achieved following the i.v. injection of the beta-agonist, salbutamol (1 mg/kg, i.v.). This response was clearly sensitive to propranolol but was not modified in rats submitted to adrenalectomy or reserpine pretreatment. The results suggest that the blood neutrophilia induced by the i.v. administration of PAF in rats is dependent on the stimulation of beta-adrenoceptors by catecholamines released from adrenal glands.

Postnatal development of rats exposed to fluoxetine or venlafaxine during the third week of pregnancy.

The aim of the present study was to compare the toxic effects of fluoxetine (F) (8 and 16 mg/kg) and venlafaxine (V) (40 and 80 mg/kg) administered during the third week of pregnancy on early development of rats. Both antidepressants were administered by gavage on pregnancy days 15 to 20 to groups of 10 to 12 animals each. Duration of gestation, food and water consumtion, number of live pups and birth weight were recorded. Litters were culled to six pups at birth (day 1) and followed for growth until weaning (day 25). On day 60, a male and a female from each litter were injected with the 5-HT1 agonist, 5-methoxy-N,N-dimethyltryptamine (6 mg/kg, i.p.) and the serotonergic syndrome was graded. Fluoxetine but not venlafaxine reduced the duration of pregnancy when compared to the control (C) group (F = 21.1 days and C = 21.6 days, mean, P < 0.02: maximum = 22 days and minimum = 21 days in both groups). The highest doses of both fluoxetine, 16 mg/kg (F16), and venlafaxine, 80 mg/kg (V80), reduced the food intake of pregnant rats, resulting in different rates of body weight gain during treatment (from pregnancy day 15 to day 20): F16 = 29.0 g, V80 = 28.7 g vs C = 39.5 g (median). Birth weight was influenced by treatment and sex (P < 0.05; two-way ANOVA). Both doses of fluoxetine or venlafaxine reduced the body weight of litters; however, the body weight of litters from treated dams was equal to the weight of control litters by the time of weaning. At weaning there was no significant difference in weight between sexes. There was no difference among groups in number of live pups at birth, stillbirths, mortality during the lactation period or in the manifestation of serotonergic syndrome in adult rats. The occurrence of low birth weight among pups born to dams which did not show reduced food ingestion or reduction of body weight gain during treatment with lower doses of fluoxetine or venlafaxine suggests that these drugs may have a deleterious effect on prenatal development when administered during pregnancy. In addition, fluoxetine slightly but significantly affected the duration of pregnancy (about half a day), an effect not observed in the venlafaxine treated groups.

Tizanidine protects mice against convulsions induced by lidocaine: involvement of alpha 2-adrenoceptors.

The effects of alpha-adrenoceptors agents on seizures induced by intraperitoneal administration of lidocaine (75 mg/kg) were studied in mice. Pretreatment with the selective alpha 2-adrenoceptor agonist, tizanidine, decreased the incidence of seizures induced by lidocaine. Tizanidine increased the latency to the first seizure in those animals which progressed to seizures. The blockade of alpha 2-adrenoceptors with yohimbine or phentolamine counteracted the protection induced by tizanidine. The selective alpha 2-adrenoceptor antagonist, prazosin, did not modify the protection induced by tizanidine. The alpha 2-adrenoceptor agonist clonidine also increased the latency to the first seizure induced by lidocaine. The protective effect of clonidine was also reversed by pretreatment with the selective alpha 2-adrenoceptor antagonist yohimbine. Taken together, these results suggest that alpha 2-adrenoceptors are involved in seizures induced by lidocaine.

Systemic neutrophilia observed during anaphylactic shock in rats is inhibited by dopaminergic antagonists.

The involvement of the sympathetic and dopaminergic systems on blood neutrophilic leucocytosis observed during anaphylaxis was investigated. Blood neutrophil counts impressively increased 1 h after intravenous injection of ovalbumin (OVA, 250 micrograms/kg) into OVA-immunized rats. The increase in neutrophil counts induced by OVA was abrogated after catecholamine depletion by reserpine. Either adrenalectomy or the alpha- and beta-adrenoceptor antagonists phentolamine and propranolol, respectively, had only minor inhibitory effects on neutrophilia induced by antigen. On the other hand, pretreatment with the dopaminergic antagonists chlorpromazine and pimozide significantly inhibited the neutrophilia. The intravenous injection of apomorphine, a dopaminergic agonist, increased neutrophil counts in naive animals, while chlorpromazine completely inhibited this phenomenon. These results suggest that dopaminergic mechanisms play a role in the systemic neutrophilia observed during anaphylactic shock.

Postnatal development of rats exposed to fluoxetine or venlafaxine during the third week of pregnancy

The aim of the present study was to compare the toxic effects of fluoxetine (F) (8 and 16 mg/kg) and venlafaxine (V) (40 and 80 mg/kg) administered during the third week of pregnancy on early development of rats. Both antidepressants were administered by gavage on pregnancy days 15 to 20 to groups of 10 to 12 animals each. Duration of gestation, food and water consumption, number of live pups and birth weight were recorded. Litters were culled to six pups at birth (day 1) and followed for growth until weaning (day 25). On day 60, a male and a female from each litter were injected with the 5-HT1 agonist, 5-methoxy-N,N-dimethyltryptamine (6 mg/kg, ip) and the serotonergic syndrome was graded. Fluoxetine but not venlafaxine reduced the duration of pregnancy when compared to the control (C) group (F = 21.1 days and C = 21.6 days, mean, P<0.02; maximum = 22 days and minimum = 21 days in both groups). The highest doses of both fluoxetine, 16 mg/kg (F16), and venlafaxine, 80 mg/kg (V80), reduced the food intake of pregnant rats, resulting in different rates of body weight gain during treatment (from pregnancy day 15 to day 20): F16 = 29.0 g, V80 = 28.7 g vs C = 39.5 g (median). Birth weight was influenced by treatment and sex (P<0.05; two-way ANOVA). Both doses of fluoxetine or venlafaxine reduced the body weight of litters; however, the body weight of litters from treated dams was equal to the weight of control litters by the time of weaning. At weaning there was no significant difference in weight between sexes. There was no difference among groups in number of live pups at birth, stillbirths, mortality during the lactation period or in the manifestation of serotonergic syndrome in adult rats. The occurrence of low birth weight among pups born to dams which did not show reduced food ingestion or reduction of body weight gain during treatment with lower doses of fluoxetine or venlafaxine suggests that these drugs may have a deleterious effect on prenatal development when administered during pregnancy. In addition, fluoxetine slightly but significantly affected the duration of pregnancy (about half a day), an effect not observed in the venlafaxine-treated groups