Long-term ethanol intoxication reduces inflammatory responses in rats.

The anti-inflammatory effects of long-term ethanol intoxication were determined during ethanol treatment and withdrawal on the basis of neutrophil and eosinophil migration, hind paw edema and mast cell degranulation. Male Wistar rats (180-200 g, around 2 months of age) were exposed to increasing concentrations of ethanol vapor over a 10-day period. One group was evaluated immediately after exposure (treated group - intoxicated), and another was studied 7 h later (withdrawal group). Ethanol inhalation treatment significantly inhibited carrageenan--(62% for the intoxicated group, N = 5, and 35% for the withdrawal group, N = 6) and dextran-induced paw edema (32% for intoxicated rats and 26% for withdrawal rats, N = 5 per group). Ethanol inhalation significantly reduced carrageenan-induced neutrophil migration (95% for intoxicated rats and 41% for withdrawn rats, N = 6 per group) into a subcutaneous 6-day-old air pouch, and Sephadex-induced eosinophil migration to the rat peritoneal cavity (100% for intoxicated rats and 64% for withdrawn rats, N = 6 per group). A significant decrease of mast cell degranulation was also demonstrated (control, 82%; intoxicated, 49%; withdrawn, 51%, N = 6, 6 and 8, respectively). Total leukocyte and neutrophil counts in venous blood increased significantly during the 10 days of ethanol inhalation (leukocytes, 13, 27 and 40%; neutrophils, 42, 238 and 252%, respectively, on days 5, 9 and 10, N = 7, 6 and 6). The cell counts decreased during withdrawal, but were still significantly elevated (leukocytes, 10%; neutrophils, 246%, N = 6). These findings indicate that both the cellular and vascular components of the inflammatory response are compromised by long-term ethanol intoxication and remain reduced during the withdrawal period.

Long-term ethanol intoxication reduces inflammatory responses in rats

The anti-inflammatory effects of long-term ethanol intoxication were determined during ethanol treatment and withdrawal on the basis of neutrophil and eosinophil migration, hind paw edema and mast cell degranulation. Male Wistar rats (180-200 g, around 2 months of age) were exposed to increasing concentrations of ethanol vapor over a 10-day period. One group was evaluated immediately after exposure (treated group - intoxicated), and another was studied 7 h later (withdrawal group). Ethanol inhalation treatment significantly inhibited carrageenan- (62 percent for the intoxicated group, N = 5, and 35 percent for the withdrawal group, N = 6) and dextran-induced paw edema (32 percent for intoxicated rats and 26 percent for withdrawal rats, N = 5 per group). Ethanol inhalation significantly reduced carrageenan-induced neutrophil migration (95 percent for intoxicated rats and 41 percent for withdrawn rats, N = 6 per group) into a subcutaneous 6-day-old air pouch, and Sephadex-induced eosinophil migration to the rat peritoneal cavity (100 percent for intoxicated rats and 64 percent for withdrawn rats, N = 6 per group). A significant decrease of mast cell degranulation was also demonstrated (control, 82 percent; intoxicated, 49 percent; withdrawn, 51 percent, N = 6, 6 and 8, respectively). Total leukocyte and neutrophil counts in venous blood increased significantly during the 10 days of ethanol inhalation (leukocytes, 13, 27 and 40 percent; neutrophils, 42, 238 and 252 percent, respectively, on days 5, 9 and 10, N = 7, 6 and 6). The cell counts decreased during withdrawal, but were still significantly elevated (leukocytes, 10 percent; neutrophils, 246 percent, N = 6). These findings indicate that both the cellular and vascular components of the inflammatory response are compromised by long-term ethanol intoxication and remain reduced during the withdrawal period.

Effects of the water soluble fraction from leaves of Ageratum conyzoides on smooth muscle.

The water soluble fraction of Ageratum conyzoides L. (WSF) was studied in isolated rat uterus and intestinal smooth muscles in order to evaluate its popular use as a spasmolytic. WSF (0.2 and 0.4 mg/mL) increased EC(50) values and decreased maximum responses to acetylcholine and calcium chloride. WSF (0.5-3.3 mg/mL) also produced direct myorelaxant effect on smooth muscle preparations. Theophylline (10(-3) M) potentiated the relaxant action of WSF. Theophylline also prevented the decrease in maximum response promoted by WSF in acetylcholine concentration-effect curves. These results seem to be partially linked to calcium mobilization. The data also suggest that WSF could act synergistically with theophylline in the inhibition of cyclic AMP phosphodiesterase. The results give support to the popular medicinal indications of the plant.

Effect of active sensitization on the bronchopulmonary responses to tachykinins in the guinea pig. Modulation by peptidase inhibitors.

The i.v. administration of substance P (SP, 0.25-16 micrograms/kg) or of the selective metabolic stable NK-1 agonist, [Glp6,Pro9]SP-(6-11) (septide, 0.03-0.25 microgram) to atropine-treated guinea pigs or to isolated perfused lungs triggered a dose-dependent bronchoconstriction, which was enhanced in animals actively sensitized to ovalbumin. In vivo, bronchial hyper-responsiveness was restricted to SP and to septide, inasmuch as neurokinin A (0.06-1 microgram/kg)- or capsaicin (0.5-32 micrograms/kg)-induced bronchoconstriction were not modified. In contrast, isolated lungs from sensitized guinea pigs exhibited an increased bronchoconstriction also in response to capsaicin (0.01-10 micrograms), which was inhibited by atropine in the medium. Pretreatment of actively sensitized guinea pigs either with indomethacin plus mepyramine, the lipoxygenase inhibitor BW A4C or with the platelet-activating factor antagonist SR 27417, did not modify bronchial hyper-reactivity to SP. Captopril (5 mg/kg i.v.), but not thiorphan (0.8 mg/kg i.v.), increased the SP-induced bronchoconstriction in actively sensitized animals, whereas both inhibitors were equally effective in nonsensitized guinea pigs. Thiorphan, however, did not modify the in vivo response to septide. Our results demonstrate that guinea pigs sensitized to ovalbumin exhibit bronchial hyperreactivity to SP, but not to neurokinin A, as compared to nonsensitized animals, suggesting a decrease in the neutral endopeptidase activity in the airways brought by the immunization. However, the results obtained by using septide indicate that other mechanisms may be involved in the bronchial hyper-reactivity to SP.

Pharmacological study of the internal and sphincter in patients with chronic anal fissure.

A pharmacological study of the internal anal sphincter (IAS) was undertaken in patients with chronic and fissure. The sensitivity of the IAS to the contractile effect of phenylephrine and potassium chloride and to relaxation by isoproterenol was evaluated. Supersensitivity of the IAS to relaxation by isoproterenol was noted. Further research is necessary to determine the pharmacological basis of such a disturbance.

Reduction by acute restraint stress of noradrenaline sensitivity in the isolated pacemaker of the rat.

Acute restraint stress induced subsensitivity of the isolated pacemaker of the rat to the chronotropic effect of noradrenaline and reduced the affinity of atrial beta 1-adrenoceptors for metoprolol. The effects of restraint stress were abolished two days after bilateral adrenalectomy. The controlled venous infusion of noradrenaline plus adrenaline was without effect on the atrial sensitivity to noradrenaline and the pA2 value of metoprolol. It is concluded that the effects of restraint stress on atrial beta 1-adrenoceptors are mediated at least partially by adrenal corticosteroids.

The effects of ethanol dependence on drug responsiveness of mouse isolated vas deferens.

The effects of ethanol dependence on the responsiveness of the mouse vas deferens to noradrenaline (NA), carbachol, barium and calcium were studied. Ethanol dependence increases the maximum responses to NA and carbachol whereas responsiveness to barium remains unaltered. The concentration-effect curve to calcium was shifted to the left (3.0-fold at the EC50 level). It is concluded that in vas deferens isolated from ethanol-dependent mice the increased responsiveness to NA, carbachol and calcium is a consequence of an enhanced calcium entry through voltage-independent calcium channels, as it has been reported for brain tissue.

Adrenoceptor supersensitivity in the isolated rat vas deferens during barbital withdrawal.

Long-term treatment with sodium barbital did not alter significantly the responsiveness of the isolated rat vas deferens to noradrenaline. However, three days after barbital withdrawal there was a 4.5-fold increase in the sensitivity and an enhanced maximum response to the neurotransmitter. Pharmacological analysis of the affinity of postjunctional adrenoceptors showed no alteration of the pA2 of phentolamine, a decrease in the apparent dissociation constant (KA) for noradrenaline and an increase in the fraction of adrenoceptors (q) remaining active after exposure to phenoxybenzamine. Comparison between ED50 and KA indicates the presence of spare receptors in the rat vas deferens. There was also a decrease in the blocking activity of phenoxybenzamine, in vasa deferentia obtained from rats three days after barbital withdrawal. These results suggest that an increased affinity of postjunctional adrenoceptors could be responsible, at least partially, for this supersensitivity to noradrenaline. The increased maximum response to the neurotransmitter could be the consequence of an improved coupling of adrenoceptor occupation to the final contractile response.

The open field: a simple method to show ethanol withdrawal symptoms.

The effects of withdrawal from chronic ethanol administration on locomotion and rearing frequencies of rats and mice were studied. Ethanol withdrawal induced a significant increase in animal's activity. In mice a positive correlation was found between locomotion plus rearing frequencies and audiogenic-induced seizures susceptibility 25 hr after ethanol removal. Results show that general activity evaluated through the open-field method might be used as a simple, non-drastic and reliable procedure to detect ethanol withdrawal symptoms in laboratory animals.

An analysis of the effects of cocaine on the responsiveness of the isolated guinea pig vas deferens to noradrenaline and other agonists.

In the isolated guinea pig vas deferens, 10(-4) M cocaine shifts to the left (13.5-fold at the EC50 level) the concentration-effect curve and increases the maximum response to noradrenaline, whilst supersensitivity to phenylephrine, an amine with a low affinity for the neuronal uptake, was smaller (4.1-fold) and the maximum response was not increased. Cocaine did not enhance sensitivity and maximum response to acetylcholine, potassium and calcium. Supersensitivity to noradrenaline was caused by a decreased dissociation constant (Km) for the agonist-adrenoreceptor interaction without alteration of the tissue's maximum response (Rmax). pA2 and pD'2 values in the presence of cocaine were not significantly different from control which indicates that cocaine did not increase the affinity of adrenoreceptors for the sympathomimetic amines used. It is concluded that the supersensitivity of the isolated guinea pig vas deferens to noradrenaline and phenylephrine by cocaine is entirely of prejunctional origin and results from the blockade of the neuronal uptake process.