Pharmacological research communications最新文献

Five fractions of an aqueous extract obtained from the roots of Echinacea angustifolia were separated on the basis of molecular weight. The topical anti-inflammatory activity of the fractions has been evaluated in mice using the Croton oil ear test. The fraction with a molecular weight between 30,000 and 100,000 was the most active in inhibiting the oedema; it also reduced the infiltration of inflammatory cells. The activity of this fraction was comparable with that of a raw polysaccharidic extract obtained from E. angustifolia roots by differential solubility. The high-molecular weigth polysaccharides are therefore proposed as the anti-inflammatory principles of the plant.

Different doses of the new chemically stable PGE₂ analogue, PCE 20700, (150, 300, 450, 900, 1200 and 1800 μg kg⁻¹) and of 16,16-dimethyl PGE₂, DMPGE₂, (1, 3, 10, 30 and 100 μg kg⁻¹) were administered by gavage to pylorus-ligated rats. The dose-response relationship in preventing gastric mucosal damage and in inhibiting gastric acid and pepsin secretion was investigated. In the same animals, a simultaneous evaluation of barrier and luminal mucus was also performed. Both compounds were markedly active in preventing the macroscopic damage of the gastric mucosa and, at higher doses, in inhibiting gastric acid secretion. FCE 20700 was approximately 100–150 times less potent than DMPGE₂. Mucosal protection appeared to be exerted by the two prostaglandins independently of any action on mucus. Furthermore, as the antisecretory doses were approached, a decline in protective activity became evident, suggesting that the dosage of prostaglandins is critical, making it possible to orient their activity either towards mucosal protection or towards acid inhibition.

Dissociated primary cultures of glial cells released a remarkable amount of purines, at rest and during field electrical stimulation.

The HPLC identification of labelled compounds derived from 3H-Adenosine (3H-Ado) (employed to preload the cultures) indicated that nucleotides and nucleosides were represented in the superfusate in equivalent proportions (43.86% and 56.14% respectively). Very much higher amounts of unlabelled purines prevalently constituted by nucleotides compounds (91.10%) were also released and detectable in the superfusate. In all the experimental conditions their evoked release did not result frequency-dependent.

Since:o

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   a linear increase related to the stimulation frequencies was found for the released labelled compounds;

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   no labelled purines were assayed in 5×10-5M Dipyridamole-treated cultures;

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   any significant presence of labelled nucleotides, inosine and hypoxantine was not found in cultures simultaneously treated with 1×10-5M 2′-deoxycoformycin and 1×10-4M 1-(-5-isoquinolinsulfonyl)-2-methylpiperizine (H7) (3H-Ado amounts resulted more than doubled in these experimental conditions);

labelled compounds have been assumed as tracers of a glial purine rate whose release can be connetted to electrically-evoked action potentials.

Purine outflow from glial cells is not sodium dependent, in fact TTX (5×10-7M) did not affect their basal or electrically-evoked release. A remarkable calcium-dependence was also evidentiated by the 1×10-4M Verapamil-induced inhibition of basal and evoked release. TEA (1×10-2M), a specific inhibitor of potassium efflux throughout calcium-mediated specific channels, strongly reduced the evoked purine outflow and any additive effect of its was not detectable when administered simultaneously to the calcium antagonist.

These findings indicate that the frequency-dependent purine release from cultured glial cells is linked to ionic mechanisms, which calcium and potassium are mainly involved in.

Benzimidazole and some of its derivatives as 4-nitro and 5-nitro-benzimidazoles, 2-amino-, 4-amino- and 5-aminobenzimidazoles have been tested on gastric acid secretion in Shay-rats. Only 5-aminobenzimidazole decreased the gastric secretory process basal or stimulated by betazole.

The antisecretory properties of 5-aminobenzimidazole seem to be linked to an anti H₂-histamine activity, since this compound depresses the amplitude of contractions of guinea pig isolated auricle stimulated by betazole.

The antisecretive activity appears to be associated to a definite distance between the amino group and the imidazolyl nitrogen, since it appears only when the amino function is located in position 5 of the benzimidazole structure.

A series of adrenoceptor agonists were investigated for their prejunctional effects on field stimulated rat vas deferens. Tissues were stimulated in 10 s trains of impulses, frequency to Hz, every 100 s. This produced a biphasic response comprising an initial twitch followed by a prolonged, plateau phase of contraction. The order of potency for a series of α₂-agonists against the twitch phase of contractions was UK14304 > clonidine > noradrenaline = α-methyl noradrenaline > B-HT920. The same order of potency was observed against the plateau phase, but approximately 10 fold higher concentrations of agonist were needed. Surprisingly, B-HT920 was inactive against the plateau phase of contraction. Characteristic differences in the slopes and maximum responses of the dose-response curves to the imidazolines (UK14304 and clonidine) and the β-phenethylamines (noradrenaline and α-methyl noradrenaline) were seen against both phases of contraction. It is concluded that the two phases of contraction are influenced by activation of two distinct heterogeneous populations of prejunctional α₂-adrenoceptors.

Dopamine (DA) synthesis in rat striatal synaptosomes was approximately doubled either by treating the animals from which the synaptosomes were obtained with reserpine, or by treating the preparations in vitro with d-amphetamine, ouabain or dibutyryl cyclic AMP. The concentration-response curve of DA synthesis inhibition by apomorphine was shifted to the right after treatment with all these compounds. The inhibitory effect of bromocriptine on DA synthesis was reduced completely after treatment with all the above compounds with the exception of dibutyryl cyclic AMP. When the inhibitory effect of bromocriptine was eliminated by treatment with reserpine or d-amphetamine, bromocriptine antagonized the inhibitory effect of apomorphine. This indicates that bromocriptine could still be bound to the DA autoreceptors and that the reduced sensitivity was due to a reduced functioning of the DA autoreceptors. The reduced sensitivity to apomorphine observed after all the above treatments was possibly due both to a reduced function of and/or to a reduced binding to the DA autoreceptors. The increase in DA synthesis produced by treatment with reserpine in vivo or with d-amphetamine or ouabain in vitro was additive to that produced by a maximally effective concentration of dibutyryl cyclic AMP in vitro, and thus mediated by a presumably non-cyclic AMP-dependent mechanism. Our results obtained with bromocriptine suggest that stimulation of the DA autoreceptors may inhibit DA synthesis by diminishing Ca²⁺-dependent and not cyclic AMP-dependent phosphorylation of tyrosine hydroxylase.

Alterations in vascular alpha-adrenoceptor responsiveness following sinoaortic denervation was studied in conscious rats. The arterial hypertension observed in baroreceptor denervated rats decreased progressively during the 30 days of observation. A pressor hyperresponsiveness to methoxamine (10–80 μg/kg, iv), was observed 3 to 7 days after baroreceptor denervation followed by a gradual normalization of the vascular reactivity. The results indicate a possible participation of an enhanced alpha₁-adrenoceptor-mediated vasoconstrictor component in the early phase of neurogenic hypertension.

Inflammatory process of the airways has been claimed to be relevant to the development of bronchial hyperreactivity in different experimental models. We investigated the consequences of pleural inflammation induced in the guinea-pigs by croton oil injection into the pleural space. Croton oil injection was followed by the development of an inflammatory reaction localized to the pleura as shown by recovery of inflammatory exudate from the pleural cavity of treated animals. An increased number of white cells was observed in the pleural fluid of treated animals as compared to control. Moreover, the croton oil induced inflammation was characterized by development of pulmonary hyperreactivity which involved both airway and vascular smooth muscles. We also studied this phenomenon in an animal model of asthma, such as the actively sensitized guinea-pigs. Polymorphonuclear leukocyte and particularly eosinophil recruitment was increased in this experimental condition and a different trend in the development of the hyperreactive phenomenon was observed. Our data support the relationship between inflammatory process within the pleural space and increased reactivity of pulmonary tissues. The possible involvement of different classes of white cells in this phenomenon has also been discussed.