Comparative effects of beta-agonists on central and peripheral rat airways.
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Animals↗
Biomedical subjects
N Frossard
Publications and source records attributed to N Frossard.
Inhibition of antigen-induced histamine release from rat mast cells by a cyclic GMP-phosphodiesterase inhibitor and sodium nitrite.
Antianaphylactic properties have been attributed to cyclic nucleotide phosphodiesterase inhibitors through increase of cyclic AMP levels, according to the concept that increases in cyclic AMP reduce release and increases in cyclic GMP enhance release. However, Coulson et al. [3] showed that the inhibition of histamine release from human lung is correlated to the inhibition of cyclic GMP hydrolysis. We studied the effect of specific inhibitors of cyclic AMP and cyclic GMP hydrolysis on the antigen-induced mediator release from rat mass cells and human basophils and on airways relaxation [4]. The results suggested that the modulation of mediator release was different from one cell type to the other, enhancement of cyclic AMP levels leading to the inhibition of release from basophils, while cyclic GMP appears to be predominantly involved in mast cells. The present paper shows that high concentrations of sodium nitrite, a stimulating agent of guanylate cyclase, inhibit histamine release from rat mast cells in the presence or absence of M&B 22948, a selective cyclic GMP phosphodiesterase inhibitor.
3',5'-Cyclic-GMP Phosphodiesterases↗
Effects of cyclic AMP- and cyclic GMP- phosphodiesterase inhibitors on immunological release of histamine and on lung contraction.
1 Cyclic adenosine 3',5'-monophosphate (cyclic AMP)- and cyclic guanosine 3',5'-monophosphate (cyclic GMP)-phosphodiesterase activities from rat lung were selectively inhibited by ZK 62711 and M & B 22948, respectively. Theophylline and papaverine inhibited both activities. 2 Rat lung strips contracted by carbachol were relaxed by 4-(3-cyclopentyloxy-4-methoxyphenyl)-2-pyrrolidone (ZK 26711, EC25 = 7 x 10(-8)M) and 2-O-propoxyphenyl-8-azapurin-6-one (M & B 22948, EC25 = 5 x 10(-7)M) indicating relaxant properties of both cyclic AMP and cyclic GMP. 3 The antigen-induced histamine release from human basophils was inhibited by ZK 62711 (IC25 = 8 x 10(-7)M), whereas M & B 22948 had no effect. On the contrary, the release from rat mast cells was inhibited by M & B 22948 (IC25 = 10(-6)M), while ZK 62711 had no effect. 4 These data show an inhibitory effect of cyclic AMP on histamine release to be involved with basophils, whereas cyclic GMP is predominantly involved with mast cells. Is is suggested that the antianaphylactic properties of cyclic nucleotide phosphodiesterase inhibitors are mainly linked to the increase of cyclic GMP.
3',5'-Cyclic-AMP Phosphodiesterases↗
Activity of ebastine (10 and 20 mg) and cetirizine at 24 hours of a steady state treatment in the skin of healthy volunteers.
We have compared the inhibitory effects of ebastine (10 mg), ebastine (20 mg) and cetirizine (10 mg) on histamine-induced wheal and flare skin reactions 24 h following a 6-day-long treatment. This was a double-blind, randomised, crossover, placebo-controlled study involving 24 healthy volunteers (18-65 years) with negative skin prick tests and the absence of specific IgEs to common allergens. Subjects were randomised to receive each of the following treatments once daily for 6 days: ebastine (10 mg), ebastine (20 mg), cetirizine (10 mg) or placebo with a washout period of 5 days. Twenty-four hours after the last dose of each treatment, histamine skin prick tests were performed (0, 0.5, 1, 2.5, 5, 10, 20, 50, 100 and 200 mg/mL), and wheal and flare responses were measured. All active treatments produced significant inhibition of the wheal responses compared to placebo (P < 0.001). Wheal response inhibition was significantly better with 20 mg of ebastine compared with 10 mg of ebastine and 10 mg of cetirizine. In a comparison to histamine concentrations required to produce a wheal surface area of 10 mm2, 20 mg of ebastine was also significantly better than ebastine 10 mg and cetirizine (P < 0.001), and 10 mg ebastine was significantly better than cetirizine (P < 0.05). Highly significant (P < 0.001) effects on the flare response were observed with each active treatment compared to placebo, with no difference between groups. The frequency of adverse events, primarily somnolence, was similar among the four treatment groups. Our results clearly indicate that ebastine, at either recommended dosage of 10 and 20 mg, and cetirizine produced significant inhibition of the histamine-induced wheal and flare reaction compared to placebo for up to 24 h. A superior efficacy of 20 mg of ebastine is observed compared with 10 mg of ebastine and 10 mg of cetirizine on the skin wheal response 24 h after the last dose of a 6-day-long treatment. This study clearly proves ebastine to be an effective, truly once-daily antihistamine.
Adult↗
[Mechanisms of asthma. II. Potential pharmacological targets].
The pharmacological modifications of the airways contraction and of the secretion of mediators of anaphylaxis appear as the main way to therapeutic control of asthma. Calcium antagonists which inhibit calcium influx in the pulmonary smooth muscle have been proposed as antiasthmatic drugs. The pharmacological use of inhibitors of calmodulin, the intracellular target of calcium, requires the development of specific calmodulin inhibitors. The secretion of the mediators of anaphylaxis involves modifications of membranous phospholipids metabolism. The cytoskeleton might control the exocytosis of stored mediators. The multiplicity of putative mediators, of cellular systems and of various interrelationships between mediators of anaphylaxis and neuromediators, suggest multiple potential pharmacological targets in asthma.
Anaphylaxis↗
Cyclosporine does not affect in vitro bronchial smooth muscle contractions in treated Lewis rats.
The purpose of this study was to investigate whether cyclosporine treatment could modify airway responses, thus playing a role in bronchial hyperresponsiveness observed in patients after lung transplantation. We have studied the effect of cyclosporine treatment in rats on subsequent bronchial responses to electrical field stimulation, to exogeneous 5-hydroxytryptamine, and acetylcholine in organ baths. The isometric force of contraction of bronchial smooth muscle was measured. Voltage and frequency responses produced by electrical field stimulation were similar in control and in rat bronchi treated with cyclosporine. Concentration-response curves to exogeneous acetylcholine were superimposed for both groups of animals, as were those to 5-hydroxytryptamine. Our results show that cyclosporine treatment does not affect bronchial smooth muscle contraction and rule out possible contribution of cyclosporine to the bronchial hyperresponsiveness described after lung transplantation.
Acetylcholine↗