Bronchodilator action of an agonist for histamine H3-receptors in guinea pig perfused bronchioles and lung parenchymal strips

Abstract

Isolated guinea pig perfused bronchioles and lung parenchymal strips were examined as an in vitro model for assessment of the direct effect of pharmacologic agents on the airway smooth muscle. The experiments were performed with a perfusion technique in bronchioles, the input pressure being measured as an index of the state of dilation, while changes in tension of the lung parenchymal strips were measured with an isometric force transducer. In both preparations, histamine and acetylcholine elicited dose-related contractile responses whereas fenoterol induced a concentration-dependent relaxation. After the 3 agonists' activities were compared in these 2 preparations, we tested the intrinsic effects of a specific H3 agonist, (R) alpha-methylhistamine ([R] alpha-MeHA). Statistical analysis was by Student's t test on the Emax (expressed as a percentage of 10(-4) M papaverine relaxation), EC50, and slopes of regression lines calculated from the concentration-response curves plotted for (R) alpha-MeHA alone or in presence of antagonists. Our results showed that (R) alpha-MeHA induced a concentration-dependent relaxation of perfused bronchioles and lung parenchymal strips competitively inhibited by 10(-7) M thioperamide (H3-antagonist), whereas 10(-5) M cimetidine (H2-antagonist) failed to prevent this effect. These results suggest the presence of H3-histaminergic dilatory receptors in the guinea pig airway.

Histamine and Serotonin

“…Although (R)--methylhistamine relaxes rodent peripheral airways in vitro, 116 it has no effect when given by inhalation on airway calibre or metaEffect of antagonists bisulfite-induced bronchoconstriction in asthmatic Histamine mediates most of its effects on airway patients, indicating that a useful clinical effect is unfunction via H 1 -receptors, suggesting that H 1 -antlikely. 68 agonists may have therapeutic effects in airway disease.…”

In Vitro Systems for Studying Respiratory System Toxicology

“…Thus, a working categorization would include any viable section of tissue that maintains a degree of structural and organizational integrity. Applications include, for example, characterizations of toxicant metabolism and toxicant effects on metabolic pathways (Dinsdale et al 1991;Foth et al 1990;Plopper et al 1991), assessments of cell-specific cytotoxicity Plopper et al 1994;Van Winkle et al 2004), functional (physiological) determinations (vascular or bronchial smooth muscle tone/contractility) (Ben-Jebria et al 1993;Burguad et al 1992;el-Fawal and Schlesinger 1994;Holden et al 1990;Hulsmann and de Jongste 1993;Smith et al 1993;Van Winkle et al 2004), and as seeding material for explant-derived cell outgrowth cultures (Xiang et al 2008). To avoid prolonged discussion, the myriad of methodologies used for tissue sections will not be discussed in detail.…”

Bronchodilatation of guinea‐pig perfused bronchioles induced by the H3‐receptor for histamine: role of epithelium

“…We have modified the perfusion technique of Oudart et al (1981) in the rabbit cerebral artery according to Burgaud et al (1992) in guinea-pig perfused bronchioles. Hartley guineapigs of either sex weighing 400-500 g were anaesthetized with urethane (1.5 g kg-', i.p.)…”

“…Recently, we have shown that (R)a-methylhistamine [(R)xMeHist], a potent and selective H3-agonist (Arrang et al, 1987), induced a concentration-dependent relaxation on the resting tone of the guinea-pig perfused bronchioles (Burgaud et al, 1992).…”