title: beta(2)-adrenoceptor antagonist ICI 118,551 decreases pulmonary vascular tone in mice via a G(i/o) protein/nitric oxide-coupled pathway.
abstract: beta(2)-adrenoceptors are important modulators of vascular tone, particularly in the pulmonary circulation. Because neurohormonal activation occurs in pulmonary arterial hypertension, we have investigated the effect of different adrenergic vasoactive substances on tone regulation in large and small pulmonary arteries, as well as in systemic vessels of mice. We found that the beta(2)-adrenoceptor antagonist ICI 118,551 (ICI) evoked a decrease of vascular tone in large pulmonary arteries and reduced the sensitivity of pulmonary arteries toward different contracting agents, eg, norepinephrine, serotonin, or endothelin. ICI proved to act specifically on pulmonary vessels, because it shifted the dose-response curve of norepinephrine to the right in pulmonary arteries, whereas there was no effect in the aorta. Pharmacological experiments proved that the right shift of the norepinephrine dose-response curve by ICI was mediated via a beta(2)-adrenoceptor/G(i/o) protein-dependent pathway enhancing NO production in the endothelium; these results were corroborated in beta-adrenoceptor and endothelial NO synthase knockout mice where ICI had no effect. ICI increased vascular lumen diameter in lung sections and reduced pulmonary arterial pressure under normoxia and under hypoxia in the isolated perfused lung model. These effects were found to be physiologically relevant, because ICI specifically decreased pulmonary but not systemic blood pressure in vivo. Thus, the beta(2)-adrenoceptor antagonist ICI is a pulmonary arterial-specific vasorelaxant and, therefore, a potentially interesting novel therapeutic agent for the treatment of pulmonary arterial hypertension.
authors.affiliation: Institute of Physiology I, University of Bonn, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Wenzel
authors.forename: Ralf
authors.initials: R
authors.lastname: Knies
authors.forename: Michaela
authors.initials: M
authors.lastname: Matthey
authors.forename: Alexandra M
authors.initials: AM
authors.lastname: Klein
authors.forename: Julia
authors.initials: J
authors.lastname: Welschoff
authors.forename: Vanessa
authors.initials: V
authors.lastname: Stolle
authors.forename: Philipp
authors.initials: P
authors.lastname: Sasse
authors.forename: Wilhelm
authors.initials: W
authors.lastname: Röll
authors.forename: Johannes
authors.initials: J
authors.lastname: Breuer
authors.forename: Bernd K
authors.initials: BK
authors.lastname: Fleischmann
mesh_terms: D058672:Adrenergic beta-2 Receptor Antagonists; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D004305:Dose-Response Relationship, Drug; D005260:Female; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism*; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D051379:Mice; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D009638:Norepinephrine / Q000494:pharmacology; D011412:Propanolamines / Q000494:pharmacology*; D011651:Pulmonary Artery / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology
chemical_list: D058672:Adrenergic beta-2 Receptor Antagonists; D000319:Adrenergic beta-Antagonists; D011412:Propanolamines; D018343:Receptors, Adrenergic, beta-2; D014662:Vasoconstrictor Agents; D009569:Nitric Oxide; C026777:ICI 118551; D052250:Nitric Oxide Synthase Type III; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D009638:Norepinephrine