Inhibition by SR 59119A of Isoprenaline-, Forskolin- and VIP-induced Relaxation of Human Isolated Bronchi

• Published in: Pulmonary pharmacology & therapeutics Vol. 13; no. 4; pp. 167 - 174
• Main Authors: Naline, Emmanuel, Bardou, Marc, Devillier, Philippe, Molimard, Mathieu, Dumas, Monique, Chalon, Pascale, Manara, Luciano, Advenier, Charles
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.01.2000
• Subjects: Adenosine Monophosphate - metabolism; Adenylate Cyclase Toxin; Adrenergic beta-Agonists - pharmacology; Bronchi - drug effects; Bronchi - physiology; Colforsin - antagonists & inhibitors; Colforsin - pharmacology; Ethanolamines - pharmacology; Humans; In Vitro Techniques; Interleukin-1; Isoproterenol - antagonists & inhibitors; Isoproterenol - pharmacology; Middle Aged; Pertussis Toxin; Receptors, Adrenergic, beta - physiology; Tetrahydronaphthalenes - pharmacology; Vasoactive Intestinal Peptide - antagonists & inhibitors; Vasoactive Intestinal Peptide - pharmacology; Virulence Factors, Bordetella; β3-adrenoceptor agonists, β2-adrenoceptor, Human bronchi, Smooth muscle, Gi protein; β3-adrenoceptor agonists, β2-adrenoceptor, Human bronchi, Smooth muscle, Gi protein
• ISSN: 1094-5539; 1522-9629
• DOI: 10.1006/pupt.2000.0246

In the human isolated bronchus (HIB) it has been shown that β3-adrenoceptor stimulation fails to induce relaxation of airway smooth muscle. It has however been reported in human ventricular endomyocardial biopsies that β3-adrenoceptor stimulation induced a marked negative inotropic effect which could be linked to Gi protein activation. The aims of this study were: (1) to determine in HIB (internal diameter 1–2 mm) whether the selective β3-adrenoceptor agonist SR 59119A (N[7-methoxy-1,2,3,4-tetrahydronaphthalen-(2R)methyl]-(2R)-2-hydroxy-2-(3-chlorophenyl)ethanamine hydrochloride) was able to inhibit adenylate–cyclase-mediated airway smooth muscle relaxation induced by isoprenaline, forskolin or vasoactive intestinal peptide (VIP) and (2) to investigate the role of the Gi protein in this interaction. SR 59119A (0.1 μM and 1 μM) induced a shift to the right of concentration response curve for isoprenaline (−0.15±0.06 and −0.54±0.21 log unit, P<0.05 and P<0.01 respectively), forskolin (−0.12±0.02 and −0.30±0.05 log unit, P<0.001), and VIP (−0.42±0.12 log unit, P<0.01 with SR59119A 10−6M). The inhibitory effect of SR 59119A was (1) abolished by an incubation of HIB with pertussis toxin (1 μg/ml, during 15 h in Krebs–Henseleit solution, at 21°C), which is known to inactivate the Gi protein and (2) increased after an incubation of HIB with the pro-inflammatory cytokine IL-1β (10 ng/ml, during 15 h in Krebs–Henseleit solution, at 21°C), which is known to up-regulate Gi protein expression. Our results suggest that the selective β3-adrenoceptor agonist SR59119A might inhibit the cAMP-dependent relaxation of human isolated bronchus through Gi protein-mediated inhibition of adenylate cyclase.