title: Increased contractile response to 5-hydroxytryptamine1-receptor stimulation in pulmonary arteries from chronic hypoxic rats: role of pharmacological synergy.
abstract: 1. 5-Hydroxytryptamine (5-HT)(1)-receptor-induced contraction is enhanced, or uncovered, by elevated vascular tone in many arteries including pulmonary arteries. In hypoxia-induced pulmonary hypertension, the endogenous tone of pulmonary arteries is elevated and this may contribute to increased 5-HT(1)-receptor-induced contraction. Here we investigate the influence of vascular tone induced by endothelin-1 (ET-1), neuropeptide Y (NPY), KCl, 4-aminopyridine (inactivator of K(v) channels, 4-AP) or the calcium ionophore A23187 on contractile responses to the 5-HT(1)-receptor agonist 5-carboxamidotryptamine (5-CT) in small muscular pulmonary arteries from control rats and rats exposed to chronic hypoxia. The influence of the nitric oxide synthase inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME, 100 microM) was also studied. These conditions were chosen to mimic those that influence pulmonary vascular tone in hypoxia-induced pulmonary hypertension. 2. In control rat small pulmonary arteries, only high concentrations of 5-CT (>1 microM) induced vasoconstriction. Tone induced by NPY, 4-AP and A23187 had no effect on responses to 5-CT whilst responses to 5-CT were increased by ET-1- and KCl-induced tone. In the presence of L-NAME these responses to 5-CT were enhanced further. 3. Responses to 5-CT were enhanced 3 - 4 fold in small pulmonary arteries from hypoxia-exposed, pulmonary hypertensive rats and neither L-NAME nor increasing tone with NPY, 4-AP, A23187, ET-1 or KCl had any further effect on responses to 5-CT. 4. The results suggest that inhibition of nitric oxide synthase combined with KCl- or ET-1-induced vascular tone potentiates responses to 5-HT(1)-receptor-induced contraction in pulmonary arteries in a synergistic fashion and this mimics the effects of chronic hypoxic exposure.
authors.affiliation: Institute of Biomedical and Life Sciences, University of Glasgow, Glasgow G12 8QQ. M.MacLean@bio.gla.ac.uk
authors.forename: M R
authors.initials: MR
authors.lastname: MacLean
authors.forename: I
authors.initials: I
authors.lastname: Morecroft
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004357:Drug Synergism; D000860:Hypoxia / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D011651:Pulmonary Artery / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D011985:Receptors, Serotonin / Q000502:physiology*; D044263:Receptors, Serotonin, 5-HT1; D012701:Serotonin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology*
chemical_list: D004338:Drug Combinations; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D017366:Serotonin Receptor Agonists; D012701:Serotonin; C047087:5-carboxamidotryptamine