Regulation of sensitivity to 5-hydroxytryptamine in pulmonary supernumerary but not conventional arteries by a 5-HT(1D)-like receptor.
Bovine pulmonary supernumerary arteries are more sensitive to 5-hydroxtryptamine (5-HT) (pD(2) 6.43+/-0.25) than conventional arteries (pD(2) 5.32+/-0.16). This study investigated receptors for 5-HT in ring segments of these arteries. The 5-HT(2) receptor agonist, 2,5 dimethoxy-4-iodoamphetamine hydrobromide (DOI) constricts both arteries. The selective 5-HT(2) receptor antagonist ritanserin produced insurmountable antagonism of 5-HT concentration-response curves in both arteries, whereas the 5-HT(1B/1D) receptor antagonist N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2'-methyl-4'(5-methyl- 1,2,4-oxadiazol-3-yl[1,1,-biphenyl]-4-carboxamide hydrochloride (GR127935) produced much greater antagonism in supernumerary arteries. In rings preconstricted with 9,11-dideoxy-9, 11-methanoepoxy prostalagdin F(2alpha) (U46619) and relaxed with the adenylyl cyclase activator forskolin, the selective 5-HT(ID) receptor agonist 2-[5-[3-(4-methylsulphonylamino) benzyl-1,2, 4-oxadiazol-5-yl]-1H-indole-3-yl] ethylamine (L694247) reversed the relaxation. Concentration-response curves for L694247-induced reversal of forskolin-relaxation were antagonised by GR127935 in supernumerary (pK(B) 8.6) and conventional (pK(B) 8.4) arteries, whereas concentration-response curves to 5-HT-were less sensitive to antagonism by GR127935T and this was more obvious in conventional (pK(B) 7.6) than supernumerary (pK(B) 8.1) arteries. Neither the selective 5-HT(1D) receptor antagonist (1-(3-chlorophenyl)-4-[3, 3-diphenyl (2-(S,R) hydroxypropanyl)piperazine] hydrochloride (BRL15572) nor the 5-HT(1B) receptor antagonist (2,3,6, 7-tetrahydro-1'-methyl-5-[2'methyl-4'5-(methyl-1,2,4-oxadiazol-3-y l) biphenyl-4-carbonyl]furo[2,3-f]indole-3-spiro-4'-piperidine hydrochloride (SB224289) antagonised concentration-response curves induced by 5-HT or 5-HT(1)-receptor-selective agonists. In addition to the 5-HT(2A) receptor, 5-HT activates a GR127935-sensitive and a GR127935-insensitive receptor in these arteries. Supernumerary arteries have a greater proportion of GR127935-sensitive receptors, which display only some of the pharmacological characteristics of the cloned 5-HT(ID) receptor. It is possible that the GR127935-sensitive receptor could be a species homologue of the human 5-HT(1B) receptor that is insensitive to SB224289.
Shaw
A M
AM
School of Biological and Biomedical Sciences, Glasgow Caledonian University, Cowcaddens Rd., Glasgow, G4 OBA, UK. a.m.shaw@gcal.ac.uk
Bunton
D C
DC
Brown
T
T
Irvine
J
J
MacDonald
A
A
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D002417:Cattle; D005576:Colforsin / Q000494:pharmacology; D066298:In Vitro Techniques; D009126:Muscle Relaxation / Q000187:drug effects; D011651:Pulmonary Artery / Q000378:metabolism*; D044346:Receptor, Serotonin, 5-HT1D; D011985:Receptors, Serotonin / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology
D044346:Receptor, Serotonin, 5-HT1D; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D005576:Colforsin; D012701:Serotonin; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000262:Adenylyl Cyclases