Premium
Exposure and characterization of the action of noradrenaline at dopamine receptors mediating endothelium‐independent relaxation of rat isolated small mesenteric arteries
Author(s) -
Graaf Pieter H.,
Saxena Pramod R.,
Shankley Nigel P.,
Black James W.
Publication year - 1995
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1995.tb15130.x
Subject(s) - prazosin , rauwolscine , schild regression , chemistry , endocrinology , medicine , agonist , thromboxane a2 , forskolin , antagonist , receptor
1 Previously, we reported that noradrenaline (NA), in addition to its α 1 ‐adrenoceptor‐mediated contractile effect, may relax the rat small mesenteric artery (SMA) in order to account for steep Schild plots obtained with compounds classified as α 1 ‐adrenoceptor antagonists. In this study, a relaxant action of NA has been exposed in the rat isolated, endothelium‐denuded SMA precontracted by the thromboxane A 2 ‐mimetic, U46619. 2 NA, but not the selective α 2 ‐adrenoceptor agonist, UK14304, produced concentration‐dependent contraction of the SMA (pEC 50 = 5.7 ± 0.1). After precontraction with 0.1 μ m U46619, 10 nM – 30 μ m NA produced a further contraction (pEC 50 = 6.1 ± 0.2), while higher concentrations of NA produced small, but significant, relaxant responses. 3 In the presence of 1 μ m prazosin, 0.1–30 μ m NA produced concentration‐dependent relaxation (pIC 50 = 5.9 ± 0.1) after precontraction with 0.1 μ m U46619. The NA relaxation concentration‐effect curve was completely inhibited by 1 μ m of the β/β‐adrenoceptor antagonist, timolol. However, when the concentration of prazosin was increased by 10 fold (10 μ m ), NA once again produced concentration‐ dependent relaxation (pIC 50 = 4.5 ± 0.2). This relaxation concentration‐effect curve was not blocked by a 10 fold higher concentration of timolol (10 μ m ), nor by the presence of idazoxan (10 μ m ), cyanopindolol (10 μ m ), N G ‐nitro‐L‐arginine methyl ester (L‐NAME, 100 μ m ), indomethacin (10 μ m ) or sulpiride (1 μ m ). However, haloperidol (10 μ m ) and ±‐SCH‐23390 (10 nM) produced significant inhibition of the relaxation, suggesting the involvement of dopamine D 1 receptors. 4 Dopamine also produced concentration‐dependent relaxation following U46619 precontraction (pIC 50 = 5.4 ± 0.1) which was significantly inhibited by haloperidol and (±)‐SCH‐23390. Pretreatment with 10 μ m phenoxybenzamine for 60 min produced a significant inhibition of the dopamine and NA relaxation curves and application of the operational model of agonism yielded estimates of the affinity (pK A = 5.3 ± 0.2 and 4.4 ± 0.2) and efficacy (log τ = 0.06 ± 0.11 and 0.01 ± 0.10) for dopamine and NA, respectively, at D 1 receptors. 5 HV723 (0.1 and 1 μ m ), a ligand that yielded a Schild plot slope parameter of unity as an antagonist of NA in the contractile assay, produced concentration‐dependent inhibition of the NA‐mediated relaxation (pA2∼8). 6 The results of this study indicate that NA can activate D 1 receptors mediating relaxation in the rat SMA at concentrations which were encountered in our previous receptor classification experiments using competitive α 1 ‐adrenoceptors; antagonists.