Exposure and characterization of the action of noradrenaline at dopamine receptors mediating endothelium-independent relaxation of rat isolated small mesenteric arteries.
1. Previously, we reported that noradrenaline (NA), in addition to its alpha 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 alpha 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 A2-mimetic, U46619. 2. NA, but not the selective alpha 2-adrenoceptor agonist, UK14304, produced concentration-dependent contraction of the SMA (pEC50 = 5.7 +/- 0.1). After precontraction with 0.1 microM U46619, 10 nM-30 microM NA produced a further contraction (pEC50 = 6.1 +/- 0.2), while higher concentrations of NA produced small, but significant, relaxant responses. 3. In the presence of 1 microM prazosin, 0.1-30 microM NA produced concentration dependent relaxation (pIC50 = 5.9 +/- 0.1) after precontraction with 0.1 microM U46619. The NA relaxation concentration-effect curve was completely inhibited by 1 microM of the beta 1/beta 2-adrenoceptor antagonist, timolol. However, when the concentration of prazosin was increased by 10 fold (10 microM), NA once again produced concentration-dependent relaxation (pIC50 = 4.5 +/- 0.2). This relaxation concentration-effect curve was not blocked by a 10 fold higher concentration of timolol (10 microM), nor by the presence of idazoxan (10 microM), cyanopindolol (10 microM), NG-nitro-L-arginine methyl ester (L-NAME, 100 microM), indomethacin (10 microM) or sulpiride (1 microM). However, haloperidol (10 microM) and (+/-)-SCH-23390 (10 nM) produced significant inhibition of the relaxation, suggesting the involvement of dopamine D1 receptors. 4. Dopamine also produced concentration-dependent relaxation following U46619 precontraction (pIC50 = 5.4 +/- 0.1) which was significantly inhibited by haloperidol and (+)-SCH-23390. Pretreatment with 10 microM 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 (pKA = 5.3 +/- 0.2 and 4.4 +/- 0.2) and efficacy (log gamma = 0.06 +/- 0.11 and 0.01 +/- 0.10) for dopamine and NA, respectively, at D1 receptors. 5. HV723 (0.1 and 1 microM), 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 approximately 8). 6. The results of this study indicate that NA can activate D1 receptors mediating relaxation in the rat SMA at concentrations which were encountered in our previous receptor classification experiments using competitive alpha 1-adrenoceptor antagonists.
Van der Graaf
P H
PH
Department of Pharmacology, Erasmus University Rotterdam, The Netherlands.
Saxena
P R
PR
Shankley
N P
NP
Black
J W
JW
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000097:Acetonitriles / Q000494:pharmacology; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D000068438:Brimonidine Tartrate; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004298:Dopamine / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D008833:Microcirculation / Q000187:drug effects; D019331:NG-Nitroarginine Methyl Ester; D009569:Nitric Oxide / Q000037:antagonists & inhibitors; D009638:Norepinephrine / Q000494:pharmacology*; D010643:Phenoxybenzamine / Q000494:pharmacology; D011450:Prostaglandin Endoperoxides, Synthetic; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011954:Receptors, Dopamine / Q000187:drug effects*; D012702:Serotonin Antagonists / Q000494:pharmacology; D013152:Splanchnic Circulation / Q000187:drug effects*; D013928:Thromboxane A2 / Q000031:analogs & derivatives; D014662:Vasoconstrictor Agents
D000097:Acetonitriles; D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D016861:Cyclooxygenase Inhibitors; D018492:Dopamine Antagonists; D011450:Prostaglandin Endoperoxides, Synthetic; D011810:Quinoxalines; D011954:Receptors, Dopamine; D012702:Serotonin Antagonists; D014662:Vasoconstrictor Agents; D010643:Phenoxybenzamine; C058562:HV 723; D009569:Nitric Oxide; D000068438:Brimonidine Tartrate; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D001120:Arginine; D019331:NG-Nitroarginine Methyl Ester; D004298:Dopamine; D009638:Norepinephrine; D007213:Indomethacin