Beta 3-adrenoceptor stimulation induces vasorelaxation mediated essentially by endothelium-derived nitric oxide in rat thoracic aorta.
1. The relaxant effects of isoprenaline may result from activation of another beta-adrenoceptor subtype in addition to beta1 and beta2. This study evaluated the role of a third beta-adrenoceptor subtype, beta3, in beta-adrenoceptor-induced relaxation of rat thoracic aorta by isoprenaline. 2. Isoprenaline produced a concentration-dependent relaxation of phenylephrine pre-contracted rings of the thoracic aorta (pD2=7.46+/-0.15; Emax=85.9+/-3.4%), which was partially attenuated by endothelium removal (Emax=66.5+/-6.3%) and administration of the nitric oxide (NO) synthase inhibitor, L-NG-monomethyl arginine (L-NMMA) (Emax=61.3+/-7.9%). 3. In the presence of nadolol, a beta1- and beta2-adrenoceptor antagonist, isoprenaline-induced relaxation persisted (Emax=55.6+/-5.3%), but occurred at higher concentrations (pD2=6.71+/-0.10) than in the absence of nadolol and lasted longer. 4. Similar relaxant effects were obtained with two beta3-adrenoceptor agonists: SR 58611 (a preferential beta3-adrenoceptor agonist), and CGP 12177 (a partial beta3-adrenoceptor with beta1- and beta2-adrenoceptor antagonistic properties). SR 58611 caused concentration-dependent relaxation (pD2=5.24+/-0.07; Emax=59.5+/-3.7%), which was not modified by pre-treatment with nadolol but antagonized by SR 59230A, a beta3-adrenoceptor antagonist. The relaxation induced by SR 58611 was associated with a 1.7 fold increase in tissue cyclic GMP content. 5 Both relaxation and the cyclic GMP increase induced by SR 58611 were greatly reduced by endothelium removal and in the presence of L-NMMA. 6 We conclude that in the rat thoracic aorta, beta3-adrenoceptors are mainly located on endothelial cells, and act in conjuction with beta1- and beta2-adrenoceptors to mediate relaxation through activation of an NO synthase pathway and subsequent increase in cyclic GMP levels.
Trochu
J N
JN
Laboratoire de Physiopathologie et Pharmacologie Cellulaires et Moléculaires, INSERM CJF 96-01, CHU de Nantes, Nantes, France.
Leblais
V
V
Rautureau
Y
Y
Bévérelli
F
F
Le Marec
H
H
Berdeaux
A
A
Gauthier
C
C
D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000502:physiology; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008297:Male; D009248:Nadolol / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D010656:Phenylephrine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D011412:Propanolamines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011943:Receptors, Adrenergic, beta / Q000502:physiology*; D022702:Receptors, Adrenergic, beta-3; D013764:Tetrahydronaphthalenes / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects*; D019323:omega-N-Methylarginine / Q000494:pharmacology
D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D011412:Propanolamines; D011943:Receptors, Adrenergic, beta; D022702:Receptors, Adrenergic, beta-3; D013764:Tetrahydronaphthalenes; D010656:Phenylephrine; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D009248:Nadolol; D019001:Nitric Oxide Synthase; D006152:Cyclic GMP; D007545:Isoproterenol; C076252:amibegron; C033394:CGP 12177