Relaxations to beta-adrenoceptor subtype selective agonists in wild-type and NOS-3-KO mouse mesenteric arteries.
We have investigated the role of nitric oxide (NO) in relaxations to beta-adrenoceptor agonists in mesenteric artery from wild-type (WT) and NO synthase-3 knockout (NOS-3-KO) mice. Isoprenaline, formoterol and BRL 37344 ((R(),R())-(+/-)-4-[2-[(2-(3-chlorophenyl)-2-hydroxyethyl)amino]propyl]phenoxyacetic acid) were chosen as non-selective and beta(2)- and beta(3)-adrenoceptor agonists, respectively. Atenolol, ICI 118,551 ((+/-)-1-[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl)amino]-2-butanol hydrochloride) and SR59230A (1-(2-ethylphenoxy)-3-[[(1S)-1,2,3,4-tetrahydro-1-naphthalenyl]amino]-(2S)-2-propanol hydrochloride) were chosen as selective beta(1)-, beta(2)- and beta(3)-adrenoceptor antagonists, respectively. Experiments employing isoprenaline were carried out in the presence of prazosin (0.1 microM). Isoprenaline produced relaxations with a potency of 5.68+/-0.36 (-log M, n=6) in WT mice. Relaxations to isoprenaline were blocked by atenolol (10 microM) and were absent in vessels from NOS-3-KO animals. Formoterol produced relaxations with two components. ICI 118,551 (1 microM) abolished relaxations to low concentrations of formoterol (0.1-10 microM), but failed to affect relaxations to formoterol (100 microM). In NOS-3-KO mice only the highest concentration of formoterol (100 microM) produced relaxations: the relaxation was resistant to all of the beta-adrenoceptor antagonists employed. BRL 37344 (5.75+/-0.28, n=9) was approximately equipotent with isoprenaline but produced a smaller degree of relaxation, in WT mice. SR59230A (1 microM) abolished relaxations to BRL 37344 in WT mice. In NOS-3-KO mice, BRL 37344 produced concentration-dependent relaxations which were abolished by SR59230A. It is concluded that the predominant beta-adrenoceptor mediating relaxations in mouse mesenteric artery is beta(1), and relaxations involve NOS-3. In addition, beta(3)-adrenoceptors mediate smaller relaxations at least partly independent of NOS-3, and beta(2)-adrenoceptors may mediate smaller relaxations dependent on NOS-3.
Al Zubair
Khaled
K
Department of Physiology, Royal College of Surgeons in Ireland, 123 St. Stephens's Green, Dublin 2, Ireland.
Bexis
Sotiria
S
Docherty
James R
JR
D058665:Adrenergic beta-1 Receptor Agonists; D058671:Adrenergic beta-1 Receptor Antagonists; D058666:Adrenergic beta-2 Receptor Agonists; D058672:Adrenergic beta-2 Receptor Antagonists; D058667:Adrenergic beta-3 Receptor Agonists; D058673:Adrenergic beta-3 Receptor Antagonists; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004983:Ethanolamines / Q000494:pharmacology; D005260:Female; D000068759:Formoterol Fumarate; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D008638:Mesenteric Arteries / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000502:physiology*; D052250:Nitric Oxide Synthase Type III; D011189:Potassium Chloride / Q000494:pharmacology; D011943:Receptors, Adrenergic, beta / Q000187:drug effects*
D058665:Adrenergic beta-1 Receptor Agonists; D058671:Adrenergic beta-1 Receptor Antagonists; D058666:Adrenergic beta-2 Receptor Agonists; D058672:Adrenergic beta-2 Receptor Antagonists; D058667:Adrenergic beta-3 Receptor Agonists; D058673:Adrenergic beta-3 Receptor Antagonists; D000318:Adrenergic beta-Agonists; D004983:Ethanolamines; D011943:Receptors, Adrenergic, beta; C057368:BRL 37344; D011189:Potassium Chloride; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D007545:Isoproterenol; D000068759:Formoterol Fumarate