Relaxations to β-adrenoceptor subtype selective agonists in wild-type and NOS-3-KO mouse mesenteric arteries

May 6, 2008European journal of pharmacology

Relaxation responses to specific beta-adrenoceptor activators in normal and nitric oxide–deficient mouse blood vessels

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Abstract

Isoprenaline produced relaxations with a potency of 5.68 in wild-type mice.

Relaxations to isoprenaline were blocked by atenolol and absent in vessels from nitric oxide synthase-3 knockout (NOS-3-KO) mice.
Formoterol induced relaxations with two components; low concentrations were affected by a specific beta(2)-adrenoceptor antagonist, while high concentrations were not.
In NOS-3-KO mice, only the highest concentration of formoterol resulted in relaxations that were resistant to all tested beta-adrenoceptor antagonists.
BRL 37344 showed a potency of 5.75 and produced smaller relaxations compared to isoprenaline in wild-type mice.
In NOS-3-KO mice, BRL 37344 induced concentration-dependent relaxations that were abolished by a specific beta(3)-adrenoceptor antagonist.
The predominant beta-adrenoceptor mediating relaxations in mouse mesenteric artery is beta(1), and these relaxations involve nitric oxide synthase-3.

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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.

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Relaxations to β-adrenoceptor subtype selective agonists in wild-type and NOS-3-KO mouse mesenteric arteries

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