Relaxations to β-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 β-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 β2- and β3-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 β1-, β2- and β3-adrenoceptor antagonists, respectively. Experiments employing isoprenaline were carried out in the presence of prazosin (0.1 µM). 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 µM) and were absent in vessels from NOS-3-KO animals. Formoterol produced relaxations with two components. ICI 118,551 (1 µM) abolished relaxations to low concentrations of formoterol (0.1–10 µM), but failed to affect relaxations to formoterol (100 µM). In NOS-3-KO mice only the highest concentration of formoterol (100 µM) produced relaxations: the relaxation was resistant to all of the β-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 µM) 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 β-adrenoceptor mediating relaxations in mouse mesenteric artery is β1, and relaxations involve NOS-3. In addition, β3-adrenoceptors mediate smaller relaxations at least partly independent of NOS-3, and β2-adrenoceptors may mediate smaller relaxations dependent on NOS-3.