Jn. Trochu et al., Beta 3-adrenoceptor stimulation induces vasorelaxation mediated essentially by endothelium-derived nitric oxide in rat thoracic aorta, BR J PHARM, 128(1), 1999, pp. 69-76
1 The relaxant effects of isoprenaline may result from activation of anothe
r beta-adrenoceptor subtype in addition to beta(1) and beta(2). This study
evaluated the role of a third beta-adrenoceptor subtype, beta(3), in beta-a
drenoceptor-induced relaxation of rat thoracic aorta by isoprenaline.
2 Isoprenaline produced a concentration-dependent relaxation of phenylephri
ne pre-contracted rings of the thoracic aorta (pD(2) = 7.46 +/- 0.15; E-max
= 85.9 +/- 3.4%), which was partially attenuated by endothelium removal (E
-max = 66.5 +/- 6.3%) and administration of the nitric oxide (NO) synthase
inhibitor, L-NG-monomethyl arginine (L-NMMA:) (E-max = 61.3 +/- 7.9%).
3 In the presence of nadolol, a beta(1)- and beta(2)-adrenoceptor antagonis
t, isoprenaline-induced relaxation persisted (E-max = 55.6 +/- 5.3%), but o
ccurred at higher concentrations (pD(2) = 6.71 +/- 0.10) than in the absenc
e of nadolol and lasted longer.
4 Similar relaxant effects were obtained with two beta(3)-adrenoceptor agon
ists: SR 58611 (a preferential beta(3)-adrenoceptor agonist), and CGP 12177
(a partial beta(3)-adrenoceptor with beta(1)- and beta(2)-adrenoceptor ant
agonistic properties). SR 58611 caused concentration-dependent relaxation (
pD(2) = 5.24 +/- 0.07; E-max = 59.5 +/- 3.7%), which was not modified by pr
e-treatment with nadolol but antagonized by SR 59230A, a beta(3)-adrenocept
or 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 grea
tly reduced by endothelium removal and in the presence of L-NMMA.
6 We conclude that in the rat thoracic aorta, beta(3)-adrenoceptors are mai
nly located on endothelial cells, and act in conjuction with beta(1)- and b
eta(2)-adrenoceptors to mediate relaxation through activation of an NO synt
hase pathway and subsequent increase in cyclic GMP levels.