Journal
BRITISH JOURNAL OF PHARMACOLOGY
Volume 148, Issue 5, Pages 629-639Publisher
WILEY
DOI: 10.1038/sj.bjp.0706749
Keywords
isoproterenol; beta-adrenoceptor; vascular reactivity; endothelium; nitric oxide; superoxide anions
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1 The aim of this study was to assess the effects of treatment with isoproterenol (ISO, 0.3 mg kg(-1) day(-1), s.c.) for 7 days on the vascular reactivity of rat-isolated aortic rings. Additionally, potential mechanisms underlying the changes that involved the endothelial modulation of contractility were investigated. 2 Treatment with ISO induced cardiac hypertrophy without changes in haemodynamic parameters. Aortic rings from ISO-treated rats showed an increase in the contraction response to phenylephrine (PHE) and serotonin, but did not change relaxations produced by acetylcholine or isoproterenol. Removal of the endothelium increased the responses to PHE in both groups. However, this procedure was less effective in ISO-treated as compared with control rats. Endothelial cell removal abolished the increase in the response to PHE in ISO-treated rats. The presence of N-omega-nitro-L-arginine methyl ester shifted the concentration-response curve to PHE to the left in both groups of rats. However, this effect was more pronounced in the ISO group. In addition, aminoguanidine (50 mM) potentiated the actions of PHE only in the ISO group. ISO treatment increased nitric oxide synthase ( NOS) activity and neuronal NOS and endothelial NOS protein expression in the aorta. 3 Neither losartan ( 10 mM) nor indomethacin ( 10 mM) abolished the effects of ISO on the actions of PHE. Superoxide dismutase ( SOD, 150 U ml(-1)) and L-arginine (5 mM), but neither catalase (300 U ml(-1)) nor apocynin ( 100 mM), blocked the effect of ISO treatment. In addition, we observed an increase in superoxide anion levels as measured by ethidium bromide fluorescence and of copper and zinc superoxide dismutase protein expression in ISO-treated rats. 4 In conclusion, our data suggest that ISO treatment alters the endothelial cell-mediated modulation of the contraction to PHE in rat aorta. The increased maximal response of PHE seems to be due to an increase in superoxide anion generation, which inactivates some of the basal NO produced and counteracts NO-mediated negative modulation even in the presence of high NO production and antioxidant defence.
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