Double disruption of alpha(2A)- and alpha(2C)-adrenoceptors induces endothelial dysfunction in mouse small arteries: role of nitric oxide synthase uncoupling

作者：Couto Gisele K; Davel Ana P; Brum Patricia C; Rossoni Luciana V^*

来源：Experimental Physiology, 2014, 99(10): 1427-1438.

DOI：10.1113/expphysiol.2014.079236

Knockout mice lacking both alpha(2A)- and alpha(2C)-adrenergic receptors (alpha(2A)/alpha(2C)-ARKO) provide a model for understanding the mechanisms underlying the deleterious effects of sympathetic hyperactivity on the cardiovascular system. Thus, in the present study we investigated the vascular reactivity of large and small arteries of alpha(2A)/alpha(2C)-ARKO mice. Aorta and mesenteric small arteries (MSAs) from 7-month-old male alpha(2A)/alpha(2C)-ARKO mice and congenic C57BL6/J mice (wild-type, WT) were studied. In the aorta, noradrenaline-and serotonin-induced contraction was similar between groups, but in MSAs there was an increase in agonist-induced contraction in alpha(2A)/alpha(2C)-ARKO compared with WT. The l-NAME effect was reduced in MSAs of alpha(2A)/alpha(2C)-ARKO mice compared with WT mice, as was basal NO evaluated by a 4,5-diaminofluorescein diacetate probe. Increased total endothelial nitric oxide synthase (eNOS) protein expression was observed in MSAs from alpha(2A)/alpha(2C)-ARKO mice, while the dimer/monomer ratio of eNOS was decreased. Mesenteric small arteries from alpha(2A)/alpha(2C)-ARKO mice showed an increase in ethidium bromide-positive nuclei, indicating oxidative stress, which was attenuated by incubation with l-NAME. The sympathetic hyperactivity present in alpha(2A)/alpha(2C)-ARKO mice alters vascular reactivity only in certain types of arteries. Moreover, after chronic sympathetic hyperactivity, uncoupling eNOS may be a significant source of superoxide anion and reduced NO bioavailability in small vessels, increasing the contractile tone.

• 出版日期2014-10-1