Activation of α_1A‐adrenoceptors desensitizes the rat aorta response to phenylephrine through a neuronal NOS pathway, a mechanism lost with ageing

Abstract

The α -adrenoceptor subtype, through endothelial nNOS-derived NO, may act as a physiological 'brake' against the detrimental effects of excessive α -adrenoceptor-mediated vasoconstriction. Reduced α -adrenoceptor- and nNOS-mediated desensitization in aged patients could be involved in the age-dependent elevation of adrenergic activity.

Stenosis coexists with compromised α1-adrenergic contractions in the ascending aorta of a mouse model of Williams-Beuren syndrome

“…Endothelial NO can exert an opposing modulatory influence on α1-adrenoceptor agonist vasoconstriction 24,49,50 . eNOS plays an important role in the decreased ability of a vessel to respond to subsequent stimulation Figure 6.…”

“…Agonist-induced contractile responses were studied by evaluating stimulation of α1-adrenoceptors with phenylephrine (10 −9 to 3 × 10 −5 M) or thromboxane A 2 receptors with U46619 (10 −9 to 3 × 10 −6 M). The effects of the non-selective nitric oxide synthase (NOS) inhibitor Nω-nitro-l-arginine methyl ester (L-NAME; 3 × 10 −4 M) 41 , the selective iNOS inhibitor 1400 W (10 −5 M) 41 , and the selective nNOS inhibitor SMTC (10 −6 M) 24 were determined by adding each treatment 30 min before phenylephrine-or ACh-induced responses.…”

“…A -adrenoceptor and nNOS were found in aortas from CD mice. A modulatory role of nNOS associated to activation of the α1 A -adrenoceptor subtype in aorta has been proposed as a physiological 'brake' against the detrimental effects of excessive adrenergic vasoconstriction 24 . We observed an increase (P < 0.05) in aortic Adra1a (α1 A -adrenoceptors) mRNA levels in CD compared to WT mice (Fig.…”

“…NO plays an important role in the decreased ability of a vessel to respond to persistent stimulation by α1-adrenoceptor agonists, a process called 'NO-mediated desensitization' 23 . Moreover, in aorta, a modulatory role of neuronal NOS (nNOS) associated to activation of the α1 A -adrenoceptor subtype has been proposed as a physiological 'brake' against the detrimental effects of excessive adrenergic vasoconstriction 24 . Remarkably, an impairment of NO responsiveness is reported in patients with aortic stenosis [25][26][27] , and a proportion of WBS patients manifest higher levels of oxidative stress 28 ; effects that might be associated with aortic dysfunction.…”

Updates in the function and regulation of α1‐adrenoceptors

“…However, information on the role of each of the individual α 1 -adrenoceptor subtype is limited to receptors expressed in vascular smooth muscle. Exceptions are the clear identification of NO production in endothelial cells from the rat aorta by α 1Aadrenoceptors (Arce et al, 2017), by α 1B -adrenoceptors in cultured endothelial cells from coronary arteries (Jensen, Swigart, Montgomery, & Simpson, 2010), and by α1Dadrenoceptors in endothelial cells from the rat mesenteric vascular bed and carotid artery (de Andrade et al, 2006;Filippi et al, 2001). With the increasing recognition of the importance of the perivascular adipose tissue for normal vascular function (Bulloch & Daly, 2014), it is expected that the roles of individual α 1adrenoceptor subtypes in the tunica adventitia will be soon elucidated.…”