Sympathetic 2-adrenoceptors prevent cardiac hypertrophy and fibrosis in mice at baseline but not after chronic pressure overload

Abstract

alpha(2)-Adrenoceptors modulate cardiovascular function by vasoconstriction or dilatation, by central inhibition of sympathetic activity, or by feedback inhibition of norepinephrine release from sympathetic neurons. Despite detailed knowledge about subtype-specific functions of alpha(2)-receptors, the relative contributions of sympathetic vs. non-sympathetic receptors involved in these cardiovascular effects have not been identified. The aim of this study was to define the physiological and pharmacological role of alpha(2A)-adrenoceptors in adrenergic vs. non-adrenergic cells at baseline and during sympathetic stress. Transgenic mice expressing alpha(2A)-adrenoceptors under control of the dopamine beta-hydroxylase (Dbh) promoter were generated and crossed with mice carrying a constitutive deletion in the alpha(2A)- and alpha(2C)-adrenoceptor genes. alpha(2AC)-deficient mice showed increased norepinephrine plasma levels, cardiac hypertrophy, and fibrosis at baseline. Expression of the Dbh-alpha(2A) transgene in sympathetic neurons prevented these effects. In contrast, Dbh-alpha(2A) receptors mediated only a minor part of the bradycardic and hypotensive effects of the alpha(2)-agonist medetomidine. After chronic pressure overload as induced by transverse aortic constriction in mice, the Dbh-alpha(2A) transgene did not reduce norepinephrine spillover, cardiac dysfunction, hypertrophy, or fibrosis. In isolated wild-type atria, alpha(2)-agonist-induced inhibition of [3H]norepinephrine release was significantly desensitized after pressure overload. In primary sympathetic neurons from Dbh-alpha(2A) transgenic mice, norepinephrine and medetomidine induced endocytosis of alpha(2A)-adrenoceptors into neurite processes. alpha(2A)-Adrenoceptors expressed in adrenergic cells are essential feedback inhibitors of sympathetic norepinephrine release to prevent cardiac hypertrophy and fibrosis at baseline. However, these receptors are desensitized by chronic pressure overload which in turn may contribute to the pathogenesis of this condition.