Institute of Experimental and Clinical Pharmacology and Toxicology, University of Freiburg, Albertstrasse 25, Freiburg 79104, Germany.
Cardiovasc Res. 2010 Jun 1;86(3):432-42. doi: 10.1093/cvr/cvq014. Epub 2010 Jan 18.
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.
α2-肾上腺素受体通过血管收缩或扩张、通过对交感神经活动的中枢抑制、或通过反馈抑制来自交感神经元的去甲肾上腺素释放来调节心血管功能。尽管对α2-受体的亚型特异性功能有详细的了解，但涉及这些心血管效应的交感神经与非交感神经受体的相对贡献尚未确定。本研究的目的是确定在基线和交感神经应激期间，α2A-肾上腺素受体在肾上腺素能与非肾上腺素能细胞中的生理和药理学作用。
生成了在多巴胺β-羟化酶（Dbh）启动子控制下表达α2A-肾上腺素受体的转基因小鼠，并与携带α2A-和α2C-肾上腺素受体基因组成型缺失的小鼠杂交。α2AC-缺陷型小鼠在基线时表现出较高的去甲肾上腺素血浆水平、心脏肥大和纤维化。Dbh-α2A 转基因在交感神经元中的表达可预防这些效应。相反，Dbh-α2A 受体仅介导了α2-激动剂美托咪定的部分心动过缓和低血压作用。在小鼠的横主动脉缩窄引起的慢性压力超负荷后，Dbh-α2A 转基因并未减少去甲肾上腺素溢出、心脏功能障碍、肥大或纤维化。在分离的野生型心房中，α2-激动剂诱导的[3H]去甲肾上腺素释放抑制在压力超负荷后明显脱敏。在来自 Dbh-α2A 转基因小鼠的原代交感神经元中，α2-激动剂诱导α2A-肾上腺素受体进入轴突过程的内吞作用。
在肾上腺素能细胞中表达的α2A-肾上腺素受体是防止基线时心脏肥大和纤维化的交感神经去甲肾上腺素释放的必需反馈抑制剂。然而，这些受体在慢性压力超负荷下脱敏，这反过来可能有助于这种情况的发病机制。
