Brede Marc, Wiesmann Frank, Jahns Roland, Hadamek Kerstin, Arnolt Carsten, Neubauer Stefan, Lohse Martin J, Hein Lutz
Institut für Pharmakologie und Toxikologie, Universität Würzburg, Germany.
Circulation. 2002 Nov 5;106(19):2491-6. doi: 10.1161/01.cir.0000036600.39600.66.
Elevated plasma norepinephrine levels are associated with increased mortality in patients and in animal models with chronic heart failure. To test which alpha2-adrenoceptor subtypes operate as presynaptic inhibitory receptors to control norepinephrine release in heart failure, we investigated the response of gene-targeted mice lacking alpha2-adrenoceptor subtypes (alpha2-KO) to chronic left ventricular pressure overload. In addition, we determined the functional consequences of genetic variants of alpha2-adrenoceptors in human patients with chronic heart failure.
Cardiac pressure overload was induced by transverse aortic constriction. Three months after aortic banding, survival was dramatically reduced in alpha2A-KO (52%) and alpha2C-KO (47%) mice compared with wild-type and alpha2B-deficient (86%) animals. Excess mortality in alpha2A- and alpha2C-KO strains was attributable to heart failure with enhanced left ventricular hypertrophy and fibrosis and elevated circulating catecholamines. The clinical importance of this finding is emphasized by the fact that heart failure patients with a dysfunctional variant of the alpha2C-adrenoceptor had a worse clinical status and decreased cardiac function as determined by invasive catheterization and by echocardiography.
Our results indicate an essential function of alpha2A- and alpha2C-adrenoceptors in the prevention of heart failure progression in mice and human patients. Identification of heart failure patients with genetic alpha2-adrenoceptor variants as well as new alpha2-receptor subtype-selective drugs may represent novel therapeutic strategies in chronic heart failure and other diseases with enhanced sympathetic activation.
在慢性心力衰竭患者及动物模型中，血浆去甲肾上腺素水平升高与死亡率增加相关。为了测试哪种α2-肾上腺素能受体亚型作为突触前抑制性受体来控制心力衰竭时去甲肾上腺素的释放，我们研究了缺乏α2-肾上腺素能受体亚型（α2-KO）的基因靶向小鼠对慢性左心室压力超负荷的反应。此外，我们还确定了慢性心力衰竭患者中α2-肾上腺素能受体基因变异的功能后果。
通过横断主动脉缩窄诱导心脏压力超负荷。主动脉缩窄三个月后，与野生型和α2B缺陷型（86%）动物相比，α2A-KO（52%）和α2C-KO（47%）小鼠的存活率显著降低。α2A-和α2C-KO品系的高死亡率归因于心力衰竭，伴有左心室肥厚和纤维化加重以及循环儿茶酚胺升高。侵入性导管检查和超声心动图显示，α2C-肾上腺素能受体功能异常的心力衰竭患者临床状况较差且心功能降低，这一事实强调了这一发现的临床重要性。
我们的结果表明α2A-和α2C-肾上腺素能受体在预防小鼠和人类患者心力衰竭进展中具有重要作用。识别具有α2-肾上腺素能受体基因变异的心力衰竭患者以及新型α2-受体亚型选择性药物可能代表慢性心力衰竭和其他交感神经激活增强疾病的新治疗策略。
