Bouzinova Elena V, Norregaard Rikke, Boedtkjer Donna M B, Razgovorova Irina A, Moeller Anaïs M J, Kudryavtseva Olga, Wiborg Ove, Aalkjaer Christian, Matchkov Vladimir V
From the Department of Clinical Medicine (E.V.B., R.N., O.W.), Aarhus University Hospital, Aarhus, Denmark; Department of Biomedicine (D.M.B.B., A.M.J.M., O.K., C.A.,V.V.M), MEMBRANES, Aarhus University, Aarhus, Denmark; and Department of General Physiology (I.A.R.), St Petersburg State University, St Petersburg, Russia.
Psychosom Med. 2014 May;76(4):268-76. doi: 10.1097/PSY.0000000000000062.
Cardiovascular diseases have high comorbidity with major depression. Endothelial dysfunction may explain the adverse cardiovascular outcome in depression; therefore, we analyzed it in vitro. In the chronic mild stress model, some rats develop depression-like symptoms (including "anhedonia"), whereas others are stress resilient.
After 8 weeks of chronic mild stress, anhedonic rats reduced their sucrose intake by 55% (7%), whereas resilient rats did not. Acetylcholine-induced endothelium-dependent relaxation of norepinephrine-preconstricted mesenteric arteries was analyzed in nonstressed, anhedonic, and resilient rat groups.
Small resistance arteries from anhedonic rats were less sensitive to acetylcholine than those of the nonstressed and resilient groups (p = .029). Pathways of endothelium-dependent relaxation were altered in arteries from anhedonic rats. Nitric oxide (NO)-dependent relaxation and endothelial NO synthase expression were increased in arteries from anhedonic rats (0.235 [0.039] arbitrary units and 155.7% [8.15%]) compared with the nonstressed (0.135 [0.012] arbitrary units and 100.0% [8.08%]) and resilient (0.152 [0.018] arbitrary units and 108.1% [11.65%]) groups (p < .001 and p = .002, respectively). Inhibition of cyclooxygenase (COX) activity revealed increased COX-2-dependent relaxation in the anhedonic group. In contrast, endothelial NO synthase- and COX-independent relaxation to acetylcholine (endothelium-dependent hyperpolarization-like response) was reduced in anhedonic rats (p < .001). This was associated with decreased transcription of intermediate-conductance Ca-activated K channels.
Our findings demonstrate that depression-like symptoms are associated with reduced endothelium-dependent relaxation due to suppressed endothelium-dependent hyperpolarization-like relaxation despite up-regulation of the NO and COX-2-dependent pathways in rat mesenteric arteries. These changes could affect peripheral resistance and organ perfusion in major depression.
心血管疾病与重度抑郁症的共病率很高。内皮功能障碍可能解释了抑郁症患者不良的心血管结局；因此，我们进行了体外分析。在慢性轻度应激模型中，一些大鼠出现类似抑郁的症状（包括“快感缺失”），而另一些大鼠则具有应激恢复能力。
经过8周的慢性轻度应激后，快感缺失的大鼠蔗糖摄入量减少了55%（7%），而具有应激恢复能力的大鼠则没有。在未受应激、快感缺失和具有应激恢复能力的大鼠组中，分析了乙酰胆碱诱导的去甲肾上腺素预收缩肠系膜动脉的内皮依赖性舒张。
与未受应激和具有应激恢复能力的大鼠组相比，快感缺失大鼠的小阻力动脉对乙酰胆碱的敏感性较低（p = 0.029）。快感缺失大鼠动脉中内皮依赖性舒张途径发生改变。与未受应激组（0.135[0.012]任意单位和100.0%[8.08%]）和具有应激恢复能力组（0.152[0.018]任意单位和108.1%[11.65%]）相比，快感缺失大鼠动脉中一氧化氮（NO）依赖性舒张和内皮型一氧化氮合酶表达增加（分别为0.235[0.039]任意单位和155.7%[8.15%]）（p < 0.001和p = 0.002）。环氧合酶（COX）活性的抑制显示快感缺失组中COX-2依赖性舒张增加。相反，快感缺失大鼠中对乙酰胆碱的内皮型一氧化氮合酶和COX非依赖性舒张（内皮依赖性超极化样反应）减少（p < 0.001）。这与中电导钙激活钾通道转录减少有关。
我们的研究结果表明，尽管大鼠肠系膜动脉中NO和COX-2依赖性途径上调，但类似抑郁的症状与内皮依赖性舒张减少有关，这是由于内皮依赖性超极化样舒张受到抑制。这些变化可能会影响重度抑郁症患者的外周阻力和器官灌注。
