Department of Veterans' Affairs Medical Center, Iowa City, Iowa, USA.
Hypertension. 2010 Mar;55(3):652-9. doi: 10.1161/HYPERTENSIONAHA.109.142836. Epub 2010 Feb 8.
Inflammation is associated with increased sympathetic drive in cardiovascular diseases. Blood-borne proinflammatory cytokines, markers of inflammation, induce cyclooxygenase 2 (COX-2) activity in perivascular macrophages of the blood-brain barrier. COX-2 generates prostaglandin E(2), which may enter the brain and increase sympathetic nerve activity. We examined the contribution of this mechanism to augmented sympathetic drive in rats after myocardial infarction (MI). Approximately 24 hours after acute MI, rats received an intracerebroventricular injection (1 microL/min over 40 minutes) of clodronate liposomes (MI+CLOD) to eliminate brain perivascular macrophages, liposomes alone, or artificial cerebrospinal fluid. A week later, COX-2 immunoreactivity in perivascular macrophages and COX-2 mRNA and protein had increased in hypothalamic paraventricular nucleus of MI rats treated with artificial cerebrospinal fluid or liposomes alone compared with sham-operated rats. In MI+CLOD rats, neither perivascular macrophages nor COX-2 immunoreactivity was seen in the paraventricular nucleus, and COX-2 mRNA and protein levels were similar to those in sham-operated rats. Prostaglandin E(2) in cerebrospinal fluid, paraventricular nucleus neuronal excitation, and plasma norepinephrine were less in MI+CLOD rats than in MI rats treated with artificial cerebrospinal fluid or liposomes alone but more than in sham-operated rats. Intracerebroventricular CLOD had no effect on interleukin 1beta and tumor necrosis factor-alpha mRNA and protein in the paraventricular nucleus or plasma interleukin-1beta and tumor necrosis factor-alpha, which were increased in MI compared with sham-operated rats. In normal rats, pretreatment with intracerebroventricular CLOD reduced (P<0.05) the renal sympathetic, blood pressure, and heart rate responses to intracarotid artery injection of tumor necrosis factor-alpha (0.5 microg/kg); intracerebroventricular liposomes had no effect. The results suggest that proinflammatory cytokines stimulate sympathetic excitation after MI by inducing COX-2 activity and prostaglandin E(2) production in perivascular macrophages of the blood-brain barrier.
炎症与心血管疾病中交感神经驱动的增加有关。血源性促炎细胞因子，炎症的标志物，诱导血脑屏障血管周围巨噬细胞中环氧化酶 2（COX-2）的活性。COX-2 产生前列腺素 E（2），其可能进入大脑并增加交感神经活性。我们研究了这种机制在心肌梗死（MI）后大鼠交感神经驱动增加中的作用。急性 MI 后约 24 小时，大鼠接受脑室内注射（40 分钟内以 1μL/min 注射）氯膦酸盐脂质体（MI+CLOD）以消除脑血管周围巨噬细胞，单独脂质体或人工脑脊液。一周后，与假手术大鼠相比，用人工脑脊液或单独脂质体处理的 MI 大鼠下丘脑室旁核中的血管周围巨噬细胞 COX-2 免疫反应性以及 COX-2 mRNA 和蛋白均增加。在 MI+CLOD 大鼠中，室旁核中未见血管周围巨噬细胞和 COX-2 免疫反应性，COX-2 mRNA 和蛋白水平与假手术大鼠相似。MI+CLOD 大鼠脑脊液中的前列腺素 E（2）、室旁核神经元兴奋和血浆去甲肾上腺素均低于 MI 大鼠用人工脑脊液或单独脂质体处理，但高于假手术大鼠。脑室内 CLOD 对室旁核中的白细胞介素 1β和肿瘤坏死因子-α mRNA 和蛋白以及与假手术大鼠相比 MI 大鼠中增加的血浆白细胞介素-1β和肿瘤坏死因子-α没有影响。在正常大鼠中，脑室内预先给予 CLOD 降低了（P<0.05）肿瘤坏死因子-α（0.5μg/kg）经颈动脉内注射引起的肾交感神经、血压和心率反应；脑室内脂质体没有作用。结果表明，促炎细胞因子通过诱导血脑屏障血管周围巨噬细胞中环氧化酶 2（COX-2）的活性和前列腺素 E（2）的产生来刺激 MI 后交感神经兴奋。
