Department of Kinesiology, Kansas State University, Manhattan, Kansas.
Am J Physiol Heart Circ Physiol. 2019 Nov 1;317(5):H1050-H1061. doi: 10.1152/ajpheart.00399.2019. Epub 2019 Aug 30.
Mechanical and metabolic stimuli within contracting skeletal muscles reflexly increase sympathetic nervous system activity and blood pressure. That reflex, termed the exercise pressor reflex, is exaggerated in patients with peripheral artery disease (PAD) and in a rat PAD model with a chronically ligated femoral artery. The cyclooxygenase (COX) pathway contributes to the exaggerated pressor response during rhythmic skeletal muscle contractions in patients with PAD, but the specific mechanism(s) of the COX-mediated exaggeration are not known. In decerebrate, unanesthetized rats with a chronically ligated femoral artery ("ligated" rats), we hypothesized that hindlimb arterial injection of the COX inhibitor indomethacin would reduce the pressor response during 1-Hz dynamic hindlimb skeletal muscle stretch; a model of the activation of the mechanical component of the exercise pressor reflex (i.e., the mechanoreflex). In ligated rats ( = 7), indomethacin reduced the pressor response during stretch (control: 30 ± 4; indomethacin: 12 ± 3 mmHg; < 0.01), whereas there was no effect in rats with "freely perfused" femoral arteries ( = 6, control: 18 ± 5; indomethacin: 17 ± 5 mmHg; = 0.87). In ligated rats ( = 4), systemic indomethacin injection had no effect on the pressor response during stretch. Femoral artery ligation had no effect on skeletal muscle COX protein expression or activity or concentration of the COX metabolite prostaglandin E. Conversely, femoral artery ligation increased expression of the COX metabolite receptors endoperoxide 4 and thromboxane A-R in dorsal root ganglia tissue. We conclude that, in ligated rats, the COX pathway sensitizes the peripheral endings of mechanoreflex afferents, which occurs principally as a result of increased expression of COX metabolite receptors. We demonstrate that the mechanoreflex is sensitized by the cyclooxygenase (COX) pathway within hindlimb skeletal muscles in the rat chronic femoral artery ligation model of simulated peripheral artery disease (PAD). The mechanism of sensitization appears attributable to increased receptors for COX metabolites on sensory neurons and not increased concentration of COX metabolites. Our data may carry important clinical implications for patients with PAD who demonstrate exaggerated increases in blood pressure during exercise compared with healthy counterparts.
在收缩的骨骼肌中，机械和代谢刺激会反射性地增加交感神经系统活动和血压。这种反射称为运动加压反射，在周围动脉疾病（PAD）患者和股动脉慢性结扎的大鼠 PAD 模型中会被夸大。环氧化酶（COX）途径有助于 PAD 患者在节律性骨骼肌收缩期间的加压反应过度，但 COX 介导的夸张的具体机制尚不清楚。在股动脉慢性结扎的去大脑、未麻醉大鼠（“结扎”大鼠）中，我们假设向股动脉内注射 COX 抑制剂吲哚美辛会减少 1Hz 动态后肢骨骼肌拉伸过程中的加压反应；这是运动加压反射机械成分（即机械反射）的激活模型。在结扎大鼠中（n=7），吲哚美辛降低了拉伸过程中的加压反应（对照：30±4mmHg；吲哚美辛：12±3mmHg；<0.01），而在股动脉自由灌注的大鼠中则没有影响（n=6，对照：18±5mmHg；吲哚美辛：17±5mmHg；=0.87）。在结扎大鼠中（n=4），全身给予吲哚美辛对拉伸过程中的加压反应没有影响。股动脉结扎对骨骼肌 COX 蛋白表达或活性或 COX 代谢产物前列腺素 E 的浓度没有影响。相反，股动脉结扎增加了背根神经节组织中 COX 代谢产物受体环氧合酶 4 和血栓素 A-R 的表达。我们得出结论，在结扎大鼠中，COX 途径使机械反射传入纤维的外周末梢敏感化，这主要是由于 COX 代谢产物受体表达增加所致。我们证明，在大鼠慢性股动脉结扎模拟周围动脉疾病（PAD）模型中，后肢骨骼肌中的环氧化酶（COX）途径使机械反射敏感化。敏感化的机制似乎归因于感觉神经元上 COX 代谢产物受体的增加，而不是 COX 代谢产物浓度的增加。与健康对照组相比，我们的数据可能对 PAD 患者具有重要的临床意义，因为他们在运动过程中血压升高过度。
