Varin R, Mulder P, Richard V, Tamion F, Devaux C, Henry J P, Lallemand F, Lerebours G, Thuillez C
Department of Pharmacology, VACOMED, Rouen University Medical School, Rouen, France.
Circulation. 1999 Jun 8;99(22):2951-7. doi: 10.1161/01.cir.99.22.2951.
Flow-mediated dilatation (FMD) of the peripheral arteries may be impaired in chronic heart failure (CHF), and this could contribute to the increased peripheral resistance and exercise intolerance that occur with this disease. Physical exercise improves the FMD of large conduit arteries in CHF, but whether a similar impairment also occurs in smaller arteries is unknown. The mechanisms of the changes in FMD after CHF or exercise are also unknown.
FMD was assessed in isolated, perfused, and preconstricted gracilis muscle arteries from sham-operated rats or CHF rats (coronary artery ligation) who were either sedentary or exercised (30-minute swimming period twice a day for 10 weeks, starting 7 days after ligation). In animals with hemodynamic and echographic signs of CHF, FMD was abolished and converted into vasoconstriction (percent change in diameter after 370 microL/min flow: sham, 42+/-5%; CHF, -4+/-3%; P<0.05). Exercise partially restored FMD (18+/-3%; P<0.05 versus CHF). In sham rats, FMD was abolished by the nitric oxide-synthase inhibitor Nomega-nitro-L-arginine (L-NA) but unaffected by the cyclooxygenase inhibitor diclofenac or the free radical scavenger N-(2-mercaptopropionyl)-glycine (MPG). In arteries from sedentary CHF rats, FMD was not modified by L-NA, but it was partially restored by diclofenac or MPG. In exercised CHF rats, FMD was abolished by L-NA and only moderately improved by diclofenac or MPG. Likewise, endothelial nitric oxide synthase mRNA expression (determined by reverse transcription polymerase chain reaction at the level of the gracilis muscle) was reduced by CHF, and this was prevented by exercise.
CHF abolishes the FMD of small arteries by impairing the nitric oxide pathway, increasing oxidant stress, and releasing a prostanoid-contracting factor. Exercise partially restores FMD by increasing expression of endothelial nitric oxide synthase and preventing the production of vasoconstrictor prostanoids and free radicals. Such restoration of FMD might contribute to the increase in exercise capacity after physical exercise in CHF.
慢性心力衰竭（CHF）患者外周动脉的血流介导的血管舒张（FMD）可能受损，这可能导致该疾病出现外周阻力增加和运动耐量下降。体育锻炼可改善CHF患者大的输送动脉的FMD，但较小动脉是否也存在类似损伤尚不清楚。CHF或运动后FMD变化的机制也不清楚。
对假手术大鼠或CHF大鼠（冠状动脉结扎）的分离、灌注并预先收缩的股薄肌动脉进行FMD评估，这些大鼠要么久坐不动，要么进行运动（结扎7天后开始，每天两次30分钟游泳，持续10周）。在有CHF血流动力学和超声心动图体征的动物中，FMD消失并转变为血管收缩（370微升/分钟血流后直径的百分比变化：假手术组，42±5%；CHF组，-4±3%；P<0.05）。运动部分恢复了FMD（18±3%；与CHF组相比P<,0.05）。在假手术大鼠中，一氧化氮合酶抑制剂Nω-硝基-L-精氨酸（L-NA）消除了FMD，但环氧合酶抑制剂双氯芬酸或自由基清除剂N-（2-巯基丙酰基）-甘氨酸（MPG）对其无影响。在久坐的CHF大鼠的动脉中，L-NA未改变FMD，但双氯芬酸或MPG部分恢复了FMD。在运动的CHF大鼠中，L-NA消除了FMD，双氯芬酸或MPG仅使其适度改善。同样，CHF降低了内皮型一氧化氮合酶mRNA表达（通过股薄肌水平的逆转录聚合酶链反应测定），而运动可防止这种降低。
CHF通过损害一氧化氮途径、增加氧化应激和释放一种前列腺素收缩因子来消除小动脉的FMD。运动通过增加内皮型一氧化氮合酶的表达并防止血管收缩性前列腺素和自由基产生来部分恢复FMD。FMD的这种恢复可能有助于CHF患者体育锻炼后运动能力的提高。
