Thakali Keshari M, Lau Yanny, Fink Gregory D, Galligan James J, Chen Alex F, Watts Stephanie W
Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824-1317, USA.
J Cardiovasc Pharmacol. 2006 Jun;47(6):742-50. doi: 10.1097/01.fjc.0000211789.37658.e4.
Loss of endothelial cell-derived nitric oxide (NO) in hypertension is a hallmark of arterial dysfunction. Experimental hypertension created by the removal of NO, however, involves mechanisms in addition to decreased arterial vasodilator activity. These include augmented endothelin-1 (ET-1) release, increased sympathetic nervous system activity, and elevated tissue oxidative stress. We hypothesized that increased venous smooth muscle (venomotor) tone plays a role in Nomega-nitro-L-arginine (LNNA) hypertension through these mechanisms. Rats were treated with the NO synthase inhibitor LNNA (0.5 g/L in drinking water) for 2 weeks. Mean arterial pressure of conscious rats was 119 +/- 2 mm Hg in control and 194 +/- 5 mm Hg in LNNA rats (P<0.05). Carotid arteries and vena cava were removed for measurement of isometric contraction. Maximal contraction to norepinephrine was modestly reduced in arteries from LNNA compared with control rats whereas the maximum contraction to ET-1 was significantly reduced (54% control). Maximum contraction of vena cava to norepinephrine (37% control) also was reduced but no change in response to ET-1 was observed. Mean circulatory filling pressure, an in vivo measure of venomotor tone, was not elevated in LNNA hypertension at 1 or 2 weeks after LNNA. The superoxide scavenger tempol (30, 100, and 300 micromol kg(-1), IV) did not change arterial pressure in control rats but caused a dose-dependent decrease in LNNA rats (-18 +/- 8, -26 +/- 15, and -54 +/- 11 mm Hg). Similarly, ganglionic blockade with hexamethonium caused a significantly greater fall in LNNA hypertensive rats (76 +/- 9 mm Hg) compared with control rats (35 +/- 10 mm Hg). Carotid arteries, vena cava, and sympathetic ganglia from LNNA rats had higher basal levels of superoxide compared with those from control rats. These data suggest that while NO deficiency increases oxidative stress and sympathetic activity in both arterial and venous vessels, the impact on veins does not make a major contribution to this form of hypertension.
高血压患者中内皮细胞源性一氧化氮（NO）的缺失是动脉功能障碍的一个标志。然而，通过去除NO所产生的实验性高血压涉及的机制除了动脉血管舒张活性降低外，还包括内皮素-1（ET-1）释放增加、交感神经系统活性增强以及组织氧化应激升高。我们推测静脉平滑肌（静脉运动）张力增加通过这些机制在N-ω-硝基-L-精氨酸（LNNA）高血压中起作用。将大鼠用NO合酶抑制剂LNNA（饮用水中0.5 g/L）处理2周。清醒大鼠的平均动脉压在对照组为119±2 mmHg，在LNNA大鼠中为194±5 mmHg（P<0.05）。取出颈动脉和腔静脉用于测量等长收缩。与对照大鼠相比，LNNA大鼠动脉对去甲肾上腺素的最大收缩略有降低，而对ET-1的最大收缩则显著降低（为对照的54%）。腔静脉对去甲肾上腺素的最大收缩（为对照的37%）也降低，但未观察到对ET-1反应的变化。平均循环充盈压是静脉运动张力的一种体内测量指标，在LNNA处理1周或2周后的LNNA高血压中并未升高。超氧化物清除剂tempol（30、100和300 μmol kg⁻¹，静脉注射）在对照大鼠中未改变动脉压，但在LNNA大鼠中引起剂量依赖性降低（-18±8、-26±15和-54±11 mmHg）。同样，与对照大鼠（35±10 mmHg）相比，六甲铵进行神经节阻断导致LNNA高血压大鼠的血压下降幅度显著更大（76±9 mmHg）。与对照大鼠相比，LNNA大鼠的颈动脉、腔静脉和交感神经节的超氧化物基础水平更高。这些数据表明，虽然NO缺乏会增加动脉和静脉血管中的氧化应激和交感神经活性，但对静脉的影响对这种形式的高血压没有主要贡献。
