Bratz Ian N, Kanagy Nancy L
Vascular Physiology Research Group, MSC 08-4750, Dept. of Cell Biology and Physiology, 1 Univ. of New Mexico Health Sciences Center, Albuquerque, NM 87131-0218, USA.
Am J Physiol Heart Circ Physiol. 2004 Dec;287(6):H2394-401. doi: 10.1152/ajpheart.00628.2004. Epub 2004 Aug 19.
We reported previously that endothelium-intact superior mesenteric arteries (SMA) from N(omega)-nitro-L-arginine (L-NNA)-treated hypertensive rats (LHR) contract more to norepinephrine (NE) than SMA from control rats. Others have shown that nitric oxide (NO) synthase (NOS) inhibition increases cyclooxygenase (COX) function and expression. We hypothesized that augmented vascular sensitivity to NE in LHR arteries is caused by decreased NOS-induced dilation and increased COX product-induced constriction. We observed that the EC50 for NE is lower in LHR SMA compared with control SMA (control -6.37 +/- 0.04, LHR -7.89 +/- 0.09 log mol/l; P <0.05). Endothelium removal lowered the EC50 (control -7.95 +/- 0.11, LHR -8.44 +/- 0.13 log mol/l; P <0.05) and increased maximum tension in control (control 1,036 +/- 38 vs. 893 +/- 21 mg; P <0.05) but not LHR (928 +/- 30 vs. 1,066 +/- 31 mg) SMA. Thus augmented NE sensitivity in LHR SMA depends largely on decreased endothelial dilation. NOS inhibition (L-NNA, 10(-4) mol/l) increased maximum tension and EC50 in control arteries but not in LHR arteries. In contrast, COX inhibition decreased maximum tension in control arteries, suggesting that COX products augment contraction. Indomethacin did not affect NE-induced contraction in L-NNA-treated or denuded arteries. In control SMA loaded with the fluorescent NO indicator 4-amino-5-methylamino-2',7'-difluorofluorescein diacetate, indomethacin increased and L-NNA decreased NO release. Therefore, COX products appear to inhibit NO production to augment NE-induced contraction. With chronic NOS inhibition, this modulating influence is greatly diminished. Thus, in NOS-inhibition hypertension, decreased activity of both COX and NOS pathways profoundly disrupts endothelial modulation of contraction.
我们之前报道过，用N（ω）-硝基-L-精氨酸（L-NNA）处理的高血压大鼠（LHR）的内皮完整的肠系膜上动脉（SMA）对去甲肾上腺素（NE）的收缩反应比对照大鼠的SMA更强。其他人已经表明，一氧化氮（NO）合酶（NOS）抑制会增加环氧合酶（COX）的功能和表达。我们假设，LHR动脉对NE的血管敏感性增强是由NOS诱导的舒张减少和COX产物诱导的收缩增加所致。我们观察到，与对照SMA相比，LHR SMA中NE的半数有效浓度（EC50）更低（对照-6.37±0.04，LHR -7.89±0.09 log mol/l；P<0.05）。去除内皮降低了EC50（对照-7.95±0.11，LHR -8.44±0.13 log mol/l；P<0.05），并增加了对照SMA的最大张力（对照1036±38对893±21 mg；P<0.05），但LHR SMA未增加（928±30对1066±31 mg）。因此，LHR SMA中NE敏感性增强很大程度上取决于内皮舒张的减少。NOS抑制（L-NNA，10⁻⁴ mol/l）增加了对照动脉的最大张力和EC50，但LHR动脉未增加。相反，COX抑制降低了对照动脉的最大张力，表明COX产物增强了收缩。吲哚美辛对L-NNA处理的或去内皮的动脉中NE诱导的收缩没有影响。在装载荧光NO指示剂4-氨基-5-甲基氨基-2'，7'-二氟荧光素二乙酸酯的对照SMA中，吲哚美辛增加而L-NNA减少NO释放。因此，COX产物似乎抑制NO生成以增强NE诱导的收缩。随着慢性NOS抑制，这种调节作用大大减弱。因此，在NOS抑制性高血压中，COX和NOS途径的活性降低深刻地破坏了内皮对收缩的调节。
