某些胍基化合物对人脑动脉的影响。
Effects of some guanidino compounds on human cerebral arteries.
作者信息
Segarra G, Medina P, Ballester R M, Lluch P, Aldasoro M, Vila J M, Lluch S, Pelligrino D A
机构信息
Department of Physiology, University of Valencia, 46010, Valencia, Spain.
出版信息
Stroke. 1999 Oct;30(10):2206-10; discussion 2210-11. doi: 10.1161/01.str.30.10.2206.
BACKGROUND AND PURPOSE
Accumulation of endogenous guanidino-substituted analogues of L-arginine in chronic renal failure might contribute to some of the vascular and neurological disorders of this pathology. We tested the hypothesis that in human cerebral arteries, some guanidino compounds may increase vascular tone, through nitric oxide (NO) synthase inhibition, and impair endothelium-dependent relaxation.
METHODS
Rings of human middle cerebral artery were obtained during autopsy of 26 patients who had died 3 to 12 hours before. The rings were suspended in organ baths for isometric recording of tension. We then studied the responses to N(G)-monomethyl-L-arginine (L-NMMA), N(G),N(G)-dimethyl-L-arginine (asymmetrical dimethylarginine; ADMA), aminoguanidine (AG), and methylguanidine (MG).
RESULTS
L-NMMA (10(-6) to 3x10(-4) mol/L) and ADMA (10(-6) to 3x10(-4) mol/L) caused concentration- and endothelium-dependent contractions (median effective concentrations [EC(50)]=1.1x10(-5) and 1.6x10(-5) mol/L, respectively; E(max)=35. 5+/-7.9% and 43.9+/-5.9% of the response to 100 mmol/L KCl). AG (10(-5) to 3x10(-3) mol/L) and MG (10(-5) to 3x10(-3) mol/L) produced endothelium-independent contractions (E(max)=44.3+/-8.8% and 45.7+/-5.8% of the response to 100 mmol/L KCl, respectively). L-Arginine (10(-3) mol/L) prevented the contractions by L-NMMA and ADMA but did not change contractions induced by AG and MG. L-NMMA and ADMA inhibited endothelium-dependent relaxation induced by acetylcholine in a concentration-dependent manner; AG and MG were without effect.
CONCLUSIONS
The results suggest that the contractions induced by L-NMMA and ADMA are due to inhibition of endothelial NO synthase activity, whereas AG and MG do not affect the synthesis of NO. An increase in the plasma concentration of L-NMMA and ADMA associated with uremia is likely to represent a diminished release or effect of NO, and consequently, an increased cerebrovascular tone in uremic patients is highly conceivable.
背景与目的
慢性肾衰竭时内源性L - 精氨酸的胍基取代类似物蓄积可能与该病理状态下的一些血管和神经紊乱有关。我们检验了这样一个假说：在人脑动脉中，一些胍基化合物可能通过抑制一氧化氮（NO）合酶来增加血管张力，并损害内皮依赖性舒张功能。
方法
从26例在死亡前3至12小时进行尸检的患者获取大脑中动脉环。将血管环悬挂于器官浴槽中进行等长张力记录。然后我们研究了血管环对N(G)-单甲基-L-精氨酸（L-NMMA）、N(G),N(G)-二甲基-L-精氨酸（不对称二甲基精氨酸；ADMA）、氨基胍（AG）和甲基胍（MG）的反应情况。
结果
L-NMMA（10⁻⁶至3×10⁻⁴mol/L）和ADMA（10⁻⁶至3×10⁻⁴mol/L）引起浓度和内皮依赖性收缩（半数有效浓度[EC₅₀]分别为1.1×10⁻⁵和1.6×10⁻⁵mol/L；最大效应[E(max)]分别为对100mmol/L氯化钾反应的35.5±7.9%和43.9±5.9%）。AG（10⁻⁵至3×10⁻³mol/L）和MG（10⁻⁵至3×10⁻³mol/L）产生非内皮依赖性收缩（E(max)分别为对100mmol/L氯化钾反应的44.3±8.8%和45.7±5.8%）。L-精氨酸（10⁻³mol/L）可阻止L-NMMA和ADMA引起的收缩，但不改变AG和MG诱导的收缩。L-NMMA和ADMA以浓度依赖性方式抑制乙酰胆碱诱导内皮依赖性舒张；AG和MG则无此作用。
结论
结果表明，L-NMMA和ADMA诱导的收缩是由于内皮型NO合酶活性受到抑制，而AG和MG不影响NO的合成。与尿毒症相关的L-NMMA和ADMA血浆浓度升高可能意味着NO释放减少或作用减弱，因此，尿毒症患者脑血管张力增加是完全可以想象的。
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