Department of Pharmacology and Toxicology, Cardiovascular Research Institute Maastricht (CARIM), University of Maastricht, The Netherlands.
Br J Pharmacol. 2009 Apr;156(8):1239-47. doi: 10.1111/j.1476-5381.2009.00128.x. Epub 2009 Mar 19.
We tested the hypothesis that activated arterial smooth muscle (ASM) stimulates endothelial vasomotor influences via gap junctions and that the significance of this myoendothelial coupling increases with decreasing arterial diameter.
From WKY rats, first-, second-, third- and fourth-order branches of the superior mesenteric artery (MA1, MA2, MA3 and MA4 respectively) were isolated and mounted in wire-myographs to record vasomotor responses to 0.16-20 micromol x L(-1) phenylephrine.
Removal of endothelium increased the sensitivity (pEC(50)) to phenylephrine in all arteries. The nitric oxide (NO) synthase inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME) (100 micromol x L(-1)) did not modify pEC(50) to phenylephrine in all denuded arteries, and increased it in intact MA1, MA2 and MA3 to the same extent as denudation. However, in intact MA4, the effect of L-NAME was significantly larger (DeltapEC(50) 0.57 +/- 0.02) than the effect of endothelium removal (DeltapEC(50) 0.20 +/- 0.06). This endothelium-dependent effect of L-NAME in MA4 was inhibited by (i) steroidal and peptidergic uncouplers of gap junctions; (ii) a low concentration of the NO donor sodium nitroprusside; and (iii) by the endothelin-receptor antagonist bosentan. It was also observed during contractions induced by (i) calcium channel activation (BayK 8644, 0.001-1 micromol x L(-1)); (ii) depolarization (10-40 mmol x L(-1) K(+)); and (iii) sympathetic nerve stimulation (0.25-32 Hz).
These pharmacological observations indicated feedback control by endothelium of ASM reactivity involving gap junctions and a balance between endothelium-derived NO and endothelin-1. This myoendothelial coupling was most prominent in distal resistance arteries.
我们通过实验验证了这样一个假说，即激活的动脉平滑肌（ASM）通过缝隙连接刺激内皮血管舒缩功能，并且这种肌内皮偶联的重要性随着动脉直径的减小而增加。
从 WKY 大鼠中分离出肠系膜上动脉（MA1、MA2、MA3 和 MA4）的第一、二、三和四级分支，并将其安装在带有线的肌动描记器中，以记录对 0.16-20 μmol/L 苯肾上腺素的血管舒缩反应。
去除内皮增加了所有动脉对苯肾上腺素的敏感性（pEC50）。一氧化氮（NO）合酶抑制剂 N（ω）-硝基-L-精氨酸甲酯（L-NAME）（100 μmol/L）在所有去内皮动脉中均不改变苯肾上腺素的 pEC50，并且在完整的 MA1、MA2 和 MA3 中增加了与去内皮相同的程度。然而，在完整的 MA4 中，L-NAME 的作用明显更大（pEC50 差值 0.57 ± 0.02），大于内皮去除的作用（pEC50 差值 0.20 ± 0.06）。MA4 中 L-NAME 的这种内皮依赖性作用被（i）缝隙连接的甾体和肽偶联阻断剂；（ii）低浓度的一氧化氮供体硝普钠；和（iii）内皮素受体拮抗剂波生坦抑制。在由（i）钙通道激活（BayK 8644，0.001-1 μmol/L）；（ii）去极化（10-40 mmol/L K+）；和（iii）交感神经刺激（0.25-32 Hz）引起的收缩期间也观察到了这种作用。
这些药理学观察结果表明，内皮通过缝隙连接反馈控制 ASM 反应性，涉及内皮衍生的一氧化氮和内皮素-1 之间的平衡。这种肌内皮偶联在远端阻力血管中最为明显。
