Erdei Nóra, Bagi Zsolt, Edes István, Kaley Gabor, Koller Akos
Dept. of Physiology, New York Medical College, Valhalla, NY 10595, USA.
Am J Physiol Heart Circ Physiol. 2007 Jan;292(1):H649-56. doi: 10.1152/ajpheart.00596.2006. Epub 2006 Sep 22.
Our previous study showed that arteriolar tone is enhanced in Type 2 diabetes mellitus (T2-DM) due to an increased level of constrictor prostaglandins. We hypothesized that, in mice with T2-DM, hydrogen peroxide (H(2)O(2)) is involved in the increased synthesis of constrictor prostaglandins, hence enhanced basal tone in skeletal muscle arterioles. Isolated, pressurized gracilis muscle arterioles ( approximately 100 microm in diameter) of mice with T2-DM (C57BL/KsJ-db(-)/db(-)) exhibited greater basal tone to increases in intraluminal pressure (20-120 mmHg) than that of control vessels (at 80 mmHg, control: 25 +/- 5%; db/db: 34 +/- 4%, P < 0.05), which was reduced back to control level by catalase (db/db: 24 +/- 4%). Correspondingly, in carotid arteries of db/db mice, the level of dichlorofluorescein-detectable and catalase-sensitive H(2)O(2) was significantly greater. In control arterioles, exogenous H(2)O(2) (0.1-100 micromol/l) elicited dilations (maximum, 58 +/- 10%), whereas in arterioles of db/db mice H(2)O(2) caused constrictions (-28 +/- 8%), which were converted to dilations (maximum, 16 +/- 5%) by the thromboxane A(2)/prostaglandin H(2) (TP) receptor antagonist SQ-29548. In addition, arteriolar constrictions in response to the TP receptor agonist U-46619 were not different between the two groups of vessels. Endothelium denudation did not significantly affect basal tone and H(2)O(2)-induced arteriolar responses in either control or db/db mice. Also, in arterioles of db/db mice, but not in controls, 3-nitrotyrosine staining was detected in the endothelial layer of vessels. Thus we propose that, in mice with T2-DM, arteriolar production of H(2)O(2) is enhanced, which leads to increased synthesis of the constrictor prostaglandins thromboxane A(2)/prostaglandin H(2) in the smooth muscle cells, which enhance basal arteriolar tone. These alterations may contribute to disturbed regulation of skeletal muscle blood flow in Type 2 diabetes mellitus.
我们之前的研究表明，由于缩血管前列腺素水平升高，2型糖尿病（T2-DM）患者的小动脉张力增强。我们推测，在T2-DM小鼠中，过氧化氢（H₂O₂）参与了缩血管前列腺素合成的增加，从而增强了骨骼肌小动脉的基础张力。与对照血管相比，T2-DM（C57BL/KsJ-db⁻/db⁻）小鼠分离的、加压的股薄肌小动脉（直径约100微米）对管腔内压力升高（20 - 120 mmHg）表现出更大的基础张力（在80 mmHg时，对照：25±5%；db/db：34±4%，P < 0.05），而过氧化氢酶可将其恢复到对照水平（db/db：24±4%）。相应地，在db/db小鼠的颈动脉中，二氯荧光素可检测到的、对过氧化氢酶敏感的H₂O₂水平显著更高。在对照小动脉中，外源性H₂O₂（0.1 - 100微摩尔/升）引起血管舒张（最大舒张幅度为58±10%），而在db/db小鼠的小动脉中，H₂O₂引起血管收缩（-28±8%），血栓素A₂/前列腺素H₂（TP）受体拮抗剂SQ - 29548可将其转变为血管舒张（最大舒张幅度为16±5%）。此外，两组血管对TP受体激动剂U - 46619的小动脉收缩反应没有差异。内皮剥脱对对照或db/db小鼠的基础张力和H₂O₂诱导的小动脉反应均无显著影响。同样，在db/db小鼠的小动脉中，而非对照小鼠中，在内皮层检测到3 - 硝基酪氨酸染色。因此，我们提出，在T2-DM小鼠中，小动脉H₂O₂的生成增强，这导致平滑肌细胞中缩血管前列腺素血栓素A₂/前列腺素H₂的合成增加，从而增强了小动脉的基础张力。这些改变可能导致2型糖尿病患者骨骼肌血流调节紊乱。
