Zimmermann P A, Knot H J, Stevenson A S, Nelson M T
Department of Pharmacology, University of Vermont, Burlington 05405-0068, USA.
Circ Res. 1997 Dec;81(6):996-1004. doi: 10.1161/01.res.81.6.996.
Diabetes mellitus has profound adverse effects on vascular and, in particular, endothelial function. Although pressure-induced constriction ("myogenic tone") is a major contributor to the regulation of blood flow, little is known about the effects of diabetes on this response. Diabetes has been shown to diminish the dilation of cerebral arteries to synthetic ATP-sensitive K+ (KATP) channel openers. In this study, we explored the effects of diabetes induced in rats by streptozotocin on cerebral artery (250 to 300 microns) myogenic tone and on vasodilations to the synthetic KATP channel openers pinacidil and levcromakalim. Elevation of intravascular pressure caused a graded membrane potential depolarization and constriction, which was greater in arteries from diabetic rats compared with normal rats (at 60 mm Hg, 5 mV more depolarized and 22 microns more constricted). Pressurized arteries (at 60 mm Hg) from diabetic rats were 5- to 15-fold less sensitive to pinacidil and levcromakalim than were control arteries (EC50 values for pinacidil and levcromakalim were 1.4 and 0.6 mumol/L, respectively, in diabetic animals and 0.3 and 0.04, respectively, in control animals; P < .05). Removal of the endothelium or addition of a NO synthase inhibitor, NG-nitro-L-arginine (LNNA), in control arteries decreased the sensitivity to KATP channel openers and depolarized and constricted control arteries to levels similar to those observed in arteries from diabetic animals. Sodium nitroprusside caused a membrane potential hyperpolarization and enhanced the response to pinacidil in arteries from diabetic animals. Removal of the endothelium or LNNA had little effect on the apparent KATP channel opener sensitivity, the membrane potential, and pressure-induced constrictions of arteries from diabetic animals. The results are consistent with the hypothesis that this type of diabetes leads to a decrease in tonic NO release from the endothelium, which in turn causes membrane potential depolarization and vasoconstriction, resulting in a diminished response to KATP channel openers.
糖尿病对血管尤其是内皮功能有深远的不良影响。尽管压力诱导的收缩（“肌源性张力”）是调节血流的主要因素，但关于糖尿病对这种反应的影响却知之甚少。糖尿病已被证明会减弱脑动脉对合成的ATP敏感性钾（KATP）通道开放剂的舒张作用。在本研究中，我们探讨了链脲佐菌素诱导的大鼠糖尿病对脑动脉（250至300微米）肌源性张力以及对合成KATP通道开放剂吡那地尔和左卡尼汀的血管舒张作用的影响。血管内压力升高导致分级的膜电位去极化和收缩，与正常大鼠相比，糖尿病大鼠动脉的这种变化更明显（在60毫米汞柱时，去极化多5毫伏，收缩多22微米）。与对照动脉相比，糖尿病大鼠的加压动脉（60毫米汞柱）对吡那地尔和左卡尼汀的敏感性低5至15倍（糖尿病动物中吡那地尔和左卡尼汀的EC50值分别为1.4和0.6微摩尔/升，对照动物中分别为0.3和0.04微摩尔/升；P <.05）。去除内皮或在对照动脉中添加一氧化氮合酶抑制剂NG-硝基-L-精氨酸（LNNA）会降低对KATP通道开放剂的敏感性，并使对照动脉去极化和收缩至与糖尿病动物动脉中观察到的水平相似。硝普钠导致膜电位超极化，并增强了糖尿病动物动脉对吡那地尔的反应。去除内皮或LNNA对糖尿病动物动脉的表观KATP通道开放剂敏感性、膜电位和压力诱导的收缩影响很小。这些结果与以下假设一致，即这种类型的糖尿病导致内皮细胞持续释放一氧化氮减少，进而导致膜电位去极化和血管收缩，从而使对KATP通道开放剂的反应减弱。
