Lindauer Ute, Vogt Johannes, Schuh-Hofer Sigrid, Dreier Jens P, Dirnagl Ulrich
Experimental Neurology, Charité, Humboldt-Universität, Berlin, Germany.
J Cereb Blood Flow Metab. 2003 Oct;23(10):1227-38. doi: 10.1097/01.WCB.0000088764.02615.B7.
Albeit controversial, it has been suggested by several authors that nitric oxide (NO) serves as a permissive factor in the cerebral blood flow response to systemic hypercapnia. Potassium channels are important regulators of cerebrovascular tone and may be modulated by a basal perivascular NO level. To elucidate the functional targets of the proposed NO modulation during hypercapnia-induced vasodilation, the authors performed experiments in isolated, cannulated, and pressurized rat middle cerebral arteries (MCA). Extracellular pH was reduced from 7.4 to 7.0 in the extraluminal bath to induce NO dependent vasodilation. Acidosis increased vessel diameter by 35 +/- 10%. In separate experiments, ATP-sensitive potassium channels (KATP) were blocked by extraluminal application of glibenclamide (Glib), Ca2+-activated potassium channels (KCa) by tetraethylammonium (TEA), voltage-gated potassium channels (Kv) by 4-aminopyridine, and inward rectifier potassium channels (KIR) by BaCl2. Na+-K+-ATP-ase was inhibited by ouabain. Application of TEA slightly constricted the arteries at pH 7.4 and slightly but significantly attenuated the vasodilation to acidosis. Inhibition of the other potassium channels or Na+-K+-ATP-ase had no effect. Combined blockade of KATP and KCa channels further reduced resting diameter, and abolished acidosis induced vasodilation. The authors conclude that mainly KCa channels are active under resting conditions. KATP and KCa channels are responsible for vasodilation to acidosis. Activity of one of these potassium channel families is sufficient for vasodilation to acidosis, and only combined inhibition completely abolishes vasodilation. During NO synthase inhibition, dilation to the KATP channel opener pinacidil or the KCa channel opener NS1619 was attenuated or abolished, respectively. The authors suggest that a basal perivascular NO level is necessary for physiologic KATP and KCa channel function in rat MCA. Future studies have to elucidate whether this NO dependent effect on KATP and KCa channel function is a principle mechanism of NO induced modulation of cerebrovascular reactivity and whether the variability of findings in the literature concerning a modulatory role of NO can be explained by different levels of vascular NO/cGMP concentrations within the cerebrovascular tree.
尽管存在争议，但几位作者提出，一氧化氮（NO）在脑血流对全身性高碳酸血症的反应中起允许作用。钾通道是脑血管张力的重要调节因子，可能受血管周围基础NO水平的调节。为了阐明高碳酸血症诱导血管舒张过程中所提出的NO调节的功能靶点，作者在离体、插管并加压的大鼠大脑中动脉（MCA）上进行了实验。将管腔外浴液中的细胞外pH从7.4降至7.0以诱导依赖NO的血管舒张。酸中毒使血管直径增加了35±10%。在单独的实验中，ATP敏感性钾通道（KATP）通过管腔外应用格列本脲（Glib）阻断，Ca2+激活钾通道（KCa）通过四乙铵（TEA）阻断，电压门控钾通道（Kv）通过4-氨基吡啶阻断，内向整流钾通道（KIR）通过BaCl2阻断。Na+-K+-ATP酶通过哇巴因抑制。在pH 7.4时，应用TEA使动脉轻微收缩，并且轻微但显著减弱了对酸中毒的血管舒张反应。抑制其他钾通道或Na+-K+-ATP酶没有效果。联合阻断KATP和KCa通道进一步减小了静息直径，并消除了酸中毒诱导的血管舒张。作者得出结论，在静息条件下主要是KCa通道起作用。KATP和KCa通道负责对酸中毒的血管舒张。这些钾通道家族中的一个的活性足以实现对酸中毒的血管舒张，并且只有联合抑制才能完全消除血管舒张。在一氧化氮合酶抑制期间，对KATP通道开放剂吡那地尔或KCa通道开放剂NS1619的舒张反应分别减弱或消除。作者提出，血管周围基础NO水平对于大鼠MCA中生理性KATP和KCa通道功能是必需的。未来的研究必须阐明这种对KATP和KCa通道功能的NO依赖性作用是否是NO诱导的脑血管反应性调节的主要机制，以及文献中关于NO调节作用的研究结果的变异性是否可以通过脑血管树内不同水平的血管NO/cGMP浓度来解释。
