Bratz Ian N, Falcon Ricardo, Partridge L Donald, Kanagy Nancy L
Department of Cell Biology and Physiology, University of New Mexico School of Medicine, Albuquerque, New Mexico 87131-5218, USA.
Am J Physiol Heart Circ Physiol. 2002 May;282(5):H1648-55. doi: 10.1152/ajpheart.00824.2001.
Nitric oxide (NO) synthase (NOS) inhibition with N(omega)-nitro-L-arginine (L-NNA) produces L-NNA hypertensive rats (LHR), which exhibit increased sensitivity to voltage-dependent Ca(2+) channel-mediated vasoconstriction. We hypothesized that enhanced contractile responsiveness after NOS inhibition is mediated by depolarization of membrane potential (E(m)) through attenuated K(+) channel conductance. E(m) measurements demonstrated that LHR vascular smooth muscle cells (VSMCs) are depolarized in open, nonpressurized (-44.5 +/- 1.0 mV in control vs. -36.8 +/- 0.8 mV in LHR) and pressurized mesenteric artery segments (-41.8 +/- 1.0 mV in control vs. -32.6 +/- 1.4 mV in LHR). Endothelium removal or exogenous L-NNA depolarized control VSMCs but not LHR VSMCs. Superfused L-arginine hyperpolarized VSMCs from both the control and LHR groups and reversed L-NNA-induced depolarization (-44.5 +/- 1.0 vs. -45.8 +/- 2.1 mV). A Ca(2+)-activated K(+) channel agonist, NS-1619 (10 microM), hyperpolarized both groups of arteries to a similar extent (from -50.8 +/- 1.0 to -62.5 +/- 1.2 mV in control and from -43.7 +/- 1.1 to -55.6 +/- 1.2 mV in LHR), although E(m) was still different in the presence of NS-1619. In addition, superfused iberiotoxin (50 nM) depolarized both groups similarly. Increasing the extracellular K(+) concentration from 1.2 to 45 mM depolarized E(m), as predicted by the Goldman-Hodgkin-Katz equation. These data support the hypothesis that loss of NO activation of K(+) channels contributes to VSMC depolarization in L-NNA-induced hypertension without a change in the number of functional large conductance Ca(2+)-activated K(+) channels.
用N（ω）-硝基-L-精氨酸（L-NNA）抑制一氧化氮（NO）合酶（NOS）可产生L-NNA高血压大鼠（LHR），这些大鼠对电压依赖性Ca（2+）通道介导的血管收缩表现出更高的敏感性。我们假设，NOS抑制后收缩反应性增强是通过K（+）通道电导减弱导致膜电位（E（m））去极化介导的。E（m）测量表明，LHR血管平滑肌细胞（VSMC）在开放的、未加压的肠系膜动脉段（对照组为-44.5±1.0 mV，LHR组为-36.8±0.8 mV）和加压的肠系膜动脉段（对照组为-41.8±1.0 mV，LHR组为-32.6±1.4 mV）中发生去极化。去除内皮或外源性L-NNA可使对照VSMC去极化，但不能使LHR VSMC去极化。灌注L-精氨酸可使对照组和LHR组的VSMC超极化，并逆转L-NNA诱导的去极化（-44.5±1.0对-45.8±2.1 mV）。Ca（2+）激活的K（+）通道激动剂NS-1619（10μM）使两组动脉超极化的程度相似（对照组从-50.8±1.0 mV超极化到-62.5±1.2 mV，LHR组从-43.7±1.1 mV超极化到-55.6±1.2 mV），尽管在存在NS-1619的情况下E（m）仍然不同。此外，灌注iberiotoxin（50 nM）使两组的去极化程度相似。如戈德曼-霍奇金-凯茨方程所预测的，将细胞外K（+）浓度从1.2 mM增加到45 mM会使E（m）去极化。这些数据支持以下假设：在L-NNA诱导的高血压中，NO对K（+）通道的激活丧失导致VSMC去极化，而功能性大电导Ca（2+）激活的K（+）通道数量没有变化。
