Department of Anatomy and Physiology, Kansas State University, Manhattan, KS 66506-5802, USA.
J Physiol. 2012 Aug 1;590(15):3585-96. doi: 10.1113/jphysiol.2012.235929. Epub 2012 Jun 11.
Chronic heart failure (CHF) impairs nitric oxide (NO)-mediated regulation of the skeletal muscle microvascular O(2) delivery/V(O(2)) ratio (which sets the microvascular O(2) pressure, PO(2)mv). Given the pervasiveness of endothelial dysfunction in CHF, this NO-mediated dysregulation is attributed generally to eNOS. It is unknown whether nNOS-mediated PO(2)mv regulation is altered in CHF. We tested the hypothesis that CHF impairs nNOS-mediated PO(2)mv control. In healthy and CHF (left ventricular end diastolic pressure (LVEDP): 6 ± 1 versus 14 ± 1 mmHg, respectively, P < 0.05) rats spinotrapezius muscle blood flow (radiolabelled microspheres), PO(2)mv (phosphorescence quenching), and V(O(2)) (Fick calculation) were measured before and after 0.56 mg kg(-1)i.a. of the selective nNOS inhibitor S-methyl-l-thiocitrulline (SMTC). In healthy rats, SMTC increased baseline PO(2)mv (
29.7 ± 1.4, SMTC: 34.4 ± 1.9 mmHg, P < 0.05) by reducing V(O(2)) (↓20%) without any effect on blood flow and speeded the mean response time (MRT, time to reach 63% of the overall kinetics response,
24.2 ± 2.0, SMTC: 18.5 ± 1.3 s, P < 0.05). In CHF rats, SMTC did not alter baseline PO(2)mv (
25.7 ± 1.6, SMTC: 28.6 ± 2.1 mmHg, P > 0.05), V(O(2)) at rest, or the MRT (CONTROL: 22.8 ± 2.6, SMTC: 21.3 ± 3.0 s, P > 0.05). During the contracting steady-state, SMTC reduced blood flow (↓15%) and V(O(2)) (↓15%) in healthy rats such that PO(2)mv was unaltered (
19.8 ± 1.7, SMTC: 20.7 ± 1.8 mmHg, P > 0.05). In marked contrast, in CHF rats SMTC did not change contracting steady-state blood flow, V(O(2)), or PO(2)mv (
17.0 ± 1.4, SMTC: 17.7 ± 1.8 mmHg, P > 0.05). nNOS-mediated control of skeletal muscle microvascular function is compromised in CHF versus healthy rats. Treatments designed to ameliorate microvascular dysfunction in CHF may benefit by targeting improvements in nNOS function.
研究慢性心力衰竭（CHF）是否会影响一氧化氮（NO）介导的骨骼肌微血管氧输送/耗氧量（VO2）比值（决定微血管氧压，PO2mv）的调节。由于内皮功能障碍在 CHF 中普遍存在，这种 NO 介导的失调通常归因于 eNOS。目前尚不清楚 nNOS 介导的 PO2mv 调节是否在 CHF 中发生改变。我们假设 CHF 会损害 nNOS 介导的 PO2mv 控制，并对此进行了验证。
在健康大鼠和 CHF 大鼠（左心室舒张末期压（LVEDP）分别为 6 ± 1mmHg 和 14 ± 1mmHg，P < 0.05）中，使用放射性标记微球测量斜方肌血流（血流）、PO2mv（磷光猝灭）和 VO2（Fick 计算），然后在给予选择性 nNOS 抑制剂 S-甲基-L-硫代瓜氨酸（SMTC）0.56mg/kg 后，再次测量上述指标。在健康大鼠中，SMTC 通过降低 VO2（↓20%）而增加基线 PO2mv（CONTROL：29.7 ± 1.4mmHg，SMTC：34.4 ± 1.9mmHg，P < 0.05），但对血流和速度没有任何影响，并且缩短了平均反应时间（MRT，达到整体动力学反应的 63%所需的时间，CONTROL：24.2 ± 2.0s，SMTC：18.5 ± 1.3s，P < 0.05）。在 CHF 大鼠中，SMTC 不改变基线 PO2mv（CONTROL：25.7 ± 1.6mmHg，SMTC：28.6 ± 2.1mmHg，P > 0.05）、休息时的 VO2 或 MRT（CONTROL：22.8 ± 2.6s，SMTC：21.3 ± 3.0s，P > 0.05）。在收缩稳态期间，SMTC 降低健康大鼠的血流（↓15%）和 VO2（↓15%），但 PO2mv 保持不变（CONTROL：19.8 ± 1.7mmHg，SMTC：20.7 ± 1.8mmHg，P > 0.05）。相比之下，在 CHF 大鼠中，SMTC 不改变收缩稳态血流、VO2 或 PO2mv（CONTROL：17.0 ± 1.4mmHg，SMTC：17.7 ± 1.8mmHg，P > 0.05）。与健康大鼠相比，nNOS 介导的骨骼肌微血管功能控制在 CHF 中受损。旨在改善 CHF 中微血管功能障碍的治疗方法可能受益于改善 nNOS 功能。
