MacFarlane P M, Vinit S, Mitchell G S
Department of Comparative Biosciences, University of Wisconsin, Madison, WI 53706, USA.
Neuroscience. 2014 Jun 6;269:67-78. doi: 10.1016/j.neuroscience.2014.03.014. Epub 2014 Mar 26.
Acute intermittent hypoxia (AIH) induces phrenic long-term facilitation (pLTF) by a mechanism that requires spinal serotonin (5-HT) receptor activation and NADPH oxidase (NOX) activity. Here, we investigated whether: (1) spinal nitric oxide synthase (NOS) activity is necessary for AIH-induced pLTF; (2) episodic exogenous nitric oxide (NO) is sufficient to elicit phrenic motor facilitation (pMF) without AIH (i.e. pharmacologically); and (3) NO-induced pMF requires spinal 5-HT2B receptor and NOX activation. In anesthetized, mechanically ventilated adult male rats, AIH (3 × 5-min episodes; 10% O2; 5 min) elicited a progressive increase in the amplitude of integrated phrenic nerve bursts (i.e. pLTF), which lasted 60 min post-AIH (45.1 ± 8.6% baseline). Pre-treatment with intrathecal (i.t.) injections of a neuronal NOS inhibitor (nNOS-inhibitor-1) near the phrenic motor nucleus attenuated pLTF (14.7 ± 2.5%), whereas an inducible NOS (iNOS) inhibitor (1400 W) had no effect (56.3 ± 8.0%). Episodic i.t. injections (3 × 5μl volume; 5 min) of a NO donor (sodium nitroprusside; SNP) elicited pMF similar in time-course and magnitude (40.4 ± 6.0%, 60 min post-injection) to AIH-induced pLTF. SNP-induced pMF was blocked by a 5-HT2B receptor antagonist (SB206553), a superoxide dismutase mimetic (MnTMPyP), and two NOX inhibitors (apocynin and DPI). Neither pLTF nor pMF was affected by pre-treatment with a protein kinase G (PKG) inhibitor (KT-5823). Thus, spinal nNOS activity is necessary for AIH-induced pLTF, and episodic spinal NO is sufficient to elicit pMF by a mechanism that requires 5-HT2B receptor activation and NOX-derived ROS formation, which indicates AIH (and NO) elicits spinal respiratory plasticity by a nitrergic-serotonergic mechanism.
急性间歇性低氧（AIH）通过一种需要脊髓5-羟色胺（5-HT）受体激活和NADPH氧化酶（NOX）活性的机制诱导膈神经长期易化（pLTF）。在此，我们研究了：（1）脊髓一氧化氮合酶（NOS）活性对于AIH诱导的pLTF是否必要；（2）间歇性外源性一氧化氮（NO）是否足以在无AIH的情况下（即通过药理学方法）引发膈神经运动易化（pMF）；以及（3）NO诱导的pMF是否需要脊髓5-HT2B受体和NOX激活。在麻醉、机械通气的成年雄性大鼠中，AIH（3次5分钟发作；10%氧气；5分钟）引起膈神经复合动作电位幅度的逐渐增加（即pLTF），在AIH后持续60分钟（为基线的45.1±8.6%）。在膈神经运动核附近鞘内（i.t.）注射神经元型NOS抑制剂（nNOS-抑制剂-1）进行预处理可减弱pLTF（14.7±2.5%），而诱导型NOS（iNOS）抑制剂（1400W）则无作用（56.3±8.0%）。间歇性i.t.注射（3次，每次5μl体积；5分钟）一氧化氮供体（硝普钠；SNP）引发的pMF在时间进程和幅度上（注射后60分钟为40.4±6.0%）与AIH诱导的pLTF相似。SNP诱导的pMF被5-HT2B受体拮抗剂（SB206553）、超氧化物歧化酶模拟物（MnTMPyP）以及两种NOX抑制剂（鱼藤酮和二苯基碘）阻断。pLTF和pMF均不受蛋白激酶G（PKG）抑制剂（KT-5823）预处理的影响。因此，脊髓nNOS活性对于AIH诱导的pLTF是必要的，间歇性脊髓给予NO足以通过一种需要5-HT2B受体激活和NOX衍生的活性氧形成的机制引发pMF，这表明AIH（和NO）通过一种一氧化氮能-5-羟色胺能机制引发脊髓呼吸可塑性。
