Segmental differences in the mechanism of vascular tone regulation along the serially-connected pulmonary vessels in vivo

本研究旨在探讨体内连续连接的肺血管从导管段到阻力段血管张力调节机制的节段差异。为此，我们利用x射线电视系统直接测量了一氧化氮合酶（NOS）抑制剂和K^+通道抑制剂对麻醉猫和大鼠抵抗动脉（RA）和导管动脉（CA）内径（ID）的影响。同时进行NOS蛋白免疫组化分析。急性缺氧暴露诱导的乳头状瘤病毒（HPV）局限于猫小叶内100-600μm血管，最大反应在200-300μm RA。这种反应模式是缺氧时特有的，因为吸入一氧化氮（NO）和丙环素会引起肺血管的ID反应，ID范围更广（100-1000μm）。在常氧猫中，非选择性NOS抑制导致CA比RA更大的ID收缩。在低氧暴露时，更多的抑制增强了小叶内的HPV。电压依赖性的K^+ (K_v)通道抑制在常氧状态下引起CA和RA几乎一致的ID收缩，但CA ^<2+>敏感的K^+ (K_< CA >)通道或ATP敏感的K^+ (K_<ATP>)通道抑制引起CA的大收缩和RA的小收缩。在K_<Ca>通道抑制下，低氧诱导较小Ca的ID也明显收缩，RA中的HPV略有增强。K_<ATP>通道抑制对缺氧反应无影响。结果表明，K_V通道调节所有动脉的基底电位，而NOS和K_<Ca>和K_<ATP>通道主要调节Ca。数据还表明，RA中的HPV几乎不依赖于K_<Ca>和K_<ATP>通道，而缺氧Ca反应依赖于缺氧诱导的收缩和K_<Ca>通道介导的扩张之间的平衡。在缺氧4周的大鼠中，非选择性NOS抑制引起的ID收缩在RA中增强，而在ca中没有，在RA的所有分支中都观察到增强。由于iNOS选择性抑制导致的ID收缩仅在约50%的RA中增强。nNOS选择性抑制无明显效果。缺氧4周后，enos阳性RA的比例从50%增加到95%，而iNOS阳性RA的比例仅从10%增加到50%。数据表明，在慢性缺氧期间，eNOS介导的基底张力调节在所有RA中都得到增强，但iNOS介导的基底张力调节在其分支中零星增强。这种NOS上调可能有助于减弱HPV，进而抑制肺动脉高压的进展。综上所述，NOS-和K^+通道介导的血管张力调节机制在hpv阳性RA和hpv阴性CA之间存在显著差异

This study was conducted to investigate segmental differences in the mechanism of vascular tone regulation along the in vivo serially-connected pulmonary vessels, from conduit to resistance segments. To this end, we directly measured effects of inhibitors of nitric oxide synthase (NOS) and K^+ channel on the internal diameter (ID) of resistance arteries (RA) and conduit arteries (CA), using an X-ray television system on anesthetized cats and rats. Moreover, immunohistochemistry analysis for NOS protein was also conducted.Acute hypoxic exposure-induced ID constriction (HPV) was localized in intralobular 100-600μm vessels in the cat, the maximum response being in 200-300μm RA.This response pattern was specific for hypoxia, since inhalations of nitric oxide (NO) and prostacyclin caused ID responses in pulmonary vessels with a more extensive ID range (100-1000μm).In normoxic cats, non-selective NOS inhibition caused a larger ID constriction in CA than in RA.During hypoxic exposure, the inh … More ibition enhanced HPV within the lobule. Voltage-dependent K^+ (K_v) channel inhibition caused almost uniform ID constriction in both CA and RA during normoxia, but Ca^<2+>-sensitive K^+ (K_<Ca>) channel or ATP-sensitive K^+ (K_<ATP>) channel inhibition caused a great constriction in CA and a slight constriction in RA.Under K_<Ca> channel inhibition, hypoxia induced a significant ID constriction also in smaller CA and HPV in RA was slightly enhanced. K_<ATP> channel inhibition had no effect on any of the hypoxic responses. The results suggest that K_V channels regulate basal tone in all arteries, whereas NOS and K_<Ca> and K_<ATP> channels chiefly regulate CA.The data also suggest that HPV in RA is almost independent of K_<Ca> and K_<ATP> channels, whereas the hypoxic CA response depends on the balance between the hypoxia-induced constriction and K_<Ca> channel-mediated dilatation.In rats with 4-wk hypoxic exposure, the ID constriction due to nonselective NOS inhibition was enhanced in RA, but not in CA.The enhancement was observed in all branches of RA.The ID constriction due to iNOS selective inhibition was enhanced only in 〜50% of RA.nNOS selective inhibition had no effect. The percentage of eNOS-positive RA increased to 95% (from 50%) in response to 4-wk hypoxia, but that for iNOS only to 50% (from 10%). The data suggest that eNOS mediated basal tone regulation is enhanced in all RA during chronic hypoxia, but that for iNOS sporadically among their branches. Such NOS upregulation may contribute to attenuating HPV and in turn, inhibit the pulmonary hypertension progress.Together, it is suggested that NOS- and K^+ channel-mediated mechanisms of vascular tone regulation significantly differ between the HPV-positive RA and HPV-negative CA. Less