Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK.
Br J Pharmacol. 2012 Jun;166(4):1503-12. doi: 10.1111/j.1476-5381.2012.01892.x.
ATP, UTP and UDP act at smooth muscle P2X and P2Y receptors to constrict rat intrapulmonary arteries, but the underlying signalling pathways are poorly understood. Here, we determined the roles of the Ca²⁺ -dependent chloride ion current (I(Cl,Ca)), Ca(v)1.2 ion channels and Ca²⁺ influx.
Isometric tension was recorded from endothelium-denuded rat intrapulmonary artery rings (i.d. 200-500 µm) mounted on a wire myograph.
The I(Cl,Ca) blockers, niflumic acid and 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid and the Ca(v)1.2 channel blocker, nifedipine, reduced peak amplitude of contractions evoked by UTP and UDP by ∼45-50% and in a non-additive manner. Ca²⁺-free buffer inhibited responses by ∼70%. Niflumic acid and nifedipine similarly depressed contractions to ATP, but Ca²⁺-free buffer almost abolished the response. After peaking, contractions to UTP and UDP decayed slowly by 50-70% to a sustained plateau, which was rapidly inhibited by niflumic acid and nifedipine. Contractions to ATP, however, reversed rapidly and fully. Tannic acid contracted tissues per se and potentiated nucleotide-evoked contractions.
I (Cl,Ca) and Ca²⁺ influx via Ca(v)1.2 ion channels contribute substantially and equally to contractions of rat intrapulmonary arteries evoked by UTP and UDP, via P2Y receptors. ATP also activates these mechanisms via P2Y receptors, but the greater dependence on extracellular Ca²⁺ most likely reflects additional influx through the P2X1 receptor pore. The lack of a sustained response to ATP is probably due to it acting at P2 receptor subtypes that desensitize rapidly. Thus multiple signalling mechanisms contribute to pulmonary artery vasoconstriction mediated by P2 receptors.
ATP、UTP 和 UDP 通过平滑肌 P2X 和 P2Y 受体作用于大鼠肺内动脉，导致其收缩，但相关信号通路尚不清楚。在此，我们研究了 Ca²⁺依赖性氯离子电流（I(Cl,Ca)）、Ca(v)1.2 离子通道和 Ca²⁺内流的作用。
在张力换能器肌动描记器上记录去内皮的大鼠肺内动脉环（内径 200-500μm）的等长张力。
I(Cl,Ca)阻断剂尼氟酸和 4,4'-二异硫氰酸基二苯乙烯-2,2'-二磺酸以及 Ca(v)1.2 通道阻断剂硝苯地平，可使 UTP 和 UDP 诱发的收缩峰幅度分别降低 45-50%，且呈非累加性。无钙缓冲液抑制反应约 70%。尼氟酸和硝苯地平也可使 ATP 诱发的收缩减弱，但无钙缓冲液几乎完全抑制反应。UTP 和 UDP 诱发的收缩在峰值后缓慢下降 50-70%，达到持续平台，尼氟酸和硝苯地平可迅速抑制此平台。然而，ATP 诱发的收缩迅速而完全逆转。丹宁酸本身可使组织收缩，并增强核苷酸诱发的收缩。
I(Cl,Ca)和 Ca²⁺通过 Ca(v)1.2 离子通道流入大鼠肺内动脉，通过 P2Y 受体，对 UTP 和 UDP 诱发的收缩有很大的贡献，且贡献程度相同。ATP 也通过 P2Y 受体激活这些机制，但对细胞外 Ca²⁺的更大依赖性很可能反映了通过 P2X1 受体孔的额外流入。对 ATP 缺乏持续反应可能是因为它作用于快速脱敏的 P2 受体亚型。因此，多种信号转导机制参与了 P2 受体介导的肺动脉收缩。
