Institut für Pharmazie, Freie Universität Berlin, Königin-Luise-Strasse 2 + 4, Berlin, Germany.
Naunyn Schmiedebergs Arch Pharmacol. 2012 Jun;385(6):595-603. doi: 10.1007/s00210-012-0741-3. Epub 2012 Feb 28.
Enhanced pulmonary vasoconstriction in response to injuries of the central nervous system and hypoxia result in pulmonary edema due to increased sympathetic activation. This study aimed to characterize α(2)-adrenoceptor (AR)-mediated responses in porcine pulmonary arteries. α(2)-AR-mediated vasoconstriction was studied using a tissue bath protocol. α(2)-AR protein was determined by Western blotting. UK14304 (α(2)-AR agonist) elicited only a slight contraction in pulmonary arteries compared to veins. Verapamil (voltage-operated Ca(2+) channel blocker), 2-APB (store-operated Ca(2+) channel inhibitor), and P1075 (K(ATP) channel opener) induced a marked decrease of the basal tone in veins, but not in arteries. The UK14304-induced contraction in arteries was enhanced by (S)-(-)-Bay K 8644 (L-type Ca(2+) channel activator), N (ω)-nitro-L: -arginine methyl ester hydrochloride (L-NAME, eNOS inhibitor), and (S)-(-)-Bay K 8644 plus L-NAME to the same extent. Endothelium denudation failed to affect the UK14304 response. (S)-(-)-Bay K 8644 did not increase the maximal noradrenaline (non-selective α-AR agonist) or phenylephrine (α(1)-AR agonist) response. The rightward shift of the concentration-response curve to noradrenaline by prazosin (α(1)-AR antagonist) plus (S)-(-)-Bay K 8644 was smaller and non-parallel compared to that in the presence of prazosin alone. UK14304 responses were inhibited by MK912 (α(2C)-AR antagonist). Affinity of MK912 (pA(2) 9.76) and Western blotting analysis argue for an involvement of α(2C)-ARs in noradrenaline-induced contraction of pulmonary arteries. It is concluded that postjunctional α(2C)-ARs predominantly mediate contraction in porcine pulmonary arteries when the cytosolic Ca(2+) concentration is elevated. α(2C)-AR antagonists may be beneficial in the treatment of pulmonary edema.
中枢神经系统损伤和缺氧引起的肺血管收缩增强，导致交感神经激活增加，从而引起肺水肿。本研究旨在研究猪肺动脉中α(2)-肾上腺素能受体（AR）介导的反应。使用组织浴方案研究α(2)-AR 介导的血管收缩。通过 Western 印迹法测定α(2)-AR 蛋白。与静脉相比，UK14304（α(2)-AR 激动剂）仅引起肺血管的轻微收缩。维拉帕米（电压门控 Ca(2+)通道阻滞剂）、2-APB（储存操作 Ca(2+)通道抑制剂）和 P1075（K(ATP)通道 opener）可显著降低静脉的基础张力，但不能降低动脉的基础张力。（S）-（-）-Bay K 8644（L 型 Ca(2+)通道激活剂）、N（ω）-硝基-L：-精氨酸甲酯盐酸盐（L-NAME，eNOS 抑制剂）和（S）-（-）-Bay K 8644 增强了 UK14304 诱导的动脉收缩，其程度与 L-NAME 相同。内皮剥脱对 UK14304 反应无影响。（S）-（-）-Bay K 8644 不会增加去甲肾上腺素（非选择性α-AR 激动剂）或苯肾上腺素（α(1)-AR 激动剂）的最大反应。与单独使用哌唑嗪相比，哌唑嗪（α(1)-AR 拮抗剂）加（S）-（-）-Bay K 8644 对去甲肾上腺素浓度反应曲线的右移较小且不平行。MK912（α(2C)-AR 拮抗剂）抑制 UK14304 反应。MK912 的亲和力（pA(2)9.76）和 Western 印迹分析表明，α(2C)-AR 参与了去甲肾上腺素诱导的猪肺动脉收缩。结论是，当细胞浆 Ca(2+)浓度升高时，突触后α(2C)-AR 主要介导猪肺动脉的收缩。α(2C)-AR 拮抗剂可能有益于肺水肿的治疗。
