Cornfield D N, Reeve H L, Tolarova S, Weir E K, Archer S
Department of Pediatrics, University of Minnesota School of Medicine, Minneapolis 55455, USA.
Proc Natl Acad Sci U S A. 1996 Jul 23;93(15):8089-94. doi: 10.1073/pnas.93.15.8089.
At birth, pulmonary vasodilation occurs as air-breathing life begins. The mechanism of O2-induced pulmonary vasodilation is unknown. We proposed that O2 causes fetal pulmonary vasodilation through activation of a calcium-dependent potassium channel (KCa) via a cyclic nucleotide-dependent kinase. We tested this hypothesis in hemodynamic studies in acutely prepared fetal lambs and in patch-clamp studies on resistance fetal pulmonary artery smooth muscle cells. Fetal O2 tension (PaO2) was increased by ventilating the ewe with 100% O2, causing fetal total pulmonary resistance to decrease from 1.18 +/- 0.14 to 0.41 +/- 0.03 mmHg per ml per min. Tetraethylammonium and iberiotoxin, preferential KCa-channel inhibitors, attenuated O2-induced fetal pulmonary vasodilation, while glibenclamide, an ATP-sensitive K+-channel antagonist, had no effect. Treatment with either a guanylate cyclase antagonist (LY83583) or cyclic nucleotide-dependent kinase inhibitors (H-89 and KT 5823) significantly attenuated O2-induced fetal pulmonary vasodilation. Under hypoxic conditions (PaO2 = 25 mmHg), whole-cell K+-channel currents (Ik) were small and were inhibited by 1 mM tetraethylammonium or 100 nM charybdotoxin (CTX; a specific KCa-channel blocker). Normoxia (PaO2 = 120 mmHg) increased Ik by more than 300%, and this was reversed by 100 nM CTX. Nitric oxide also increased Ik. Resting membrane potential was -37.2 +/- 1.9 mV and cells depolarized on exposure to CTX, while hyperpolarizing in normoxia. We conclude that O2 causes fetal pulmonary vasodilation by stimulating a cyclic nucleotide-dependent kinase, resulting in KCa-channel activation, membrane hyperpolarization, and vasodilation.
出生时，随着呼吸生命的开始，肺血管舒张发生。氧气诱导肺血管舒张的机制尚不清楚。我们提出，氧气通过环核苷酸依赖性激酶激活钙依赖性钾通道（KCa），从而引起胎儿肺血管舒张。我们在急性制备的胎儿羔羊的血流动力学研究以及对胎儿肺阻力动脉平滑肌细胞的膜片钳研究中检验了这一假设。通过用100%氧气给母羊通气来提高胎儿氧分压（PaO2），导致胎儿总肺阻力从1.18±0.14降至0.41±0.03 mmHg/（ml·min）。四乙铵和iberiotoxin是选择性KCa通道抑制剂，可减弱氧气诱导的胎儿肺血管舒张，而格列本脲是一种ATP敏感性钾通道拮抗剂，无此作用。用鸟苷酸环化酶拮抗剂（LY83583）或环核苷酸依赖性激酶抑制剂（H-89和KT 5823）处理可显著减弱氧气诱导的胎儿肺血管舒张。在低氧条件下（PaO2 = 25 mmHg），全细胞膜钾通道电流（Ik）很小，并被1 mM四乙铵或100 nM蝎毒素（CTX；一种特异性KCa通道阻滞剂）抑制。常氧（PaO2 = 120 mmHg）使Ik增加超过300%，而这被100 nM CTX逆转。一氧化氮也增加Ik。静息膜电位为-37.2±1.9 mV，细胞在接触CTX时去极化，而在常氧时超极化。我们得出结论，氧气通过刺激环核苷酸依赖性激酶引起胎儿肺血管舒张，导致KCa通道激活、膜超极化和血管舒张。
