The Role Of Two Pore Domain Potassium Channels TASK-1in Hypoxic Pulmonary Vasoconstriction And The Possible Mechanism Research

Purpose:1. To investigate the exact role of the two-pore domain potassium channel TASK-1inthe tension change of pulmonary vascular ring caused by hypoxia.2. To investigate the mechanism of the two-pore domain potassium channel TASK-1induced pulmonary vasoconstriction caused by hypoxia.Methods:Resected lung tissues were obtained from lung cancer patients who underwent surgeryand then the third or fourth branches of the pulmonary arteries were separated to makepulmonary artery rings. RM-6000multi-channel polygraph was used to observe theimpact on the tension of vascular rings which were pre-incubated with c-Src inhibitorPP2, PP2-like PP3, tyrosine phosphatase inhibitor bpv and TASK-1inhibitor a-293(100μM). Human pulmonary artery smooth muscle cells (hPASMCs) were isolatedfrom tissues and cultured. After identified by immunofluorescence staining,3rd to6thgeneration of hPASMCs were used for patch clamp experiments.Results:1. Under the suitable preload, pulmonary vascular was inhibited by TASK-1inhibitorA-293(vascular tension:1382±263mg vs.1138±219mg, p<0.05).2. Under the suitable preload, pulmonary vascular was inhibited by c-Src inhibitorPP2(vascular tension:1379±231mg vs.1103±215mg, p<0.05). There was nochange of PP3on vasoconstriction of pulmonary vascular (vascular tension:1403±203mg vs.1381±198mg, p>0.05). However, vasoconstriction of pulmonary vascularwas enhanced by tyrosine phosphatase inhibitor bpv (vascular tension:1351±213mgvs.1632±253mg, p<0.05).3. There was no obvious change of PP2on vasoconstriction of pulmonary vascularwhich was pre-incubated with A-293(vascular tension:1412±264mg vs.1356±243mg, p>0.05).4. TASK-1current of hPASMCs was reversibly inhibited by hypoxia (current density:0.57±0.06pA/pF vs.0.27±0.04pA/pF, p<0.01).5. TASK-1current of hPASMCs disappeared when pre-incubated with c-Src inhibitorPP2(current density:0.28±0.04pA/pF vs.0.26±0.05pA/pF, P>0.05). However, this could be reversibly inhibited by hypoxia when pre-incubated with PP2-like PP3(current density:0.58±0.04pA/pF vs.0.25±0.06pA/pF, p<0.01). Besides, TASK-1current of hPASMCs was notably increased when pre-incubated with tyrosinephosphatase inhibitor bpv (current density:0.57±0.06pA/pF vs.0.74±0.07pA/pF,p<0.01) and the current could be inhibited by hypoxia (current density:0.74±0.07pA/pF vs.0.26±0.05pA/pF, p<0.01).Conclusion:1. The two-pore domain potassium channel TASK-1was involved in thevasoconstriction of human pulmonary vascular caused by hypoxia.2. The two-pore domain potassium channel TASK-1induced human pulmonaryvasoconstriction caused by hypoxia was c-Src dependent.3. TASK-1current of hPASMCs was reversibly inhibited by hypoxia,4. The two-pore domain potassium channel TASK-1was regulated by tyrosine kinasec-Src.5. The role of two pore domain potassium channels TASK-1on pulmonary vascularoxygen deficiency is contractive reaction of potassium channels through of theregulation of c-Src.