期刊
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY
卷 302, 期 1, 页码 C307-C317出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpcell.00153.2011
关键词
hypoxia; pulmonary artery; transient receptor potential
资金
- National Research Foundation of Korea
- Ministry of Education, Science and Technology [2011-0001175, 2011-0017370]
- Seoul National University Hospital [03-2011-0020]
Yoo HY, Park SJ, Seo EY, Park KS, Han JA, Kim KS, Shin DH, Earm YE, Zhang YH, Kim SJ. Role of thromboxane A(2)-activated nonselective cation channels in hypoxic pulmonary vasoconstriction of rat. Am J Physiol Cell Physiol 302: C307-C317, 2012. First published October 12, 2011; doi: 10.1152/ajpcell.00153.2011.-Hypoxia-induced pulmonary vasoconstriction (HPV) is critical for matching of ventilation/perfusion in lungs. Although hypoxic inhibition of K+ channels has been a leading hypothesis for depolarization of pulmonary arterial smooth muscle cells (PASMCs) under hypoxia, pharmacological inhibition of K+ channels does not induce significant contraction in rat pulmonary arteries. Because a partial contraction by thromboxane A(2) (TXA(2)) is required for induction of HPV, we hypothesize that TXA(2) receptor (TP) stimulation might activate depolarizing nonselective cation channels (NSCs). Consistently, we found that 5-10 nM U46619, a stable agonist for TP, was indispensible for contraction of rat pulmonary arteries by 4-aminopyridine, a blocker of voltage-gated K+ channel (K-v). Whole cell voltage clamp with rat PASMC revealed that U46619 induced a NSC current (I-NSC,I-TXA2) with weakly outward rectifying current-voltage relation. I-NSC,I-TXA2 was blocked by ruthenium red (RR), an antagonist of the transient receptor potential vanilloid-related channel (TRPV) subfamily. 2-Aminoethoxydiphenyl borate, an agonist for TRPV1-3, consistently activated NSC channels in PASMCs. In contrast, agonists for TRPV1 (capsaicin), TRPV3 (camphor), or TRPV4 (alpha-PDD) rarely induced an increase in the membrane conductance of PASMCs. RT-PCR analysis showed the expression of transcripts for TRPV2 and -4 in rat PASMCs. Finally, it was confirmed that pretreatment with RR largely inhibited HPV in the presence of U46619. The pretreatment with agonists for TRPV1 (capsaicin) and TRPV4 (alpha-PDD) was ineffective as pretone agents for HPV. Taken together, it is suggested that the concerted effects of I-NSC,I-TXA2 activation and Kv inhibition under hypoxia induce membrane depolarization sufficient for HPV. TRPV2 is carefully suggested as the TXA(2)-activated NSC in rat PASMC.
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