title: Role of thromboxane A₂-activated nonselective cation channels in hypoxic pulmonary vasoconstriction of rat.
abstract: 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,TXA2)) with weakly outward rectifying current-voltage relation. I(NSC,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 (α-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 (α-PDD) was ineffective as pretone agents for HPV. Taken together, it is suggested that the concerted effects of I(NSC,TXA2) activation and K(v) inhibition under hypoxia induce membrane depolarization sufficient for HPV. TRPV2 is carefully suggested as the TXA(2)-activated NSC in rat PASMC.
authors: Department of Physiology, Seoul National University College of Medicine Seoul, Korea.
authors: Hae Young
authors: HY
authors: Yoo
authors: Su Jung
authors: SJ
authors: Park
authors: Eun-Young
authors: EY
authors: Seo
authors: Kyung Sun
authors: KS
authors: Park
authors: Jung-A
authors: JA
authors: Han
authors: Kyung Soo
authors: KS
authors: Kim
authors: Dong Hoon
authors: DH
authors: Shin
authors: Yung E
authors: YE
authors: Earm
authors: Yin-Hua
authors: YH
authors: Zhang
authors: Sung Joon
authors: SJ
authors: Kim
mesh_terms: D000818:Animals; D002211:Capsaicin / Q000494:pharmacology; D000860:Hypoxia / Q000378:metabolism* / Q000473:pathology*; D007473:Ion Channels / Q000819:agonists / Q000502:physiology*; D008168:Lung / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008297:Male; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000502:physiology; D011651:Pulmonary Artery / Q000378:metabolism / Q000502:physiology* / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000819:agonists / Q000502:physiology*; D014661:Vasoconstriction / Q000502:physiology*
chemical_list: D007473:Ion Channels; D044244:Receptors, Thromboxane A2, Prostaglandin H2; C491711:nonselective cation channel protein, rat; D002211:Capsaicin