Abstract
The membrane potential helps determine pulmonary artery smooth muscle cell (PASMC) contraction. The Kv7 channel activators, retigabine and flupirtine, are thought to dilate pulmonary arteries by hyperpolarising PASMC. Zinc pyrithione activates Kv7 channels by a mechanism distinct from retigabine and with different Kv7 subunit selectivity. This study aimed to determine if zinc pyrithione selectively activates Kv7 channels in rat PASMC to evoke pulmonary artery dilation. Zinc pyrithione relaxed pulmonary arteries with half-maximal effect at 4.3μM. At 10μM it activated pronounced voltage-dependent K+ current and hyperpolarized PASMCs by around 10mV. Tetraethylammonium ions (TEA, 10mM) and paxilline (1μM) abolished both the current and hyperpolarisation. XE991 (10μM) blocked the hyperpolarization and reduced the current by 30%. Iberiotoxin (50nM) had no effect on the hyperpolarisation, but reduced the current by 40%. The XE991-sensitive current activated with an exponential time course (time constant 17ms), whereas the iberiotoxin-sensitive current followed a bi-exponential time course (time constants 6 and 57ms), suggesting that the drugs blocked different components of the zinc pyrithione-induced current. Zinc pyrithione therefore appears to activate at least two types of K+ channel in PASMC; an XE991, TEA and paxilline-sensitive Kv7 channel and a TEA, paxilline and iberiotoxin-sensitive BKCa channel. Both could contribute to the relaxing effect of zinc pyrithione on pulmonary artery.
Highlights
The membrane potential of pulmonary artery smooth muscle cells (PASMCs) regulates contraction
It was not possible to test the ability of XE991 to antagonise the effect of Zinc pyrithione (ZnPy) on phenylephrine-constricted arteries
tetraethylammonium chloride (TEA) and paxilline essentially abolished both the hyperpolarization and K+ current evoked by ZnPy, whereas iberiotoxin had no effect on the membrane potential response but reduced the current
Summary
The membrane potential of pulmonary artery smooth muscle cells (PASMCs) regulates contraction. The resting potential depends on K+ ions leaking through K+ channels open at rest. Inhibitors of the resting K+ flux depolarise the membrane to open voltage-gated Ca2+ channels, resulting in Ca2+ entry and contraction. Opening additional K+ channels has the opposite effect, causing hyperpolarization, reduced Ca2+ entry and vasodilation [1,2]. PASMCs express many K+ channel genes, which yield multiple voltage-activated potassium channels, large conductance Ca2+-activated (BKCa), ATP-sensitive (KATP) and two poredomain (K2P) K+ channels.
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