Bioscience Horizons Advance Access published online on April 17, 2008
Bioscience Horizons, doi:10.1093/biohorizons/hzn019
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© Oxford University Press 2008
Effects of modulators of TASK potassium channels on rat pulmonary artery tone
Faculty of Life Sciences, University of Manchester, Core Technology Facility, Manchester, UK
* Corresponding author: 15 Crundale Avenue, Kingsbury, London NW9 9PJ, UK. Tel: +44 (0)7828 974984. Email: sajds{at}hotmail.co.uk
Supervisor: Professor A. M. Gurney, Faculty of Life Sciences, University of Manchester, Core Technology Facility, 46 Grafton Street, Manchester M13 9NT, UK.
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Abstract |
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TWIK-related acid-sensitive potassium (TASK) channels have been implicated as having a role in maintaining and mediating the tone of pulmonary arteries by influencing the membrane potential of the smooth muscle cells. Inhibition of these channels would be expected to promote depolarization, calcium influx and contraction. The purpose of this study was to investigate the effects of TASK modulators on rat intrapulmonary artery tone. The modulators included pH, an important physiological TASK modulator, and drugs that inhibit TASK channels, such as bupivacaine, methanandamide and zinc. Small vessel myography was used to measure the tone of both conduit and resistance pulmonary arteries. Cumulative bupivacaine and methanandamide dose–response curves were compared with phenylephrine (a sympathomimetic vasoconstrictor). The effects of pH were investigated on vessel tone and responses to bupivacaine, methanandamide or zinc chloride. Bupivacaine and methanandamide (>10 µM) resulted in increased artery tone, with similar effects seen in conduit and resistance vessels. Zinc had no effect, possibly reflecting an inhibitory action on calcium channels. In the presence of endothelial blockers, methanandamide (100 µM) still resulted in an increase in artery tone, implying an action on smooth muscle. The application of nifedipine resulted in the inhibition of the response seen with bupivacaine (100 µM), implying that voltage-gated calcium entry was involved. Changing the pH from 7.3 to 8.3 resulted in vasoconstriction, and a relaxation was seen in acidic conditions. This is opposite to the result expected for TASK channel modulation, but may reflect the multiple effects of pH on smooth muscle. The contractions seen with bupivacaine and methanandamide were increased at pH 8.3 but inhibited at pH 6.3, consistent with an effect on TASK channels. Responses to bupivacaine and methanandamide were, however, very small, suggesting that currents produced by TASK channels may not be a major factor in contracting intrapulmonary arteries, but may still have a minor role.
Key words: arterial tone, TASK channels, rat, bupivacaine, methanandamide, pH
Submitted on 26 September 2007; accepted on 28 January 2008