Research

Pulmonary vasoconstrictor action of KCNQ potassium channel blockers

Shreena Joshi^1,2 , Prabhu Balan¹ and Alison M Gurney^1,2

¹Department of Physiology & Pharmacology, University of Strathclyde, 27 Taylor street, Glasgow G4 0NR, UK

²Faculty of Life Sciences, University of Manchester, Floor 2, Core Technology Facility, University of Manchester, 46 Grafton Street, Manchester M13 9NT, UK

author email corresponding author email

Respiratory Research 2006, 7:31doi:10.1186/1465-9921-7-31

Published:	20 February 2006

Abstract

Background

KCNQ channels have been widely studied in the nervous system, heart and inner ear, where they have important physiological functions. Recent reports indicate that KCNQ channels may also be expressed in portal vein where they are suggested to influence spontaneous contractile activity. The biophysical properties of K⁺ currents mediated by KCNQ channels resemble a current underlying the resting K⁺ conductance and resting potential of pulmonary artery smooth muscle cells. We therefore investigated a possible role of KCNQ channels in regulating the function of pulmonary arteries by determining the ability of the selective KCNQ channel blockers, linopirdine and XE991, to promote pulmonary vasoconstriction.

Methods

The tension developed by rat and mouse intrapulmonary or mesenteric arteries was measured using small vessel myography. Contractile responses to linopirdine and XE991 were measured in intact and endothelium denuded vessels. Experiments were also carried out under conditions that prevent the contractile effects of nerve released noradrenaline or ATP, or block various Ca²⁺ influx pathways, in order to investigate the mechanisms underlying contraction.

Results

Linopirdine and XE991 both contracted rat and mouse pulmonary arteries but had little effect on mesenteric arteries. In each case the maximum contraction was almost as large as the response to 50 mM K⁺. Linopirdine had an EC₅₀ of around 1 μM and XE991 was almost 10-fold more potent. Neither removal of the endothelium nor exposure to phentolamine or α,β-methylene ATP, to block α₁-adrenoceptors or P2X receptors, respectively, affected the contraction. Contraction was abolished in Ca²⁺-free solution and in the presence of 1 μM nifedipine or 10 μM levcromakalim.

Conclusion

The KCNQ channel blockers are potent and powerful constrictors of pulmonary arteries. This action may be selective for the pulmonary circulation as mesenteric arteries showed little response. The results imply that the drugs act directly on smooth muscle cells and contraction requires voltage-dependent Ca²⁺ influx. It is concluded that the drugs probably act by blocking KCNQ channels in pulmonary artery myocytes, leading to membrane depolarization and Ca²⁺ influx through L-type Ca²⁺ channels. This implies a functional role for KCNQ channels in regulating the resting membrane potential of pulmonary artery myocytes.