Pulmonary vasoconstrictor action of KCNQ potassium channel blockers.
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 microM and XE991 was almost 10-fold more potent. Neither removal of the endothelium nor exposure to phentolamine or alpha,beta-methylene ATP, to block alpha1-adrenoceptors or P2X receptors, respectively, affected the contraction. Contraction was abolished in Ca2+-free solution and in the presence of 1 microM nifedipine or 10 microM levcromakalim.


CONCLUSIONS
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.
Joshi
Shreena
S
Department of Physiology & Pharmacology, University of Strathclyde, Glasgow G4 0NR, UK. Shreena.Joshi@postgrad.manchester.ac.uk
Balan
Prabhu
P
Gurney
Alison M
AM
D000818:Animals; D000873:Anthracenes / Q000008:administration & dosage; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology*; D066298:In Vitro Techniques; D007211:Indoles / Q000008:administration & dosage; D051656:KCNQ Potassium Channels / Q000037:antagonists & inhibitors* / Q000502:physiology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology*; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D026902:Potassium Channel Blockers / Q000008:administration & dosage*; D011651:Pulmonary Artery / Q000502:physiology*; D011725:Pyridines / Q000008:administration & dosage; D051381:Rats; D017207:Rats, Sprague-Dawley; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology*
C112297:10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone; D000873:Anthracenes; D007211:Indoles; D051656:KCNQ Potassium Channels; D026902:Potassium Channel Blockers; D011725:Pyridines; C061017:linopirdine