Interactions between potassium channels and serotonin in pulmonary arterial hypertension.
PhD thesis, University of Glasgow.
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Pulmonary arterial hypertension (PAH) is a progressive disease which results from increases in mean pulmonary artery pressure and pulmonary vascular resistance. If untreated it leads to right ventricular failure and death. 5-Hydroxytryptamine (5-HT) has been implicated in the disease process and is thought to promote both vasoconstriction and remodelling of the pulmonary vasculature. The activity of potassium ion (K+) channels plays a major role in influencing pulmonary artery tone by regulating resting membrane potential, intracellular Ca2+ concentration and contraction of vascular smooth muscle. This study aimed to investigate possible interactions between 5-HT and K+ channels in the development of PAH in the mouse.
The actions of 5-HT and a range of K+ channel blockers were investigated on isolated intralobar pulmonary arteries (IPA) from wild type (WT) mice and mice over-expressing the serotonin transporter (5HTT), which spontaneously develop PAH. Both 5-HT and linopirdine, a KCNQ K+ channel inhibitor, were found to induce contraction of IPA, but were more potent in IPA from WT mice than 5-HTT+ mice. The 5-HT induced vasoconstriction was found to involve influx of Ca2+ from the extracellular space, Ca2+ release from the sacroplasmic reticulum and a rho kinase–dependent increase in the sensitivity of the contractile machinery of pulmonary artery smooth muscle cells (PASMC) to intracellular Ca2+. Ca2+ entered the cell via both voltage operated calcium channels (VOCC), activated by membrane depolarisation, and a separate Ca2+ entry pathway, the latter appearing to contribute more in 5-HTT+ mice. The effects of linopirdine were shown to be due entirely to the entry of Ca2+ through VOCC in both WT and 5-HTT+ mice IPA. The difference in vasoconstrictor potency between WT and 5HTT+ mice was not seen with any other K+ channel blocker, suggesting a selective loss of KCNQ channels and/or VOCC in PAH resulting from 5HTT over expression.
KCNQ channel activity was further investigated using the KCNQ channel openers, flupirtine and retigabine. These agents were more potent in dilating IPA from WT mice compared to 5-HTT+ mice, consistent with the loss of expression or activity of KCNQ channels in 5-HTT+ mice. Despite this, orally administered flupirtine was shown to reverse two indices of established PAH in the 5HTT+ mice; right ventricular pressure and right ventricular hypertrophy. This action of flupirtine was also seen in chronic hypoxic mice, where it prevented the development of PAH.
In conclusion, this study provides evidence of an interaction between KCNQ channels and the 5-HT system in the development of PAH. By showing that a KCNQ channel opener can attenuate PAH, both in the developing and established disease situation, this study proposes a new potential therapeutic target in the treatment of PAH.
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