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The Pharmacology & Therapeutic Potential of Kv7 Channels in The Pulmonary Circulation

Eid, Basma

[Thesis]. Manchester, UK: The University of Manchester; 2013.

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Abstract

: The Pharmacology & Therapeutic Potential of Kv7 Channels in The Pulmonary Circulation. (The University of Manchester, Basma Ghazi Eid, Doctor of Philosophy (PhD.), 2013)Pulmonary arterial tone is regulated in part by the membrane potential (Em) of pulmonary artery smooth muscle cells (PASMCs). The Kv7 family of K+ channels was recently implicated in regulating Em in rat PASMCs and expression of KCNQ1, KCNQ4 and KCNQ5 mRNA, which encode Kv7 channels, was reported. Kv7 activators were beneficial in two-independent mouse models of pulmonary hypertension (PH), which provides further evidence for their role in regulating pulmonary tone. The goals of this study were to: 1) Elucidate the role of Kv7 channels and Em in the hypertensive pulmonary circulation and 2) Study the effects and mechanism of action of a novel Kv7 modulator, zinc pyrithione (ZnPy) on the pulmonary circulation.PH was induced in male Wistar rats by administering a single 60 µg/kg intraperitoneal injection of monocrotaline (MCT). The effects of Kv7 modulators on hypertensive and control pulmonary arteries (PA) were compared using small-vessel myography. The vasoconstrictor effect of the Kv7 blocker, XE991, was enhanced in MCT PA. The Kv7 activators retigabine and ZnPy showed enhanced efficacy in relaxing MCT PA and suppressed raised intrinsic tone identified in MCT PA relative to control PA. The effects of MCT in responses to Kv7 modulators were pulmonary specific as they were not seen in mesenteric arteries from the same animals. Real-time PCR studies revealed that PA from MCT and control rats showed a similar expression of KCNQ1, KCNQ4 and KCNQ5 mRNA transcripts. I propose that the enhanced effects of Kv7 modulators on PA from MCT rats were due to disease-induced depolarization of PASMCs, which raised intrinsic tone and increased Kv7 channel activation at rest. This is the first evidence that Kv7 channels are functional in this model of PH and may serve as potential drug targets.The effects of ZnPy on PASMCs were studied by patch-clamp electrophysiology. ZnPy consistently hyperpolarized PASMCs and significantly increased the K+ current elicited by a voltage-step from -80 to +40 mV. ZnPy also increased the non-inactivating current recorded at 0 mV in some cells. The effects of ZnPy on Em and K+ currents were inhibited by 10 mM tetraethylammonium (TEA) and 1 µM paxilline but not by 50 nM iberiotoxin. XE991 (10µM) inhibited the ZnPy-induced hyperpolarization without altering its effects on K+ currents, suggesting that the current recorded was not responsible for its effect on Em. When tested on intact vessels, ZnPy consistently produced vasodilation. Its effects were unaffected by TEA, paxilline and iberiotoxin; however, XE991 (100 nM) had an inhibitory effect. The results suggest that ZnPy hyperpolarizes PASMCs by activating a TEA, paxilline and XE991 sensitive, but iberiotoxin insensitive channel, most likely a Kv7 channel. Its ability to dilate PA depended on pharmacologically distinct mechanisms, which are unlikely to involve Kv7 channels.