Pharmacological dissection of K_v7.1 channels in systemic and pulmonary arteries

Abstract

BACKGROUND AND PURPOSEThe aim of this study was to characterize the functional impact of KCNQ1-encoded voltage-dependent potassium channels (Kv7.1) in the vasculature. EXPERIMENTAL APPROACHMesenteric arteries, intrapulmonary arteries and thoracic aortae were isolated from adult rats. Kv7.1 channel expression was established by fluorescence immunocytochemistry. Wire myography determined functionality of these channels in response to selective blockers and activators. Xenopus oocytes expressing Kv7.1 channels were used to assess the effectiveness of selective Kv7.1 channel blockers. KEY RESULTSKv7.1 channels were identified in arterial myocytes by immunocytochemistry. Kv7.1 blockers HMR1556, L-768,673 (10 mM) and JNJ39490282 (JNJ282; 1 mM) had no contractile effects in arteries, whereas the pan-Kv7 channel blocker linopirdine (10 mM) evoked robust contractions. Application of two compounds purported to activate Kv7.1 channels, L-364 373 (R-L3) and mefenamic acid, relaxed mesenteric arteries preconstricted by methoxamine. These responses were reversed by HMR1556 or L-768,673 but not JNJ282. Similar effects were observed in the thoracic aorta and intrapulmonary arteries. CONCLUSIONS AND IMPLICATIONSIn contrast to previous assumptions, Kv7.1 channels expressed in arterial myocytes are functional ion channels. Although these channels do not appear to contribute to resting vascular tone, Kv7.1 activators were effective vasorelaxants. Abbreviations

Contribution of K v 7 Channels to Basal Coronary Flow and Active Response to Ischemia

“…Similar to previous work, [4][5][6]14 we found that LAD coronary arteries from SHRs exhibited considerably less K V 7.4 protein compared with arteries from Concentration-dependent effect curve of K V 7 inhibitor XE-991 and linopirdine (C) in NT and spontaneously HT rats on arterial tone. Data are mean±SEM.…”

“…In addition, it shows that structurally different K V 7.2 to 7.5 activators ((S)-1, BMS-254352, and retigabine) are effective relaxants of precontracted coronary arteries at all orders of artery, whereas the K V 7.1 activator R-L3 has no relaxant effect at concentrations where it relaxes mesenteric and pulmonary arteries. 4 Importantly, the relaxant effect of the K V 7.2 to 7.5 activators was markedly impaired in coronary arteries from SHRs similar to findings in aorta, mesenteric and renal arteries, 6,14 which was associated with a reduction in K V 7.4 protein abundance. In contrast to the rat aorta, 6 there was no change in KCNQ expression in the coronary arteries or mesenteric arteries (also observed in gracilis muscle arteries from SHRs).…”

“…4,6,7,11,14,15 Moreover, evidence is accumulating that activation of K V 7 channels contributes to the vasodilatory response of various endogenous molecules, including β-adrenoceptor agonists 3 and H 2 S. 16 In addition, mesenteric and renal arteries from hypertensive animals exhibit considerable attenuated response to K V 7 activators and marked reduction in K V 7.4 abundance. 6,14 The present study now reveals that coronary arteries express KCNQ1, 4, and 5 transcripts, as well as all members of the KCNE gene family except KCNE1.…”

“…Voltage-gated potassium channels (K V ) have been implicated in the control of the coronary circulation and reactive hyperemia, 1,2 but little is known about the specific molecular components. Kv channels encoded by KCNQ1-5 (K V 7.1-K V 7.5) are important regulators of the smooth muscle resting membrane potential and contractility in several different rodent and human arteries, [3][4][5][6][7][8][9][10][11] which are known to be compromised in animal models of primary and secondary hypertension. 3,6 These channels, in particular K V 7.4, are also functional end points in β-adrenoceptor-mediated relaxations.…”

Contribution of Kv7.4/Kv7.5 Heteromers to Intrinsic and Calcitonin Gene-Related Peptide–Induced Cerebral Reactivity

“…In contrast, the Kv7.1-selective activator, R-L3, was an ineffective relaxant of MCAs ( Figure 1B) at concentrations that produced relaxations of other arteries. 12 Cumulative application of 5-HT concentrations evoked robust contractions of MCAs ( Figure 1C). The inhibition of Kv7 channels by linopirdine (1 μmol/L; n=4) caused a moderate enhancement in 5-HT responses.…”