Pharmacological dissection of K(v)7.1 channels in systemic and pulmonary arteries

TY - JOUR

T1 - Pharmacological dissection of K(v)7.1 channels in systemic and pulmonary arteries

AU - Chadha, Preet S

AU - Zunke, Friederike

AU - Davis, Alison J

AU - Jepps, Thomas Andrew

AU - Linders, Joannes T M

AU - Schwake, Michael

AU - Towart, Rob

AU - Greenwood, Iain A

N1 - © 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.

PY - 2012/6

Y1 - 2012/6

N2 - BACKGROUND AND PURPOSE The aim of this study was to characterize the functional impact of KCNQ1-encoded voltage-dependent potassium channels (K v7.1) in the vasculature. EXPERIMENTAL APPROACH Mesenteric arteries, intrapulmonary arteries and thoracic aortae were isolated from adult rats. K v7.1 channel expression was established by fluorescence immunocytochemistry. Wire myography determined functionality of these channels in response to selective blockers and activators. Xenopus oocytes expressing K v7.1 channels were used to assess the effectiveness of selective K v7.1 channel blockers. KEY RESULTS K v7.1 channels were identified in arterial myocytes by immunocytochemistry. K v7.1 blockers HMR1556, L-768,673 (10 μM) and JNJ39490282 (JNJ282; 1 μM) had no contractile effects in arteries, whereas the pan-K v7 channel blocker linopirdine (10 μM) evoked robust contractions. Application of two compounds purported to activate K v7.1 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 IMPLICATIONS In contrast to previous assumptions, K v7.1 channels expressed in arterial myocytes are functional ion channels. Although these channels do not appear to contribute to resting vascular tone, K v7.1 activators were effective vasorelaxants.

AB - BACKGROUND AND PURPOSE The aim of this study was to characterize the functional impact of KCNQ1-encoded voltage-dependent potassium channels (K v7.1) in the vasculature. EXPERIMENTAL APPROACH Mesenteric arteries, intrapulmonary arteries and thoracic aortae were isolated from adult rats. K v7.1 channel expression was established by fluorescence immunocytochemistry. Wire myography determined functionality of these channels in response to selective blockers and activators. Xenopus oocytes expressing K v7.1 channels were used to assess the effectiveness of selective K v7.1 channel blockers. KEY RESULTS K v7.1 channels were identified in arterial myocytes by immunocytochemistry. K v7.1 blockers HMR1556, L-768,673 (10 μM) and JNJ39490282 (JNJ282; 1 μM) had no contractile effects in arteries, whereas the pan-K v7 channel blocker linopirdine (10 μM) evoked robust contractions. Application of two compounds purported to activate K v7.1 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 IMPLICATIONS In contrast to previous assumptions, K v7.1 channels expressed in arterial myocytes are functional ion channels. Although these channels do not appear to contribute to resting vascular tone, K v7.1 activators were effective vasorelaxants.

KW - Animals

KW - Aorta, Thoracic

KW - Female

KW - Humans

KW - KCNQ Potassium Channels

KW - KCNQ1 Potassium Channel

KW - Male

KW - Membrane Potentials

KW - Mesenteric Arteries

KW - Oocytes

KW - Potassium Channel Blockers

KW - Pulmonary Artery

KW - Rats

KW - Rats, Wistar

KW - Recombinant Proteins

KW - Vasoconstrictor Agents

KW - Vasodilator Agents

KW - Xenopus laevis

U2 - 10.1111/j.1476-5381.2012.01863.x

DO - 10.1111/j.1476-5381.2012.01863.x

M3 - Journal article

C2 - 22251082

SN - 0007-1188

VL - 166

SP - 1377

EP - 1387

JO - British Journal of Pharmacology

JF - British Journal of Pharmacology

IS - 4

ER -