Pharmacological dissection of K v7.1 channels in systemic and pulmonary arteries

Abstract

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