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Abstract-KCNQ4-encoded voltage-dependent potassium (Kv7.4) channels are important regulators of vascular tone that are severely compromised in models of hypertension. However, there is no information as to the role of these channels in responses to endogenous vasodilators. We used a molecular knockdown strategy, as well as pharmacological tools, to examine the hypothesis that Kv7.4 channels contribute to ␤-adrenoceptor-mediated vasodilation in the renal vasculature and underlie the vascular deficit in spontaneously hypertensive rats. Quantitative PCR and immunohistochemistry confirmed gene and protein expression of KCNQ1, KCNQ3, KCNQ4, KCNQ5, and Kv7.1, Kv7.4, and Kv7.5 in rat renal artery. Isoproterenol produced concentration-dependent relaxation of precontracted renal arteries and increased Kv7 channel currents in isolated smooth muscle cells. Application of the Kv7 blocker linopirdine attenuated isoproterenolinduced relaxation and current. Isoproterenol-induced relaxations were also reduced in arteries incubated with small interference RNAs targeted to KCNQ4 that produced a Ϸ60% decrease in Kv7.4 protein level. Relaxation to isoproterenol and the Kv7 activator S-1 were abolished in arteries from spontaneously hypertensive rats, which was associated with Ϸ60% decrease in Kv7.4 abundance. This study provides the first evidence that Kv7 channels contribute to ␤-adrenoceptor-mediated vasodilation in the renal vasculature and that abrogation of Kv7.4 channels is strongly implicated in the impaired ␤-adrenoceptor pathway in spontaneously hypertensive rats. These findings may provide a novel pathogenic link between arterial dysfunction and hypertension. The link between renal dysfunction and primary hypertension is well established, with increased renal artery resistance elevating blood pressure through the renin-angiotensin system 4 and sodium retention. 5 Moreover, it is widely recognized that altered sympathetic effects on the renal artery are strongly implicated in the initiation and perpetuation of the hypertensive state with dysfunction of the ␤-adrenoceptor pathway a dominant feature.6-11 However, little is known about the molecular mechanisms that contribute to renal artery vasospasm and decreased ␤-adrenoceptor-mediated dilation. Potassium (K ϩ ) channels regulate resting membrane potential in smooth muscle cells (SMCs) and are, thus, key determinants of smooth muscle contractility.12 Recently, our laboratory demonstrated that voltage-gated K ϩ channels encoded by KCNQ4 (Kv7.4) were drastically downregulated in the aorta and mesenteric artery of 2 different models of hypertension, spontaneously hypertensive rats (SHRs) and angiotensin II perfused mice. 13 If a similar situation occurred in the renal artery, then the associated vasospasm and arterial stenosis would lead to reduced perfusion of the kidney and activation of the renin-angiotensin system. Although KCNQ gene expression and the functional role of Kv7 channels have been established in a number of different vascular beds, [14][15][16][17][18] there...

Background-Voltage-gated potassium (K ϩ ) channels encoded by KCNQ genes (Kv7 channels) have been identified in various rodent and human blood vessels as key regulators of vascular tone; however, nothing is known about the functional impact of these channels in vascular disease. We ascertained the effect of 3 structurally different activators of Kv7.2 through Kv7.5 channels (BMS-204352, S-1, and retigabine) on blood vessels from normotensive and hypertensive animals. Methods and Results-Precontracted thoracic aorta and mesenteric artery segments from normotensive rats were relaxed by all 3 Kv7 activators, with potencies of BMS-204352ϭS-1Ͼretigabine. We also tested these agents in the coronary circulation using the Langendorff heart preparation. BMS-204352 and S-1 dose dependently increased coronary perfusion at concentrations between 0.1 and 10 mol/L, whereas retigabine was effective at 1 to 10 mol/L. In addition, S-1 increased K ϩ currents in isolated mesenteric artery myocytes. The ability of these agents to relax precontracted vessels, increase coronary flow, or augment K ϩ currents was impaired considerably in tissues isolated from spontaneously hypertensive rats (SHRs). Of the 5 KCNQ genes, only the expression of KCNQ4 was reduced (Ϸ3.7 fold) in SHRs aorta. Kv7.4 protein levels were Ϸ50% lower in aortas and mesenteric arteries from spontaneously hypertensive rats compared with normotensive vessels. A similar attenuated response to S-1 and decreased Kv7.4 were observed in mesenteric arteries from mice made hypertensive by angiotensin II infusion compared with normotensive controls. Conclusions-In 2 different rat and mouse models of hypertension, the functional impact of Kv7 channels was dramatically downregulated. (Circulation. 2011;124:602-611.)Key Words: hypertension Ⅲ vasodilation Ⅲ KCNQ potassium channels Ⅲ gene expression P rimary hypertension is characterized by raised total peripheral resistance caused by increased arterial tone. 1 Evidence suggests increased vascular tone during hypertension is a result of a more depolarized membrane potential, which has been associated with a rise in intracellular calcium (Ca 2ϩ ). 2,3 As such, an understanding of the K ϩ channels that stabilize the resting membrane potential is crucial for delineating the pathogenesis of hypertension. Clinical Perspective on p 611KCNQ1-5 genes encode for voltage-gated K ϩ channels (Kv7.1 through Kv7.5, respectively) that have an established physiological role in neurons, 4 -7 cardiomyocytes, 8 cochlea, 9 and some epithelia. 10 There is now a growing appreciation that Kv7 channels are important regulators of smooth muscle contractility in rodent and human blood vessels. [11][12][13] In all blood vessels studied, KCNQ1 and KCNQ4 expression appears to dominate, 11,12,14 -18 although our laboratory has shown a truncated variant of KCNQ5 is also readily expressed. 15,19 Modulation of these channels provokes profound changes in vascular smooth muscle membrane potential and consequently vascular tone. [13][14][15][16][17]20 Thus, the non...

Targeting oncogenic kinase drivers with small-molecule inhibitors can have marked therapeutic benefit, especially when administered to an appropriate genomically defined patient population. Cancer genomics and mechanistic studies have revealed that heterogeneous mutations within a single kinase can result in various mechanisms of kinase activation. Therapeutic benefit to patients can best be optimized through an in-depth understanding of the disease-driving mutations combined with the ability to match these insights to tailored highly selective drugs. This rationale is presented for BLU-285, a clinical stage inhibitor of oncogenic KIT and PDGFRA alterations, including activation loop mutants that are ineffectively treated by current therapies. BLU-285, designed to preferentially interact with the active conformation of KIT and PDGFRA, potently inhibits activation loop mutants KIT D816V and PDGFRA D842V with subnanomolar potency and also inhibits other well-characterized disease-driving KIT mutants both in vitro and in vivo in preclinical models. Early clinical evaluation of BLU-285 in a phase 1 study has demonstrated marked activity in patients with diseases associated with (aggressive systemic mastocytosis and gastrointestinal stromal tumor) and (gastrointestinal stromal tumor) activation loop mutations.