Inhibition of SK channels prolongs atrial effective refractory period without affecting QT interval and prevents and terminates AF ex vivo and in vivo, thus offering a promising new therapeutic opportunity in the treatment of AF.

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...

We have identified and characterized the compound NS309 (6,7-dichloro-1H-indole-2,3-dione 3-oxime) as a potent activator of human Ca2+ -activated K+ channels of SK and IK types, whereas it is devoid of effect on BK type channels. IK- and SK-channels have previously been reported to be activated by the benzimidazolinone, 1-EBIO and more potently by its dichloronated-analogue, DC-EBIO. NS309 is at least 1000 times more potent than 1-EBIO and at least 30 times more potent than DC-EBIO when the compounds are compared on the same cell.

Aim Transient outward potassium current (Ito) is thought to be central to the activator has not been pathogenesis of the Brugada syndrome (BrS). However, an Ito available with which to validate this hypothesis. Here we provide a direct test of the hypothesis using a novel Ito activator, NS5806. Methods Isolated canine ventricular myocytes and coronary-perfused wedge preparations were used. Results Whole-cell patch-clamp studies showed that NS5806 (10 μM) increased peak Ito at +40 mV by 79±4% (24.5±2.2 to 43.6±3.4 pA/pF, n=7) and slowed the time-constant increased of inactivation from 12.6±3.2 to 20.3±2.9 ms, n=7. Total charge carried by Ito by 186% (from 363.9 ± 40.0 to 1042.0 ± 103.5 pA ms/pF, n=7). In ventricular wedge preparations, NS5806 increased phase 1 and notch amplitude of the action potential (AP) in epicardium, but not endocardium, and accentuated the ECG J-wave, leading to the development of phase 2 reentry and polymorphic ventricular tachycardia (n=9). While sodium and calcium channel blockers are capable of inducing BrS only in right ventricular wedge preparations, the Ito activator was able to induce the phenotype in wedges from both ventricles. NS5806 induced BrS in 4/6 right and 2/10 left ventricular wedge preparations. Conclusions The Ito activator NS5806 recapitulates the electrographic and arrhythmic manifestation of BrS, providing evidence in support of its pivotal role in the genesis of the disease. Our findings also suggest that a genetic defect leading to a gain of function of Ito could explain variants of BrS in which ST-segment elevation or J-waves are evident in both right and left ECG leads.

Activation of the large-conductance Ca(2+)-activated K(+) channel (BK) in the cardiac inner mitochondrial membrane has been suggested to protect the heart against ischemic injury. However, these findings are limited by the low selectivity profile and potency of the BK channel activator (NS1619) used. In the present study, we address the cardioprotective role of BK channels using a novel, potent, selective, and chemically unrelated BK channel activator, NS11021. Using electrophysiological recordings of heterologously expressed channels, NS11021 was found to activate BK alpha + beta1 channel complexes, while producing no effect on cardiac K(ATP) channels. The cardioprotective effects of NS11021-induced BK channel activation were studied in isolated, perfused rat hearts subjected to 35 min of global ischemia followed by 120 min of reperfusion. 3 microM NS11021 applied prior to ischemia or at the onset of reperfusion significantly reduced the infarct size [control: 44.6 +/- 2.0%; NS11021: 11.4 +/- 2.0%; NS11021 at reperfusion: 19.8 +/- 3.3% (p < 0.001 for both treatments compared to control)] and promoted recovery of myocardial performance. Co-administration of the BK-channel inhibitor paxilline (3 microM) antagonized the protective effect. These findings suggest that tissue damage induced by ischemia and reperfusion can be reduced by activation of cardiac BK channels.