RESUMEN
BACKGROUND: Voltage-gated potassium (K(+)) 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-204352=S-1>retigabine. 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 µmol/L, whereas retigabine was effective at 1 to 10 µmol/L. In addition, S-1 increased K(+) currents in isolated mesenteric artery myocytes. The ability of these agents to relax precontracted vessels, increase coronary flow, or augment K(+) currents was impaired considerably in tissues isolated from spontaneously hypertensive rats (SHRs). Of the 5 KCNQ genes, only the expression of KCNQ4 was reduced (≈3.7 fold) in SHRs aorta. Kv7.4 protein levels were ≈50% 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.
Asunto(s)
Hipertensión/fisiopatología , Canales de Potasio KCNQ/fisiología , Angiotensina II/farmacología , Animales , Aorta Torácica/fisiología , Presión Sanguínea/fisiología , Carbamatos/farmacología , Regulación hacia Abajo/fisiología , Hipertensión/inducido químicamente , Técnicas In Vitro , Indoles/farmacología , Canales de Potasio KCNQ/agonistas , Masculino , Potenciales de la Membrana/efectos de los fármacos , Potenciales de la Membrana/fisiología , Arterias Mesentéricas/fisiología , Ratones , Fenilendiaminas/farmacología , Ratas , Ratas Endogámicas SHR , Ratas Wistar , Vasoconstrictores/farmacologíaRESUMEN
We have shown previously that inhibition of small conductance Ca(2+)-activated K(+) (SK) channels is antiarrhythmic in models of acutely induced atrial fibrillation (AF). These models, however, do not take into account that AF derives from a wide range of predisposing factors, the most prevalent being hypertension. In this study we assessed the effects of two different SK channel inhibitors, NS8593 and UCL1684, in aging, spontaneously hypertensive rats to examine their antiarrhythmic properties in a setting of hypertension-induced atrial remodeling. Male spontaneously hypertensive rats and the normotensive Wistar-Kyoto rat strain were divided in 2×3 groups of animals aged 3, 8, and 11 months, respectively. The animals were randomly assigned to treatment with NS8593, UCL1684, or vehicle, and open chest in vivo experiments including burst pacing-induced AF were performed. The aging spontaneously hypertensive rats were more vulnerable to AF induction both by S2 stimulation and burst pacing. Vehicle affected neither the atrial effective refractory period nor AF duration. SK channel inhibition with NS8593 and UCL1684 significantly increased the atrial effective refractory period and decreased AF duration in both the normotensive and hypertensive strains with no decline in efficacy as age increased. In conclusion, SK channel inhibition with NS8593 and UCL1684 possesses antiarrhythmic properties in a rat in vivo model of paroxysmal AF with hypertension-induced atrial remodeling. The present results support the notion that SK channels may offer a promising new therapeutic target in the treatment of AF.
Asunto(s)
Fibrilación Atrial/prevención & control , Hipertensión/fisiopatología , Bloqueadores de los Canales de Potasio/farmacología , Canales de Potasio Calcio-Activados/antagonistas & inhibidores , 1-Naftilamina/administración & dosificación , 1-Naftilamina/análogos & derivados , 1-Naftilamina/farmacología , Factores de Edad , Alcanos/administración & dosificación , Alcanos/farmacología , Animales , Antiarrítmicos/administración & dosificación , Antiarrítmicos/farmacología , Fibrilación Atrial/fisiopatología , Estimulación Cardíaca Artificial , Modelos Animales de Enfermedad , Humanos , Inyecciones Intravenosas , Masculino , Bloqueadores de los Canales de Potasio/administración & dosificación , Canales de Potasio Calcio-Activados/fisiología , Compuestos de Quinolinio/administración & dosificación , Compuestos de Quinolinio/farmacología , Distribución Aleatoria , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Especificidad de la Especie , Factores de TiempoRESUMEN
AIMS: Transient outward potassium current (I(to)) is thought to be central to the pathogenesis of the Brugada syndrome (BrS). However, an I((to)) activator has not been available with which to validate this hypothesis. Here, we provide a direct test of the hypothesis using a novel I(to) activator, NS5806. METHODS AND RESULTS: Isolated canine ventricular myocytes and coronary-perfused wedge preparations were used. Whole-cell patch-clamp studies showed that NS5806 (10 microM) increased peak I(to) at +40 mV by 79 +/- 4% (24.5 +/- 2.2 to 43.6 +/- 3.4 pA/pF, n = 7) and slowed the time constant of inactivation from 12.6 +/- 3.2 to 20.3 +/- 2.9 ms (n = 7). The total charge carried by I(to) increased by 186% (from 363.9 +/- 40.0 to 1042.0 +/- 103.5 pA x ms/pF, n = 7). In ventricular wedge preparations, NS5806 increased phase 1 and notch amplitude of the action potential in the epicardium, but not in the endocardium, and accentuated the ECG J-wave, leading to the development of phase 2 re-entry and polymorphic ventricular tachycardia (n = 9). Although sodium and calcium channel blockers are capable of inducing BrS only in right ventricular (RV) wedge preparations, the I(to) 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. CONCLUSION: The I(to) 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 I(to) could explain variants of BrS, in which ST-segment elevation or J-waves are evident in both right and left ECG leads.
Asunto(s)
Síndrome de Brugada/metabolismo , Electrocardiografía , Moduladores del Transporte de Membrana/farmacología , Miocitos Cardíacos/efectos de los fármacos , Compuestos de Fenilurea/farmacología , Canales de Potasio/agonistas , Potasio/metabolismo , Tetrazoles/farmacología , Potenciales de Acción , Animales , Síndrome de Brugada/genética , Síndrome de Brugada/fisiopatología , Perros , Relación Dosis-Respuesta a Droga , Endocardio/efectos de los fármacos , Endocardio/metabolismo , Ventrículos Cardíacos/efectos de los fármacos , Ventrículos Cardíacos/metabolismo , Técnicas In Vitro , Mutación , Miocitos Cardíacos/metabolismo , Pericardio/efectos de los fármacos , Pericardio/metabolismo , Canales de Potasio/genética , Canales de Potasio/metabolismo , Factores de TiempoRESUMEN
AIMS: Impaired repolarization in cardiac myocytes can lead to long QT syndrome (LQTS), with delayed repolarization and increased susceptibility to Torsades de Pointes (TdP) arrhythmias. Current pharmacological treatment of LQTS is often inadequate. This study sought to evaluate the antiarrhythmic effect of a novel compound (NS1643) that activates the rapid delayed-rectifier K+ current, I(Kr), in two rabbit models of acquired LQTS. METHODS AND RESULTS: We used two clinically relevant in vivo rabbit models of TdP in which we infused NS1643 or vehicle: (i) three-week atrioventricular block with ventricular bradypacing; (ii) dofetilide-induced I(Kr) inhibition in methoxamine-sensitized rabbits. In addition, we studied effects on ionic currents in cardiomyocytes with I(Kr) suppressed by bradycardia remodelling or dofetilide exposure. Bradypaced rabbits developed QT interval prolongation, spontaneous ventricular ectopy, and TdP. Infusion of NS1643 completely suppressed arrhythmic activity and shortened the QT interval; vehicle had no effect. NS1643 also suppressed ventricular tachyarrhythmias caused by infusion of dofetilide to methoxamine-sensitized rabbits, and reversed dofetilide-induced QT prolongation. NS1643 increased I(Kr) in cardiomyocytes isolated from normal and bradycardia-remodelled rabbits by approximately 75% and 50%, respectively (P < 0.001 for each). Similarly, NS1643 restored I(Kr) suppressed by 5 nmol/L dofetilide (tail current 0.28 +/- 0.03 pA/pF pre-dofetilide, 0.20 +/- 0.01 pA/pF in the presence of dofetilide, 0.27 +/- 0.02 pA/pF after adding NS1643 to dofetilide-containing solution, P < 0.01). CONCLUSION: Pharmacological activation of I(Kr) reverses acquired LQTS and TdP caused by bradycardic remodelling and I(Kr)-blocking drugs. I(Kr)-activating drug therapy could be a potentially interesting treatment approach for LQTS.
Asunto(s)
Antiarrítmicos/farmacología , Cresoles/farmacología , Canales de Potasio de Tipo Rectificador Tardío/agonistas , Síndrome de QT Prolongado/prevención & control , Compuestos de Fenilurea/farmacología , Animales , Bloqueo Atrioventricular/complicaciones , Bradicardia/etiología , Bradicardia/fisiopatología , Bradicardia/prevención & control , Modelos Animales de Enfermedad , Electrocardiografía , Femenino , Síndrome de QT Prolongado/inducido químicamente , Síndrome de QT Prolongado/fisiopatología , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/fisiología , Técnicas de Placa-Clamp , Fenetilaminas , Conejos , Sulfonamidas , Torsades de Pointes/inducido químicamente , Torsades de Pointes/fisiopatología , Torsades de Pointes/prevención & controlRESUMEN
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.