RESUMEN
A series of isoindolinone compounds have been developed showing good in vitro potency on the Kv1.5 ion channel. By modification of two side chains on the isoindolinone scaffold, metabolically stable compounds with good in vivo PK profile could be obtained leaving the core structure unsubstituted. In this way, low microsomal intrinsic clearance (CLint) could be achieved despite a relatively high logD. The compounds were synthesized using the Ugi reaction, in some cases followed by Suzuki and Diels-Alder reactions, giving a diverse set of compounds in a small number of reaction steps.
Asunto(s)
Isoindoles/farmacología , Canal de Potasio Kv1.5/antagonistas & inhibidores , Bloqueadores de los Canales de Potasio/farmacología , Animales , Relación Dosis-Respuesta a Droga , Humanos , Isoindoles/síntesis química , Isoindoles/química , Ratones , Modelos Animales , Estructura Molecular , Bloqueadores de los Canales de Potasio/síntesis química , Bloqueadores de los Canales de Potasio/química , Relación Estructura-ActividadRESUMEN
A series of lactam sulfonamides has been discovered and optimized as inhibitors of the Kv1.5 potassium ion channel for treatment of atrial fibrillation. In vitro structure-activity relationships from lead structure C to optimized structure 3y are described. Compound 3y was evaluated in a rabbit PD-model and was found to selectively prolong the atrial effective refractory period at submicromolar concentrations.
Asunto(s)
Canal de Potasio Kv1.5/antagonistas & inhibidores , Lactamas/química , Bloqueadores de los Canales de Potasio/química , Pirrolidinonas/química , Sulfonamidas/química , Animales , Perros , Semivida , Humanos , Canal de Potasio Kv1.5/metabolismo , Bloqueadores de los Canales de Potasio/síntesis química , Bloqueadores de los Canales de Potasio/farmacocinética , Pirrolidinonas/síntesis química , Pirrolidinonas/farmacocinética , Conejos , Ratas , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/farmacocinéticaRESUMEN
Diphenylphosphinic amides and diphenylphosphine oxides have been synthesized and tested as inhibitors of the Kv1.5 potassium ion channel as a possible treatment for atrial fibrillation. In vitro structure-activity relationships are discussed and several compounds with Kv1.5 IC(50) values of <0.5 µM were discovered. Selectivity over the ventricular IKs current was monitored and selective compounds were found. Results from a rabbit PD-model are included.
Asunto(s)
Amidas/síntesis química , Amidas/farmacología , Canal de Potasio Kv1.5/antagonistas & inhibidores , Óxidos/síntesis química , Óxidos/farmacología , Fosfinas/síntesis química , Fosfinas/farmacología , Amidas/química , Animales , Compuestos de Bifenilo/química , Humanos , Concentración 50 Inhibidora , Estructura Molecular , Óxidos/química , Fosfinas/química , Ácidos Fosfínicos/química , Unión Proteica/efectos de los fármacos , Conejos , Relación Estructura-ActividadRESUMEN
Pharmacological treatment of atrial fibrillation (AF) exhibits limited efficacy. Further developments require a comprehensive characterization of ionic modulators of electrophysiology in human atria. Our aim is to systematically investigate the relative importance of ionic properties in modulating excitability, refractoriness, and rotor dynamics in human atria before and after AF-related electrical remodeling (AFER). Computer simulations of single cell and tissue atrial electrophysiology were conducted using two human atrial action potential (AP) models. Changes in AP, refractory period (RP), conduction velocity (CV), and rotor dynamics caused by alterations in key properties of all atrial ionic currents were characterized before and after AFER. Results show that the investigated human atrial electrophysiological properties are primarily modulated by maximal value of Na(+)/K(+) pump current (G(NaK)) as well as conductances of inward rectifier potassium current (G(K1)) and fast inward sodium current (G(Na)). G(NaK) plays a fundamental role through both electrogenic and homeostatic modulation of AP duration (APD), APD restitution, RP, and reentrant dominant frequency (DF). G(K1) controls DF through modulation of AP, APD restitution, RP, and CV. G(Na) is key in determining DF through alteration of CV and RP, particularly in AFER. Changes in ionic currents have qualitatively similar effects in control and AFER, but effects are smaller in AFER. The systematic analysis conducted in this study unravels the important role of the Na(+)/K(+) pump current in determining human atrial electrophysiology.
Asunto(s)
Función Atrial/fisiología , Atrios Cardíacos/enzimología , Periodo Refractario Electrofisiológico/fisiología , ATPasa Intercambiadora de Sodio-Potasio/fisiología , Potenciales de Acción/fisiología , Fibrilación Atrial/fisiopatología , Simulación por Computador , Atrios Cardíacos/fisiopatología , Humanos , Transporte Iónico/fisiología , Modelos CardiovascularesRESUMEN
A wide range of ion channels have been considered as potential targets for pharmacological treatment of atrial fibrillation. The Kv1.5 channel, carrying the I(Kur) current, has received special attention because it contributes to repolarization in the atria but is absent or weakly expressed in ventricular tissue. The dog serves as an important animal model for electrophysiological studies of the heart and mathematical models of the canine atrial action potential (CAAP) have been developed to study the interplay between ionic currents. To enable more-realistic studies on the effects of Kv1.5 blockers on the CAAP in silico, two continuous-time Markov models of the guarded receptor type were formulated for Kv1.5 and subsequently inserted into the Ramirez-Nattel-Courtemanche model of the CAAP. The main findings were: 1), time- and state-dependent Markov models of open-channel Kv1.5 block gave significantly different results compared to a time- and state-independent model with a downscaled conductance; 2), the outcome of Kv1.5 block on the macroscopic system variable APD(90) was dependent on the precise mechanism of block; and 3), open-channel block produced a reverse use-dependent prolongation of APD(90). This study suggests that more-complex ion-channel models are a prerequisite for quantitative modeling of drug effects.
Asunto(s)
Canal de Potasio Kv1.5/antagonistas & inhibidores , Modelos Biológicos , Potenciales de Acción/efectos de los fármacos , Animales , Fenómenos Biofísicos , Perros , Atrios Cardíacos/efectos de los fármacos , Atrios Cardíacos/metabolismo , Técnicas In Vitro , Canal de Potasio Kv1.5/metabolismo , Cadenas de Markov , Modelos Cardiovasculares , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Bloqueadores de los Canales de Potasio/farmacologíaRESUMEN
AZD7009 (tert-Butyl-2-(7-[(2S)-3-(4-cyanophenoxy)-2-hydroxypropyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)ethylcarbamate) is an antiarrhythmic agent that increases atrial refractoriness, shows high antiarrhythmic efficacy and has low proarrhythmic potential. This study was primarily undertaken to determine the effects of AZD7009 on the late sodium current and to examine the impact of late sodium current inhibition on action potential duration in various myocardial cells. AZD7009 inhibited the late sodium current in Chinese Hamster Ovary K1 (CHO K1) cells expressing hNa(v)1.5 with an IC(50) of 11+/-2 microM. The late sodium current in isolated rabbit atrial and ventricular myocytes was also concentration dependently inhibited by AZD7009. Action potentials were recorded during exposure to 5 microM E-4031 (1-[2-(6-methyl-2pyridyl)ethyl]-4-(4-methylsulfonyl aminobenzoyl)piperidine), a compound that selectively inhibits the rapid delayed rectifier potassium current (I(Kr)), and to E-4031 in combination with AZD7009 or lidocaine in rabbit atrial and ventricular tissue and Purkinje fibres. In Purkinje fibres, but not in ventricular tissue, AZD7009 and lidocaine attenuated the E-4031-induced action potential duration prolongation. In atrial cells, AZD7009, but not lidocaine, further prolonged the E-4031-induced action potential duration. E-4031 induced early afterdepolarisations (EADs) in Purkinje fibres, EADs that were totally suppressed by AZD7009 or lidocaine. In conclusion, excessive action potential duration prolongation induced by E-4031 was attenuated by AZD7009 and lidocaine in rabbit Purkinje fibre, but not in atrial or ventricular tissue, most likely by inhibiting the late sodium current. Furthermore, the opposite effect by AZD7009 on action potential duration in atrial tissue suggests that AZD7009, in addition to inhibiting I(Kr), also inhibits other repolarising currents in the atria.
Asunto(s)
Corazón/efectos de los fármacos , Lidocaína/farmacología , Compuestos Orgánicos/farmacología , Ramos Subendocárdicos/efectos de los fármacos , Bloqueadores de los Canales de Sodio/farmacología , Potenciales de Acción/efectos de los fármacos , Animales , Células CHO , Cricetinae , Cricetulus , Corazón/fisiología , Masculino , Proteínas Musculares/antagonistas & inhibidores , Canal de Sodio Activado por Voltaje NAV1.5 , Piperidinas/farmacología , Ramos Subendocárdicos/fisiología , Piridinas/farmacología , Conejos , Canales de SodioRESUMEN
Glutamate (glu) is a major excitatory transmitter and a toxin in the brain. In the present study, the immature rat hippocampal slice was used to determine the morphology, topography, ionic mediation and receptor specificity of glu toxicity. Slices were exposed to glu for 30 min, and the damage was evaluated after 3 h of recovery in regular medium. The effects on glu toxicity of changes of [Ca2+], [Cl-] and [Na+] were determined. The receptor preference of glu was assessed by using the N-methyl-D-aspartate (NMDA) antagonist MK-801 and the kainate (KA)/quisqualate (QA) antagonist DNQX, alone or in combination. Further, to see whether glu produces cytotoxicity via osmolysis, the effects of hyperosmolal sucrose on glu toxicity were studied. Glu toxicity was similar to the previously described NMDA toxicity with regard to cytopathology, but differed in some aspects from that caused by KA and QA. The severity of the lesion was determined by the proximity of neurons to the incubation fluid, probably as a consequence of cellular accumulation of the amino acid. Omission of Ca2+ abolished glu toxicity in all neurons except the granule cells of the outer blade. This population was completely protected when Ca2+ was omitted and [Cl-] was reduced. Elevation of [Ca2+] markedly aggravated the lesion caused by glu. Substitution of isethionate for Cl- worsened the glu-induced damage, whilst the amino acid produced qualitatively different neuropathology when choline substituted for Na+. Apparently glu did not damage hippocampal nerve cells through an osmolytic mechanism as medium supplemented with 100 mM sucrose increased the toxicity of glu. Since the lesion produced by glu was more widespread in the presence of high [Ca2+], the effects of receptor antagonists were studied under this condition. MK-801 inhibited glu toxicity whereas DNQX had no effect. Combination of MK-801 and DNQX did not offer better protection than did MK-801 alone. The results suggest that Ca2+ is the main (but not single) determinant of glu toxicity in the immature hippocampal slice. The ionic requirements of glu neurotoxicity are identical to those of NMDA, but differ from those of KA and QA. The notion that glu is a selective NMDA agonist in the present model was confirmed by the protection of MK-801, and by the lack of an effect of DNQX. This is the first report demonstrating that the toxicity of glu is mediated by NMDA receptors in brain tissue which has developed normally. The findings indicate that specific blockade of NMDA receptors may be the most rational strategy in the prevention of glu-related neuronal death occurring in certain neurological anomalies.
RESUMEN
OBJECTIVE: To examine the electrophysiological, hemodynamic, and antiarrhythmic effects of the novel antiarrhythmic agent AZ13395438. METHODS: The ion channel-blocking potency of AZ13395438 was assessed in Chinese hamster ovary cells stably expressing various human cardiac ion channels and in human atrial myocytes. The in vivo electrophysiological, hemodynamic, and antiarrhythmic effects of intravenously administered AZ13395438 were examined in anesthetized rabbits, in anesthetized naive dogs, and in dogs subjected to rapid atrial pacing (RAP) for 8 weeks. Pharmacokinetic/pharmacodynamic (PKPD) modeling was applied to predict the potency of AZ13395438 in increasing atrial and ventricular refractoriness. RESULTS: AZ13395438 potently and predominantly blocked the atrial repolarizing potassium currents I(Kur), I(Ach), and I(to) in vitro. In vivo, AZ13395438 caused a concentration-dependent and selective increase in atrial refractoriness with no or small effects on ventricular refractoriness and repolarization and on hemodynamics in both rabbits and dogs. The PKPD modeling predicted unbound plasma concentrations of AZ13395438 of 0.20 ± 0.039, 0.38 ± 0.084, and 0.34 ± 0.057 µmol/L to increase the right atrial effective refractory period by 20 milliseconds in the rabbit and in the naive and the RAP dogs, respectively. In the RAP dog with atrial fibrillation (AF), AZ13395438 significantly increased AF cycle length and successfully converted AF to sinus rhythm in 12 of the 12 occasions at an unbound plasma concentration of 0.48 ± 0.076 µmol/L. During saline infusion, conversion was seen only in 4 of the 10 occasions (P = .003 vs AZ13395438). Furthermore, AZ13395438 reduced AF inducibility by burst pacing from 100% to 25% (P < .001). CONCLUSION: AZ13395438 can be characterized as a mixed potassium ion channel-blocking agent that selectively prolongs atrial versus ventricular refractoriness and shows promising antiarrhythmic efficacy in a clinically relevant animal model of AF.
Asunto(s)
Antiarrítmicos/uso terapéutico , Arritmias Cardíacas/tratamiento farmacológico , Modelos Animales de Enfermedad , Drogas en Investigación/uso terapéutico , Bloqueadores de los Canales de Potasio/uso terapéutico , Propanolaminas/uso terapéutico , Piridinas/uso terapéutico , Animales , Antiarrítmicos/sangre , Antiarrítmicos/farmacocinética , Antiarrítmicos/farmacología , Células CHO , Células Cultivadas , Cricetinae , Cricetulus , Perros , Drogas en Investigación/análisis , Drogas en Investigación/farmacocinética , Drogas en Investigación/farmacología , Femenino , Atrios Cardíacos/citología , Atrios Cardíacos/efectos de los fármacos , Atrios Cardíacos/metabolismo , Hemodinámica/efectos de los fármacos , Humanos , Masculino , Miocitos Cardíacos/citología , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Bloqueadores de los Canales de Potasio/sangre , Bloqueadores de los Canales de Potasio/farmacocinética , Bloqueadores de los Canales de Potasio/farmacología , Canales de Potasio/química , Canales de Potasio/genética , Canales de Potasio/metabolismo , Propanolaminas/sangre , Propanolaminas/farmacocinética , Propanolaminas/farmacología , Piridinas/sangre , Piridinas/farmacocinética , Piridinas/farmacología , Conejos , Distribución Aleatoria , Proteínas Recombinantes/antagonistas & inhibidores , Proteínas Recombinantes/metabolismo , Periodo Refractario Electrofisiológico/efectos de los fármacosRESUMEN
INTRODUCTION: Accumulating evidence suggest that drug-induced QT prolongation per se poorly predicts repolarisation-related proarrhythmia liability. We examined whether beat-by-beat variability of the QT interval may be a complementary proarrhythmia marker to QT prolongation. METHODS: Anaesthetised rabbits sensitized towards developing torsades de pointes (TdP) were infused for 30 min maximum with explorative antiarrhythmic compounds characterised as mixed ion channel blockers. Based on the outcome in this model the compounds were classified as having a low (TdPlow; n=5), intermediate (TdPintermediate; n=7) or high (TdPhigh; n=10) proarrhythmic potential. Dofetilide (n=4) was included as a representative of a selective IKr-blocking antiarrhythmic with known high proarrhythmic potential. QT interval prolongation and beat-by-beat QT variability (quantified as the short-term variability, STV) were continuously assessed during the infusion or up to the point where ventricular proarrhythmias were induced. RESULTS: All compounds significantly prolonged the QT interval. For TdPlow and TdPhigh compounds the QT interval maximally increased from 169 ± 14 to 225 ± 28 ms (p<0.05) and from 186 ± 21 to 268 ± 42 ms (p<0.01), respectively. Likewise, in the dofetilide-infused rabbits the QT interval maximally increased from 177 ± 11 to 243 ± 25 ms (p<0.01). In contrast, whereas the STV in rabbits administered the TdPhigh compounds or dofetilide significantly increased prior to proarrhythmia induction (from 1.6 ± 0.4 to 10.5 ± 5.6 ms and from 1.6 ± 0.5 to 5.9 ± 1.8 ms, p<0.01) it remained unaltered in the TdPlow group (1.3 ± 0.6 to 2.2 ± 0.9 ms). In the TdPintermediate group, rabbits experiencing TdP had a similar maximal QT prolongation as the non-susceptible rabbits whereas the change in the STV was significantly different (from 0.9 ± 0.5 to 8.7 ± 7.3 ms vs 0.8 ± 0.3 to 2.5 ± 1.1 ms). DISCUSSION: It is concluded from the present series of experiments in a sensitive rabbit model of TdP that increased beat-by-beat QT interval variability precedes drug-induced TdP. In addition, assessment of this potential proarrhythmia marker may be useful in discriminating highly proarrhythmic compounds from compounds with a low proarrhythmic potential.
Asunto(s)
Antiarrítmicos/farmacología , Antiarrítmicos/toxicidad , Arritmias Cardíacas/inducido químicamente , Electrocardiografía , Síndrome de QT Prolongado/inducido químicamente , Torsades de Pointes/inducido químicamente , Animales , Línea Celular , Canal de Potasio ERG1 , Embrión de Mamíferos , Canales de Potasio Éter-A-Go-Go/metabolismo , Corazón/efectos de los fármacos , Corazón/fisiopatología , Humanos , Canales Iónicos/antagonistas & inhibidores , Riñón , Síndrome de QT Prolongado/fisiopatología , Masculino , Metoxamina/farmacología , Modelos Estadísticos , Fenetilaminas/farmacología , Fenetilaminas/toxicidad , Conejos , Ratas , Sulfonamidas/farmacología , Sulfonamidas/toxicidad , Torsades de Pointes/fisiopatologíaRESUMEN
Atrial fibrillation (AF) is an arrhythmia of growing clinical concern that is increasing in prevalence and is associated with significant morbidity and mortality. Pharmacological agents remain the first-line therapy for the AF patient, and the potential advantages of sinus rhythm maintenance motivate continued efforts to identify novel pharmacological means to restore and maintain sinus rhythm. Traditional antiarrhythmic agents only moderately suppress AF and present problematic concerns of proarrhythmia and extracardiac toxicity. Current investigational or recently approved strategies for improving efficacy and safety of anti-AF agents include (i) specific or predominant blockade of atrial ion channels; (ii) "upstream therapies" affecting non-ion channel targets that influence electrical and structural remodeling, inflammation and oxidative stress; (iii) amiodarone derivatives with an improved safety profile; (iv) intracellular calcium handling; and (v) therapies aiming at alleviating conduction disturbances (gap junction coupling enhancers). This review provides a succinct overview of some of these strategies.
Asunto(s)
Antiarrítmicos/farmacología , Fibrilación Atrial/tratamiento farmacológico , Sistemas de Liberación de Medicamentos , Animales , Antiarrítmicos/efectos adversos , Fibrilación Atrial/fisiopatología , Calcio/metabolismo , Atrios Cardíacos/efectos de los fármacos , Atrios Cardíacos/metabolismo , Humanos , Inflamación/tratamiento farmacológico , Inflamación/etiología , Canales Iónicos/antagonistas & inhibidores , Estrés Oxidativo/efectos de los fármacosRESUMEN
AIMS: To compare the electrophysiological and antiarrhythmic effects of AZD7009, azimilide, and AVE0118 in the acutely dilated rabbit atria in vitro. METHODS AND RESULTS: In the isolated Langendorf-perfused rabbit heart, the atrial effective refractory period (AERP) and the inducibility of atrial fibrillation (AF) were measured at increasing concentrations of AZD7009 (0.1-3 microM), azimilide (0.1-3 microM), and AVE0118 (0.3-10 microM). In separate groups of atria, termination of sustained AF was assessed. In non-dilated atria, the AERP was 82+/-1.3 ms (mean+/-SEM) and AF could not be induced. Dilation significantly reduced the AERP to 49+/-1.0 ms (P<0.001) and 92% of the atria became inducible. Perfusion with AZD7009, azimilide, and AVE0118 concentration-dependently increased the AERP and reduced the AF inducibility. At the highest concentrations of AZD7009, azimilide, and AVE0118, AERP and AF inducibility changed from 50+/-4.5 to 136+/-6.6 ms and 80 to 0% (both P<0.001) from 51+/-3.0 to 105+/-9.9 ms (P<0.001) and 80 to 0% (P<0.01) and from 46+/-2.8 to 85+/-6.0 ms and 90 to 0% (both P<0.001). Restoration of sinus rhythm was seen in 6/6, 5/6, and 5/6 hearts perfused with AZD7009, azimilide, and AVE0118, respectively. CONCLUSION: In the dilated rabbit atria, AZD7009, azimilide, and AVE0118 concentration-dependently increased AERP, effectively prevented AF induction, and rapidly restored sinus rhythm.
Asunto(s)
Antiarrítmicos/farmacología , Arritmias Cardíacas/tratamiento farmacológico , Compuestos de Bifenilo/farmacología , Atrios Cardíacos/efectos de los fármacos , Imidazolidinas/farmacología , Compuestos Orgánicos/farmacología , Piperazinas/farmacología , Análisis de Varianza , Animales , Dilatación Patológica , Hidantoínas , Técnicas In Vitro , ConejosRESUMEN
AZD7009 is a novel antiarrhythmic compound in early clinical development for management of atrial fibrillation. Electrophysiological studies in animals have shown high antiarrhythmic efficacy, predominant action on atrial electrophysiology, and low proarrhythmic activity. AZD7009 has previously been shown to inhibit hERG and hNav1.5 currents. The main objective of the present study was to characterize the effects of AZD7009 on hKv1.5 and hKv4.3/hKChIP2.2 currents to get a deeper understanding of the ion channel-blocking properties of the compound. hKv1.5 and hKv4.3/hKChIP2.2 currents were expressed in CHO cells. Currents were measured using the whole-cell configuration of the voltage-clamp technique. AZD7009 inhibited hKv1.5 and hKv4.3/hKChIP2.2 currents with equal potency: the IC50 for hKv1.5 block was 27.0 +/- 1.6 muM (n = 6), and the IC50 for hKv4.3/hKChIP2.2 block was 23.7 +/- 4.4 muM (n = 5). Block of the hKv4.3/hKChIP2.2 current was frequency dependent with larger block at higher frequency, whereas block of the hKv1.5 current was slightly decreased at higher frequency. In conclusion, AZD7009 inhibits both the hKv1.5 and the hKv4.3/hKChIP2.2 currents. These effects likely contribute to the effects described in animals in vivo.
Asunto(s)
Antiarrítmicos/farmacología , Bloqueadores de los Canales de Potasio/farmacología , Canales de Potasio/fisiología , Animales , Células CHO , Cricetinae , Cricetulus , Relación Dosis-Respuesta a Droga , Humanos , Proteínas de Interacción con los Canales Kv/genética , Proteínas de Interacción con los Canales Kv/fisiología , Canal de Potasio Kv1.5/genética , Canal de Potasio Kv1.5/fisiología , Potenciales de la Membrana/efectos de los fármacos , Potenciales de la Membrana/fisiología , Técnicas de Placa-Clamp/métodos , Canales de Potasio/genética , Propafenona/farmacología , Canales de Potasio Shal/genética , Canales de Potasio Shal/fisiología , TransfecciónRESUMEN
INTRODUCTION: AZD7009 is a novel anti-arrhythmic compound under development for short- and long-term management of atrial fibrillation and flutter. Electrophysiological studies in animals have shown high anti-arrhythmic efficacy, predominant action on atrial electrophysiology, and low proarrhythmic activity. The main aim of this study was to characterize the blocking effects of AZD7009 on the human ether-a-go-go-related gene (hERG), the hNav1.5, and the hKvLQT1/hminK currents. METHODS AND RESULTS: hERG, hKvLQT1/hminK, and hNav1.5 were expressed in CHO K1 cells. Currents were measured using the whole-cell configuration of the voltage-clamp technique. AZD7009 inhibited the hERG current with an IC50 of 0.6 +/- 0.07 microM (n = 6). AZD7009 1 microM hyperpolarized the potential for half-maximal activation from -8.2 +/- 0.1 mV to -18.0 +/- 0.6 mV (P < 0.001, n = 14) and induced pre-pulse potentiation at potentials near the activation threshold. The hNav1.5 current was blocked with an IC50 of 4.3 +/- 1.20 microM at 10 Hz (n = 6) and block developed use-dependently. Recovery from use-dependent block was slow, tau= 131 seconds. AZD7009 inhibited the hKvLQT1/hminK current only at high concentrations (IC50= 193 +/- 20 microM, n = 6). CONCLUSION: AZD7009 inhibits both the hERG and the hNav1.5 current, and it is most likely this combined current block that underlies the prolongation of the refractoriness and the low proarrhythmic activity demonstrated in animals in vivo.
Asunto(s)
Potenciales de Acción/efectos de los fármacos , Antiarrítmicos/farmacología , Proteínas de Unión al ADN/efectos de los fármacos , Potenciales de la Membrana/efectos de los fármacos , Proteínas Musculares/efectos de los fármacos , Canales de Potasio con Entrada de Voltaje/efectos de los fármacos , Canales de Sodio/efectos de los fármacos , Transactivadores/efectos de los fármacos , Antiarrítmicos/metabolismo , Fibrilación Atrial/tratamiento farmacológico , Proteínas de Transporte de Catión/efectos de los fármacos , Proteínas de Unión al ADN/antagonistas & inhibidores , Técnicas In Vitro , Proteínas Musculares/antagonistas & inhibidores , Canal de Sodio Activado por Voltaje NAV1.5 , Bloqueadores de los Canales de Potasio/metabolismo , Bloqueadores de los Canales de Potasio/farmacología , Bloqueadores de los Canales de Sodio/metabolismo , Bloqueadores de los Canales de Sodio/farmacología , Transactivadores/antagonistas & inhibidores , Regulador Transcripcional ERGRESUMEN
INTRODUCTION: The aim of this study was to analyze the block of HERG-carried membrane currents caused by H 345/52, a new antiarrhythmic compound with low proarrhythmic activity, in transfected mouse fibroblasts. METHODS AND RESULTS: Using the whole-cell configuration of the voltage patch clamp technique, it was demonstrated that H 345/52 concentration-dependently blocked HERG-carried currents with an IC50 of 230 nM. H 345/52 preferentially bound to the open channel with unusually rapid kinetics and was trapped by channel closure. Voltage-independent behavior of H 345/52 was observed during both square-pulse and action potential clamp protocols. In contrast, the Class III agents dofetilide (10 nM) and almokalant (250 nM) demonstrated significant membrane potential-dependent effects during square-pulse clamp protocols. When using action potential clamp protocols, voltage dependence was seen with dofetilide but not with almokalant. Mathematical simulations of human ventricular action potentials predicted that the different voltage-dependent behaviors would not produce marked variations in action potential duration prolongation patterns. CONCLUSION: We propose that block of IKr is the principal mechanism by which H 345/52 delays repolarization in human myocardium. The voltage independence of HERG/IKr block is unlikely to underlie the low proarrhythmic potential, and ancillary effects on other membrane currents must be considered.
Asunto(s)
Alcanos/antagonistas & inhibidores , Alcanos/farmacología , Compuestos Bicíclicos con Puentes/antagonistas & inhibidores , Compuestos Bicíclicos con Puentes/farmacología , Proteínas de Transporte de Catión , Proteínas de Unión al ADN , Canales de Potasio con Entrada de Voltaje , Canales de Potasio/efectos de los fármacos , Transactivadores , Potenciales de Acción/efectos de los fármacos , Alcanos/administración & dosificación , Animales , Antiarrítmicos/farmacología , Unión Competitiva/efectos de los fármacos , Compuestos Bicíclicos con Puentes/administración & dosificación , Línea Celular , Relación Dosis-Respuesta a Droga , Canal de Potasio ERG1 , Canales de Potasio Éter-A-Go-Go , Fibroblastos/efectos de los fármacos , Fibroblastos/fisiología , Corazón/fisiología , Humanos , Concentración 50 Inhibidora , Potenciales de la Membrana/efectos de los fármacos , Ratones , Modelos Animales , Técnicas de Placa-Clamp , Fenetilaminas/farmacología , Bloqueadores de los Canales de Potasio/farmacología , Valor Predictivo de las Pruebas , Propanolaminas/farmacología , Sulfonamidas/farmacología , Factores de Tiempo , Regulador Transcripcional ERGRESUMEN
In the present paper we studied early acid-induced changes in the passive electrical properties of the rabbit esophageal epithelium in vivo by measurements of the transluminal potential difference (PD) during acid perfusion and by estimating the transmucosal electrical resistance (Rm) using cable analysis. Perfusion with acid (pH 1) for 45 min produced a rapid (<1 min) negative shift in the lumen-negative PD followed by a slow lumen-negative drift. The acid-induced change in PD was dependent on the accompanying anion, the largest anion (sulfate) producing the largest change. The acid-induced changes in PD were parallelled by reductions in Rm, these reductions also being dependent on the accompanying anion. Interpretation of resistance and net current (estimated by Ohm's law) time curves suggest that the initial acid-induced changes of the PD reflect properties of the naive mucosa whereas the later drift will reflect a diffusion driven increase in transmucosal proton permeability. Further, coapplication of the protective drug sucrose octasulfate attenuated the hydrochloric acid-induced changes of all measured and estimated electrophysiological parameters. The electrophysiological results were to some extent corroborated by light microscopic findings, although no large acid-induced change in mucosal appearance was observed.