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1.
J Med Chem ; 60(12): 5193-5208, 2017 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-28541707

RESUMO

PI3Kδ plays an important role controlling immune cell function and has therefore been identified as a potential target for the treatment of immunological disorders. This article highlights our work toward the identification of a potent, selective, and efficacious PI3Kδ inhibitor. Through careful SAR, the successful replacement of a polar pyrazole group by a simple chloro or trifluoromethyl group led to improved Caco-2 permeability, reduced Caco-2 efflux, reduced hERG PC activity, and increased selectivity profile while maintaining potency in the CD69 hWB assay. The optimization of the aryl substitution then identified a 4'-CN group that improved the human/rodent correlation in microsomal metabolic stability. Our lead molecule is very potent in PK/PD assays and highly efficacious in a mouse collagen-induced arthritis model.


Assuntos
Artrite Experimental/tratamento farmacológico , Avaliação Pré-Clínica de Medicamentos/métodos , Inibidores Enzimáticos/farmacologia , Relação Estrutura-Atividade , Animais , Antígenos CD/metabolismo , Antígenos de Diferenciação de Linfócitos T/metabolismo , Células CACO-2/efeitos dos fármacos , Células CACO-2/imunologia , Cães , Canal de Potássio ERG1/metabolismo , Inibidores Enzimáticos/química , Feminino , Humanos , Doenças do Sistema Imunitário/tratamento farmacológico , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Lectinas Tipo C/metabolismo , Masculino , Camundongos Endogâmicos BALB C , Pirazóis/química , Pirazóis/metabolismo , Pirazóis/farmacologia , Coelhos
2.
J Med Chem ; 60(9): 3795-3803, 2017 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-28418664

RESUMO

We have recently disclosed 5-phenyl-N-(pyridin-2-ylmethyl)-2-(pyrimidin-5-yl)quinazolin-4-amine 1 as a potent IKur current blocker with selectivity versus hERG, Na and Ca channels, and an acceptable preclinical PK profile. Upon further characterization in vivo, compound 1 demonstrated an unacceptable level of brain penetration. In an effort to reduce the level of brain penetration while maintaining the overall profile, SAR was developed at the C2' position for a series of close analogues by employing hydrogen bond donors. As a result, 5-[5-phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl]pyridine-3-sulfonamide (25) was identified as the lead compound in this series. Compound 25 showed robust effects in rabbit and canine pharmacodynamic models and an acceptable cross-species pharmacokinetic profile and was advanced as the clinical candidate. Further optimization of 25 to mitigate pH-dependent absorption resulted in identification of the corresponding phosphoramide prodrug (29) with an improved solubility and pharmacokinetic profile.


Assuntos
Fibrilação Atrial/tratamento farmacológico , Bloqueadores dos Canais de Potássio/uso terapêutico , Quinazolinas/uso terapêutico , Bloqueadores dos Canais de Sódio/uso terapêutico , Sulfonamidas/uso terapêutico , Animais , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Cães , Espectrometria de Massas , Bloqueadores dos Canais de Potássio/farmacologia , Espectroscopia de Prótons por Ressonância Magnética , Quinazolinas/química , Quinazolinas/farmacologia , Coelhos , Bloqueadores dos Canais de Sódio/farmacologia , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacologia
3.
ACS Med Chem Lett ; 7(9): 831-4, 2016 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-27660686

RESUMO

A new series of phenylquinazoline inhibitors of Kv 1.5 is disclosed. The series was optimized for Kv 1.5 potency, selectivity versus hERG, pharmacokinetic exposure, and pharmacodynamic potency. 5-Phenyl-N-(pyridin-2-ylmethyl)-2-(pyrimidin-5-yl)quinazolin-4-amine (13k) was identified as a potent and ion channel selective inhibitor with robust efficacy in the preclinical rat ventricular effective refractory period (VERP) model and the rabbit atrial effective refractory period (AERP) model.

5.
Am J Physiol Heart Circ Physiol ; 297(5): H1889-98, 2009 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19783782

RESUMO

Ischemic focal ventricular tachycardia (VT) occurs in animals and humans. Angiotensin-converting enzyme inhibitors and receptor blockers reduce sudden death in patients with ischemic heart disease. In our dog model of coronary artery occlusion (CAO), we tested the hypothesis that angiotensin II (AGII) will selectively promote focal VT and that the specific AT(2) blocker PD-123319 (PD), or AT(1) blocker losartan, will affect this VT. Anesthetized dogs (n = 90) underwent CAO, followed by three-dimensional activation mapping of inducible VT. Dogs without VT in 1-3 h after CAO received AGII, and those with VT received either PD or losartan. Focal endocardium excised from ischemic sites was studied in vitro with standard microelectrode. Of 33 dogs with no inducible VT, AGII infusion resulted in sustained VT of only focal Purkinje origin in 13 (39%) compared with 0 of 20 dogs with saline. Of 26 dogs with inducible VT at baseline, given PD, reinduction was blocked in 8 of 10 (P < 0.05) focal VT, but only 1 of 15 with reentry. In contrast, of 11 dogs given losartan, reinduction of either mechanism was not blocked. In vitro triggered activity in Purkinje was blocked by PD in 13 of 19 (P < 0.05), but not by losartan in 8. Also, triggered activity was promoted by AGII, losartan, or the combination in 9 of 12 tissues. AGII promotes only focal, mainly Purkinje ischemic VT. PD, but not losartan, preferentially blocked focal VT, which is likely due to triggered activity due to delayed afterdepolarizations in Purkinje.


Assuntos
Angiotensina II/metabolismo , Isquemia Miocárdica/metabolismo , Miocárdio/metabolismo , Receptor Tipo 2 de Angiotensina/metabolismo , Transdução de Sinais , Taquicardia Ventricular/metabolismo , Potenciais de Ação , Angiotensina II/administração & dosagem , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Bloqueadores do Receptor Tipo 2 de Angiotensina II , Animais , Antiarrítmicos/farmacologia , Estimulação Cardíaca Artificial , Modelos Animais de Doenças , Cães , Eletrocardiografia , Técnicas Eletrofisiológicas Cardíacas , Endocárdio/metabolismo , Endocárdio/fisiopatologia , Feminino , Imidazóis/farmacologia , Infusões Intravenosas , Losartan/farmacologia , Masculino , Isquemia Miocárdica/complicações , Isquemia Miocárdica/tratamento farmacológico , Isquemia Miocárdica/fisiopatologia , Ramos Subendocárdicos/metabolismo , Ramos Subendocárdicos/fisiopatologia , Piridinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Taquicardia Ventricular/etiologia , Taquicardia Ventricular/fisiopatologia , Taquicardia Ventricular/prevenção & controle , Fatores de Tempo
6.
Heart Rhythm ; 6(4): 530-6, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19324315

RESUMO

BACKGROUND: Focal ventricular tachycardia (VT) in acute myocardial ischemia is closely related to triggered activity (TA), which may be blocked by scavenging reactive oxygen species (ROS). OBJECTIVE: This study analyzed effects of acutely administered ROS scavenger-2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO) on VT in vivo and TA in vitro. METHODS: Forty-three alpha chloralose anesthetized dogs with coronary artery occlusion were studied. Three-dimensional activation mapping helped to locate the origin of focal or reentrant VT. TEMPO (30 mg/kg intravenously) or vehicle was given. Endocardium excised from the site of origin of VT was studied using standard microelectrode techniques and measures of ROS. RESULTS: Reentry and focal VT induction were both highly reproducible. TEMPO blocked focal VT in 6 of 11 dogs (P <.05), but 9 of 9 dogs with reentrant VT continued to have VT re-induced after TEMPO. TEMPO did not alter effective refractory period (168 +/- 3 to 171 +/- 3 ms), mean blood pressure (88 +/- 3 to 81 +/- 3 mm Hg), and size of ischemia (42% +/- 3% vs 40% +/- 4%). In vitro, TEMPO (10(-3) M, n = 14) produced no change in action potentials. Nevertheless, TA was reversibly attenuated from 5.3 +/- 1.1 to 0.4 +/- 0.4 complexes with TEMPO (n = 15, P <.05). Lucigenin-enhanced chemiluminescence and dihydroethidium staining showed increased ROS in ischemic endocardium; TEMPO dramatically reduced ROS in ischemic sites. CONCLUSION: TEMPO, a scavenger of ROS, prevented triggered activity associated with focal VT during myocardial ischemia in areas of increased ROS. Antioxidant therapy may play an important role in blockade of focal VT under the conditions of myocardial ischemia.


Assuntos
Antioxidantes/farmacologia , Óxidos N-Cíclicos/farmacologia , Isquemia Miocárdica/etiologia , Isquemia Miocárdica/prevenção & controle , Taquicardia Ventricular/complicações , Animais , Cães , Eletrocardiografia , Técnicas Eletrofisiológicas Cardíacas , Luminescência , Isquemia Miocárdica/fisiopatologia , Ramos Subendocárdicos/fisiopatologia , Reprodutibilidade dos Testes , Coloração e Rotulagem , Taquicardia Ventricular/fisiopatologia
7.
Scand Cardiovasc J ; 41(6): 378-85, 2007 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17852790

RESUMO

OBJECTIVE: In this study we tested the hypothesis that alpha-2 adrenergic antagonism could facilitate induction of previously non-inducible ventricular tachycardia (VT) during acute ischemia. Previous reports suggest that VT during ischemia may be modulated by (alpha-2 adrenergic agonists. DESIGN: The left anterior descending artery was occluded after instrumentation of the ischemic risk zone with 21 multipolar plunge needles, each recording 6 bipolar electrograms. Three dimensional mapping characterized the mechanism of VT induced with extrastimuli. RESULTS: Of 16 non-inducible dogs included, eight which were given the alpha-2 adrenergic antagonist yohimbine all had inducible VT, while all eight in the control group remained non-inducible (p < 0.05). Six of the VTs were of focal Purkinje origin. The cycle length of the VTwas 119 +/- 4 ms. Mean arterial pressure (81+/- 8 to 82 +/- 8 mmHg, p = ns), ventricular effective refractory period (146 +/- 6 to 144 +/- 5 ms, p = ns) and ischemic zone size (55 +/-6% vs. 61 +/- 4%, p = 0.45) were not altered by yohimbine indicating minimal central or pre-junctional effects of the drug. CONCLUSIONS: Yohimbine facilitates induction of VT, especially those with focal Purkinje fiber origin, suggestive of an effect mediated through antagonism of post-junctional alpha-2 adrenoceptors on Purkinje fibers.


Assuntos
Antagonistas Adrenérgicos alfa/efeitos adversos , Isquemia Miocárdica/tratamento farmacológico , Taquicardia Ventricular/induzido quimicamente , Ioimbina/efeitos adversos , Animais , Modelos Animais de Doenças , Cães , Eletrocardiografia , Técnicas Eletrofisiológicas Cardíacas , Feminino , Masculino , Ramos Subendocárdicos/efeitos dos fármacos , Ramos Subendocárdicos/fisiopatologia , Receptores Adrenérgicos alfa 2/efeitos dos fármacos , Taquicardia Ventricular/fisiopatologia
8.
Heart Rhythm ; 4(5): 629-37, 2007 May.
Artigo em Inglês | MEDLINE | ID: mdl-17467633

RESUMO

BACKGROUND: Use of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor has been associated with reduced implantable defibrillator shocks in several multicenter trials, suggesting an antiarrhythmic effect. OBJECTIVE: The purpose of this study was to determine if lovastatin had an antiarrhythmic effect in a canine model of ischemic and inducible ventricular tachycardia (VT). METHODS: Forty-seven alpha-chloralose anesthetized dogs underwent left anterior descending coronary occlusion. Three-dimensional activation mapping identified the mechanism of reinducible VT and the response to lovastatin (0.5 mg/kg IV). The endocardium was excised from foci and studied using standard microelectrode techniques with Tyrode's solution. RESULTS: Lovastatin blocked focal VT in 8 of 13 dogs (P <.01) compared with only 1 of 12 saline-treated dogs with focal VT. Lovastatin had no effect on reentrant VT. Lovastatin did not alter the effective refractory period, arterial pressure, or percentage of ischemic electrograms. Effective plasma concentration of lovastatin hydroxy acid ranged from 21-157 ng/mL (0.8-3.7 x 10(-7) M). In vitro rapid pacing, mostly with isoproterenol (5 x 10(-7) M) superfusion, produced delayed afterdepolarizations and triggered activity (9 +/- 2 action potentials). Lovastatin (10(-7) M) produced no change in action potentials or delayed afterdepolarizations. However, triggered activity was attenuated to 2 +/- 1 action potentials with lovastatin (P <.05, n = 13) but not with vehicle alone. Triggered activity returned to control after lovastatin washout (20 minutes) as well as with co-superfusion with mevalonic acid (10(-6) M, n = 5). 2,2,6,6-Tetramethylpiperidine-N-oxyl, an antioxidant that enters tissues (10(-3) M, n = 8), prevented triggered activity in a fashion similar to lovastatin. CONCLUSION: Lovastatin, in concentrations achievable in human plasma, specifically suppresses triggered activity and focal VT due to ischemia. A prenylated protein downstream from mevalonic acid may act as an antioxidant, producing the antiarrhythmic effect.


Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Lovastatina/farmacologia , Isquemia Miocárdica/prevenção & controle , Isquemia Miocárdica/fisiopatologia , Fibrilação Ventricular/prevenção & controle , Fibrilação Ventricular/fisiopatologia , Potenciais de Ação/efeitos dos fármacos , Agonistas Adrenérgicos beta/farmacologia , Análise de Variância , Animais , Antiarrítmicos/sangue , Antiarrítmicos/farmacologia , Antioxidantes/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Mapeamento Potencial de Superfície Corporal , Estimulação Cardíaca Artificial , Óxidos N-Cíclicos/farmacologia , Modelos Animais de Doenças , Cães , Técnicas Eletrofisiológicas Cardíacas , Feminino , Inibidores de Hidroximetilglutaril-CoA Redutases/sangue , Isoproterenol/farmacologia , Lovastatina/sangue , Masculino , Ácido Mevalônico/farmacologia , Microeletrodos , Período Refratário Eletrofisiológico/efeitos dos fármacos , Projetos de Pesquisa
9.
Arterioscler Thromb Vasc Biol ; 25(10): 2122-7, 2005 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-16051883

RESUMO

OBJECTIVE: In cultured endothelium, stretch induces release of growth factors that contribute to angiogenesis. We tested the hypothesis that bradycardia, which prolongs ventricular diastolic filling time and volume, promotes collateral vessel growth. METHODS AND RESULTS: An ameroid occluder was placed on coronary arteries of dogs with normal heart rates (AM) or bradycardia (55 bpm; AM+BC). A third group had normal heart rates and no ameroid (control [CON]). Four weeks after occluder placement, myocardial blood flow at rest and maximal vasodilation (adenosine) at equivalent heart rates and vascular morphometry of hearts were measured. In AM dogs, conductance (myocardial flow/diastolic pressure) of collateral-dependent myocardium was similar to collateral-independent myocardium during rest but increased to only one third of CON during maximal vasodilation. In contrast, in AM+BC dogs, conductance was similar in collateral-dependent and -independent regions during maximal vasodilation. Arteriolar length density in collateral-dependent myocardium was 80% greater in AM+BC than AM dogs. Capillary length density in collateral-dependent region of AM dogs was lower than CON but normal in AM+BC dogs. The angiopoietin receptor Tie-2 increased in collateral-dependent regions of AM and AM+BC groups, whereas vascular endothelial growth factor increased in collateral-dependent and -independent regions only in AM+BC dogs. CONCLUSIONS: Chronic bradycardia during gradual coronary artery occlusion facilitates angiogenesis/arteriogenesis in collateral-dependent myocardium and preserves maximal perfusion.


Assuntos
Bradicardia/fisiopatologia , Circulação Coronária/fisiologia , Doença das Coronárias/fisiopatologia , Neovascularização Fisiológica/fisiologia , Animais , Arteríolas/fisiologia , Capilares/fisiologia , Doença Crônica , Vasos Coronários/fisiologia , Diástole/fisiologia , Cães , Receptor TIE-2/metabolismo , Regulação para Cima , Fator A de Crescimento do Endotélio Vascular/metabolismo
10.
Am J Physiol Heart Circ Physiol ; 288(3): H1124-30, 2005 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-15706044

RESUMO

Entrainment can be a useful method to identify reentry as a mechanism of ventricular tachycardia (VT). In this study, we evaluated the effect of gradually decreasing cycle lengths of overdrive pacing for stable VT induced in a canine model 1-3 h after coronary occlusion. Intact dogs underwent anterior descending coronary artery occlusion after instrumentation of the risk zone with 21 multipolar plunge needles, each recording 6 bipolar electrograms. Overdrive pacing was attempted if the animals had sustained hemodynamically stable VT, looking for evidence of entrainment. Subsequent three-dimensional mapping determined the mechanism of VT. Fifteen of the 21 dogs studied demonstrated entrainment with overdrive pacing by progressive QRS fusion alone (1), the first nonpaced QRS entrained to the paced cycle length only (7), or both (7). Five of these 15 dogs also had postpacing acceleration of the VT at a subsequent faster pacing cycle length. The mechanism of acceleration in four was a change to a VT with a focal origin. The prepacing mechanism in all 15 dogs was subsequently mapped to reentry. Regarding the six VTs, which demonstrated no evidence for entrainment, the site of earliest activity was mapped to a focal origin in all. These data showing entrainment of inducible reentrant VTs and lack of such for focal VTs support that the focal VTs seen in this study are unlikely the result of microreentry but possibly a mechanism as triggered activity.


Assuntos
Coração/fisiopatologia , Isquemia Miocárdica/fisiopatologia , Taquicardia Ventricular/fisiopatologia , Animais , Cães , Feminino , Ventrículos do Coração/fisiopatologia , Masculino , Marca-Passo Artificial , Fibrilação Ventricular/fisiopatologia
11.
Am J Physiol Heart Circ Physiol ; 288(2): H511-6, 2005 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-15650154

RESUMO

The role of gap junction intercellular communication (GJIC) in ischemia-induced focal ventricular tachycardia (VT) is unknown. We have developed a new, stable antiarrhythmic peptide analog named ZP123 that selectively increases GJIC and prevents reentrant VT. Our aim in this study was to use ZP123 as a tool to assess the role of GJIC on occurrence of ischemia-induced focal VT and triggered activity (TA) due to delayed afterdepolarizations (DADs). Focal VT was induced by programmed stimulation in alpha-chloralose-anesthetized, open-chest dogs 1-4 h after coronary artery occlusion. Three-dimensional activation mapping was done using 6 bipolar electrograms on each of 23 multipolar needles in the risk zone. Dogs were randomly assigned to receive either saline or ZP123 cumulatively at three dose levels (an intravenous bolus followed by a 30-min infusion per dose). Attempts to induce VT were repeated in each dose. Mass spectrometry was used to measure plasma ZP123 concentrations. Standard microelectrode techniques were used for in vitro study of DADs and TA. Twenty-six dogs with focal VT were included. ZP123 did not affect the inducibility of focal VT at any plasma concentrations vs. saline (0.8 +/- 0.1 nM, 77 vs. 75%; 7.8 +/- 0.4 nM, 86 vs. 77%; and 78.8 +/- 5.0 nM, 77 vs. 91%). In vitro, ZP123 did not affect the induction of DADs (12/12) and TAs (10/10) in ischemic tissues or tissue removed from the origin of focal VT (DADs, 8/8; TAs, 4/4). Therefore, although indirect, the data with the doses and concentrations used suggest that GJIC may not play a major role in the genesis of focal activity in the ischemic models studied.


Assuntos
Junções Comunicantes/efeitos dos fármacos , Coração/fisiopatologia , Isquemia Miocárdica/fisiopatologia , Oligopeptídeos/farmacologia , Taquicardia Ventricular/fisiopatologia , Animais , Comunicação Celular/efeitos dos fármacos , Comunicação Celular/fisiologia , Cães , Feminino , Junções Comunicantes/fisiologia , Coração/efeitos dos fármacos , Masculino , Oligopeptídeos/sangue , Taquicardia Ventricular/etiologia
12.
Am J Physiol Heart Circ Physiol ; 287(5): H2078-84, 2004 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-15475531

RESUMO

This study for the first time systematically evaluated the site of origin of focal ventricular tachycardia (VT) induced 1-3 h after acute coronary artery ligation in dogs. We determined whether delayed afterdepolarizations (DADs) and triggered activity (TA) are more often recorded from ischemic endocardium excised from focal sites of VT origin. A total of 145 alpha-chloralose-anesthetized dogs were studied: in 54 dogs without inducible VT, normal or ischemic endocardium was investigated in vitro; in 91 dogs, inducible VT was studied by three-dimensional activation mapping, with in vitro study of 51 endocardial foci compared with 40 endocardial ischemic sites not of VT origin. Incidence of DADs (71% vs. 33%, P <0.05) and TA (32% vs. 11%, P <0.05) was greater in ischemic than in normal Purkinje tissues. Purkinje sites of origin of focal VT demonstrated the greatest frequency of DADs (92%, P <0.05) and TA (75%, P <0.05), with repetitive TA predominating. Similar results were obtained in endocardial sites of origin. Action potentials were mildly depolarized and prolonged in the focal sites of origin. These abnormalities were stable up to 2.5 h of recording. This study demonstrated that DADs and TA may underlie a majority of focal VTs in ischemic endocardium and Purkinje tissue.


Assuntos
Endocárdio/fisiopatologia , Isquemia Miocárdica/complicações , Taquicardia Ventricular/etiologia , Taquicardia Ventricular/fisiopatologia , Potenciais de Ação , Animais , Cães , Eletrocardiografia , Eletrofisiologia , Feminino , Masculino , Ramos Subendocárdicos/fisiopatologia , Tempo de Reação
13.
J Cardiovasc Electrophysiol ; 14(5): 510-20, 2003 May.
Artigo em Inglês | MEDLINE | ID: mdl-12776869

RESUMO

INTRODUCTION: The aim of this study was to determine if the stable antiarrhythmic peptide (AAP) analogue ZP123 increases gap junctional intercellular conductance and prevents reentrant ventricular tachycardia (VT) during coronary artery occlusion. METHODS AND RESULTS: Voltage clamp experiments demonstrated that 10 nM ZP123 improved gap junctional intercellular conductance by 69% +/- 20% in pairs of guinea pig ventricular myocytes. VT was induced by programmed stimulation in alpha-chloralose anaesthetized open chest dogs 1 to 4 hours after coronary artery occlusion. Three-dimensional activation mapping was done using six bipolar electrograms on each of 23 multipolar needles in the risk zone. When VT was reproducibly induced, dogs were randomly assigned to receive either saline or ZP123 cumulatively at three dose levels (intravenous bolus followed by 30-min infusion per dose). Attempts to induce VT were repeated in each infusion period. Mass spectrometry was used to measure ZP123 plasma concentrations. Twenty-six dogs with reentrant VT were included. ZP123 significantly prevented reentrant VT at all plasma concentrations vs saline: 1.0 +/- 0.2 nM: 6/12 vs 0/12; 7.7 +/- 0.6 nM: 7/13 vs 1/12; and 69.2 +/- 5.4 nM: 9/13 vs 1/13. The preventive effect of ZP123 on reentrant VT was closely correlated to reversal of functional, unidirectional conduction block. ZP123 did not affect effective refractory period, surface ECG parameters, mean arterial pressure, or infarct size. CONCLUSION: The stable AAP analogue ZP123 increased gap junctional intercellular conductance and specifically prevented the induction of reentrant VT during ischemia in a broad dose range without proarrhythmic or hemodynamic side effects. ZP123 is a promising candidate for use in preventing ischemia-induced VT.


Assuntos
Junções Comunicantes/efeitos dos fármacos , Isquemia Miocárdica/fisiopatologia , Oligopeptídeos/uso terapêutico , Taquicardia Ventricular/prevenção & controle , Taquicardia Ventricular/fisiopatologia , Animais , Pressão Sanguínea/fisiologia , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Modelos Animais de Doenças , Cães , Relação Dose-Resposta a Droga , Eletrocardiografia , Feminino , Bloqueio Cardíaco/metabolismo , Bloqueio Cardíaco/fisiopatologia , Bloqueio Cardíaco/prevenção & controle , Sistema de Condução Cardíaco/efeitos dos fármacos , Sistema de Condução Cardíaco/metabolismo , Sistema de Condução Cardíaco/fisiopatologia , Incidência , Infusões Intravenosas , Masculino , Modelos Cardiovasculares , Isquemia Miocárdica/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/ultraestrutura , Oligopeptídeos/administração & dosagem , Oligopeptídeos/farmacologia , Reprodutibilidade dos Testes , Estatística como Assunto , Taquicardia Ventricular/metabolismo
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