RESUMO
BACKGROUND AND PURPOSE: Torsade de pointes (TdP) can be induced in several species by a reduction in cardiac repolarizing capacity. The aim of this study was to assess whether combined I(Kr) and I(Ks) blockade could induce TdP in anaesthetized guinea pigs and whether short-term variability (STV) or triangulation of action potentials could predict TdP. EXPERIMENTAL APPROACH: Experiments were performed in open-chest, pentobarbital-anaesthetized, adrenaline-stimulated male Dunkin Hartley guinea pigs, which received three consecutive i.v. infusions of either vehicle, the I(Kr) blocker E-4031 (3, 10 and 30 nmol kg(-1) min(-1)), the I(Ks) blocker HMR1556 (75, 250, 750 nmol kg(-1) min(-1)) or E-4031 and HMR1556 combined. Phenylephrine-stimulated guinea pigs were also treated with the K(+) channel blockers in combination. Arterial blood pressure, ECGs and epicardial monophasic action potential (MAP) were recorded. KEY RESULTS: TdP was observed in 75% of adrenaline-stimulated guinea pigs given the K(+) channel blockers in combination, but was not observed in guinea pigs treated with either I(K) blocker alone, or in phenylephrine-stimulated guinea pigs. Salvos and ventricular tachycardia occurred with adrenaline but not with phenylephrine. No changes in STV or triangulation of the MAP signals were observed before TdP. CONCLUSIONS AND IMPLICATIONS: Combined blockade of both I(Kr) and I(Ks) plus the addition of adrenaline were required to induce TdP in anaesthetized guinea pigs. This suggests that there must be sufficient depletion of repolarization reserve and an appropriate trigger for TdP to occur.
Assuntos
Canais de Potássio de Retificação Tardia/antagonistas & inibidores , Epinefrina/farmacologia , Bloqueadores dos Canais de Potássio/toxicidade , Torsades de Pointes/induzido quimicamente , Potenciais de Ação/efeitos dos fármacos , Animais , Cromanos/administração & dosagem , Cromanos/toxicidade , Relação Dose-Resposta a Droga , Eletrocardiografia , Epinefrina/administração & dosagem , Cobaias , Masculino , Modelos Biológicos , Fenilefrina/farmacologia , Piperidinas/administração & dosagem , Piperidinas/toxicidade , Bloqueadores dos Canais de Potássio/administração & dosagem , Canais de Potássio de Abertura Dependente da Tensão da Membrana/antagonistas & inibidores , Piridinas/administração & dosagem , Piridinas/toxicidade , Sulfonamidas/administração & dosagem , Sulfonamidas/toxicidadeRESUMO
BACKGROUND AND PURPOSE: Torsade de pointes (TdP) can be induced by a reduction in cardiac repolarizing capacity. The aim of this study was to assess whether IKs blockade or enhancement of INa could potentiate TdP induced by IKr blockade and to investigate whether short-term variability (STV) or triangulation of action potentials preceded TdP. EXPERIMENTAL APPROACH: Experiments were performed in open-chest, pentobarbital-anaesthetized, alpha 1-adrenoceptor-stimulated, male New Zealand White rabbits, which received three consecutive i.v. infusions of either the IKr blocker E-4031 (1, 3 and 10 nmol kg(-1) min(-1)), the IKs blocker HMR1556 (25, 75 and 250 nmol kg(-1) min(-1)) or E-4031 and HMR1556 combined. In a second study rabbits received either the same doses of E-4031, the INa enhancer, ATX-II (0.4, 1.2 and 4.0 nmol kg(-1)) or both of these drugs. ECGs and epicardial monophasic action potentials were recorded. KEY RESULTS: HMR1556 alone did not cause TdP but increased E-4031-induced TdP from 25 to 80%. ATX-II alone caused TdP in 38% of rabbits, as did E-4031; 75% of rabbits receiving both drugs had TdP. QT intervals were prolonged by all drugs but the extent of QT prolongation was not related to the occurrence of TdP. No changes in STV were detected and triangulation was only increased after TdP occurred. CONCLUSIONS AND IMPLICATIONS: Giving modulators of ion channels in combination substantially increased TdP but, in this model, neither STV nor triangulation of action potentials could predict TdP.
Assuntos
Potenciais de Ação/efeitos dos fármacos , Cromanos/toxicidade , Venenos de Cnidários/toxicidade , Piperidinas/toxicidade , Piridinas/toxicidade , Sulfonamidas/toxicidade , Torsades de Pointes/induzido quimicamente , Animais , Cromanos/administração & dosagem , Venenos de Cnidários/administração & dosagem , Canais de Potássio de Retificação Tardia/antagonistas & inibidores , Canais de Potássio de Retificação Tardia/metabolismo , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Eletrocardiografia , Eletrofisiologia , Previsões , Síndrome do QT Longo/induzido quimicamente , Masculino , Piperidinas/administração & dosagem , Canais de Potássio de Abertura Dependente da Tensão da Membrana/antagonistas & inibidores , Canais de Potássio de Abertura Dependente da Tensão da Membrana/metabolismo , Piridinas/administração & dosagem , Coelhos , Canais de Sódio/efeitos dos fármacos , Sulfonamidas/administração & dosagemRESUMO
BACKGROUND AND PURPOSE: Protease-activated receptor-2 (PAR-2) is expressed on lymphocytes and endothelial cells, and plays a significant role in inflammatory reactions. Since leukocyte-endothelial cell interaction and reactive oxygen species (ROS) generation are hallmarks of the development of inflammation, the effects of PAR-2 activation by trypsin on lymphocyte adhesion and ROS generation was examined utilising PAR-2 wild type and knockout (PAR-2-/-) mice. EXPERIMENTAL APPROACH: Lymphocyte adhesion to the luminal surface of mouse isolated aortae was measured using 51Cr-labelled leukocytes and ROS generation from isolated lymphocytes was quantified using chemiluminescence. KEY RESULTS: Trypsin induced adhesion of lymphocytes when added exogenously to the endothelial surface of the aorta for 30 min. Similarly, increased lymphocyte adhesion was also observed when mice were injected with trypsin intravenously 24 h prior to the adhesion assay, an effect which was partly ICAM-1 mediated. Trypsin also increased ROS generation from isolated mouse lymphocytes in a dose-dependent manner. The increase in lymphocyte adhesion and ROS production in response to trypsin were abolished in PAR-2-/- mice indicating a PAR-2 dependent mechanism. Superoxide dismutase had a greater inhibitory effect in PAR-2-/- mice compared to wild type mice when lymphocytes were stimulated with PMA but not trypsin. CONCLUSIONS AND IMPLICATIONS: The present study indicates that activation of PAR-2 may be an important factor in modulating lymphocyte adhesion and ROS generation. The results have implications for developing anti-inflammatory strategies.
Assuntos
Linfócitos T CD4-Positivos/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptor PAR-2/fisiologia , Animais , Aorta Torácica/citologia , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/metabolismo , Linfócitos B/citologia , Linfócitos B/efeitos dos fármacos , Linfócitos B/metabolismo , Antígeno CD11b/análise , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Adesão Celular/efeitos dos fármacos , Adesão Celular/fisiologia , Relação Dose-Resposta a Droga , Feminino , Citometria de Fluxo , Técnicas In Vitro , Molécula 1 de Adesão Intercelular/metabolismo , Medições Luminescentes/métodos , Masculino , Camundongos , Camundongos Knockout , Células Mieloides/citologia , Células Mieloides/efeitos dos fármacos , Células Mieloides/metabolismo , Selectina-P/metabolismo , Receptor PAR-2/genética , Receptor PAR-2/metabolismo , Baço/citologia , Baço/efeitos dos fármacos , Baço/metabolismo , Superóxido Dismutase/farmacologia , Acetato de Tetradecanoilforbol/farmacologia , Tripsina/farmacologiaRESUMO
The electrophysiological properties of the ventricular myocardium are extremely heterogeneous. There are intrinsic electrical differences between the myocytes from different regions of the heart (most notably between the epicardium, midmyocardium, and endocardium), which are the result of different contributions of ionic currents to the transmembrane action potential. Sources of local anisotropy include directional differences in the distribution of gap junctions between adjacent myocytes and the presence of intercalated non-myocytes (e.g., fibroblasts), propagation boundaries, and wavefront collisions, which can lead to local variability of electrical load and, therefore, to nonuniform depolarisation and repolarisation. In addition, the complex anatomical arrangement of the myocardial fibres and nonuniform distribution of transmural mechanical stresses also contribute to electrical heterogeneity. Finally, dispersion of repolarisation is dynamically modified by the restitution properties of individual myocytes, stimulation rate, and the direction of conduction. All aspects of this electrical heterogeneity can be affected by different pathological conditions, such as myocardial ischaemia and cardiac hypertrophy. In particular, differential responses of various myocyte populations to these pathological stimuli and a marked increase in nonuniform anisotropy may be responsible for increased pro-arrhythmic potential in these conditions. In addition, the clinical effectiveness of anti-arrhythmic drugs may be related to their effects on electrical heterogeneity.
Assuntos
Antiarrítmicos/farmacologia , Arritmias Cardíacas/tratamento farmacológico , Cardiopatias/fisiopatologia , Coração/anatomia & histologia , Coração/fisiologia , Potenciais de Ação/fisiologia , Animais , Anisotropia , Antiarrítmicos/uso terapêutico , Arritmias Cardíacas/patologia , Arritmias Cardíacas/fisiopatologia , Cardiomegalia/patologia , Cardiomegalia/fisiopatologia , Coração/fisiopatologia , Cardiopatias/patologia , Humanos , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Isquemia Miocárdica/patologia , Isquemia Miocárdica/fisiopatologia , Miocárdio/patologiaRESUMO
Chronic hypoxia (CH) is associated with several cardiopulmonary disorders. In vitro and in vivo studies have established the morphological changes, but yielded conflicting results about the functional changes induced by CH in the pulmonary vascular bed. CH increases the responsiveness to endothelium-dependent vasodilators in perfused lungs; however, in artery rings, a reduction is found in endothelium-dependent vasodilation. In CH, vasoconstriction induced by endothelin-1 is enhanced and vasodilation produced by atrial natriuretic peptide and K+ channel openers is increased. Vasoconstriction produced by acute hypoxia can be either enhanced or reduced by CH, depending on the experimental protocol. An understanding of the functional changes associated with CH is particularly important for a rational approach to the treatment of disorders associated with CH.
Assuntos
Hipóxia/fisiopatologia , Artéria Pulmonar/efeitos dos fármacos , Vasodilatadores/farmacologia , Animais , Doença Crônica , Humanos , Hipertensão Pulmonar/tratamento farmacológico , Hipertensão Pulmonar/etiologia , Hipóxia/complicações , Hipóxia/tratamento farmacológico , Técnicas In Vitro , Canais de Potássio/efeitos dos fármacos , Canais de Potássio/fisiologia , Artéria Pulmonar/fisiopatologia , Vasoconstrição/efeitos dos fármacos , Vasoconstrição/fisiologiaRESUMO
OBJECTIVE: The aim of this study was to investigate the influence of endogenously released and exogenously applied endothelin-1 (ET-1) on ischaemia-induced arrhythmias. METHODS: Ischaemia was induced in pentobarbitone-anaesthetised rats by ligation of a coronary artery for 30 min. To determine the role of endogenous ET-1 in ischaemic arrhythmias, either the ETA receptor antagonist BQ123 (50 micrograms/kg/min, i.v.; n = 10) or the ETB receptor antagonist PD161721 (0.1 or 1 mg/kg i.v.; n = 10 per group) was administered before the onset of ischaemia. To assess the influence of exogenous ET-1 on arrhythmias, ET-1 (1.6 nmol/kg i.v.) was administered 5 min before ischaemia in the absence (n = 12) or presence of BQ123 (n = 10) or PD161721 (n = 10). The total number of ventricular ectopic beats (VEB's) were counted and expressed as median (Q1-Q3) and the incidence of ventricular fibrillation (VF) and ventricular tachycardia (VT) in each group was determined. Mean arterial blood pressure (MABP) and heart rate (HR) were measured. RESULTS: In control animals (n = 20), the incidence of VF was 65% and the total VEB count was 2775 (1870-4041). Both BQ123 and the higher dose of PD161721 reduced the VEB count to 654 (348-1489; P < 0.05) and 782 (432-1153; P < 0.05) respectively. Only PD161721 reduced the incidence of VF (to 10%; P < 0.05). Administration of ET-1 reduced VEB's to 1530 (1204-2017); P < 0.05) and the incidence of VF to 17% (P < 0.05). Neither PD161721 nor BQ123 modified this antiarrhythmic effect of ET-1, but rather enhanced the reduction in arrhythmias. Before occlusion, ET-1 caused a transient fall in MABP (from 107 +/- 3 to 63 +/- 3 mmHg; P < 0.05). PD161721, but not BQ123, partially blocked this effect. Upon occlusion, MABP fell in control animals (from 106 +/- 4 to 67 +/- 4 mmHg at 1 min post-occlusion; P < 0.05). This was significantly attenuated by ET-1, although neither of the antagonists were able to block this effect of ET-1. CONCLUSIONS: ET-1 released endogenously during ischaemia is arrhythmogenic whereas exogenous application of ET-1 may, under certain conditions, be antiarrhythmic.
Assuntos
Arritmias Cardíacas/etiologia , Endotelinas/fisiologia , Isquemia Miocárdica/complicações , Animais , Arritmias Cardíacas/tratamento farmacológico , Arritmias Cardíacas/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Dioxinas/farmacologia , Relação Dose-Resposta a Droga , Antagonistas dos Receptores de Endotelina , Endotelina-1/farmacologia , Masculino , Isquemia Miocárdica/metabolismo , Peptídeos Cíclicos/farmacologia , Ratos , Ratos Sprague-Dawley , Receptor de Endotelina A , Receptor de Endotelina B , Fatores de Tempo , Complexos Ventriculares Prematuros/tratamento farmacológicoRESUMO
OBJECTIVE: To investigate changes in human atrial single cell functional electrophysiological properties associated with chronic atrial fibrillation (AF), and the contribution to these of accompanying ion current changes. METHODS: The whole cell patch clamp technique was used to record action potentials, the effective refractory period (ERP) and ion currents, in the absence and presence of drugs, in enzymatically isolated myocytes from 11 patients with chronic (>6 months) AF and 39 patients in sinus rhythm. RESULTS: Stimulation at high rates (up to 600 beats/min) markedly shortened late repolarisation and the ERP in cells from patients in sinus rhythm, and depolarised the maximum diastolic potential (MDP). Chronic AF was associated with a reduction in the ERP at physiological rate (from 203+/-16 to 104+/-15 ms, P<0.05), and marked attenuation in rate effects on the ERP and repolarisation. The abbreviated terminal phase of repolarisation prevented fast rate-induced depolarisation of the MDP in cells from patients with AF. The density of L-type Ca(2+) (I(CaL)) and transient outward K(+) (I(TO)) currents was significantly reduced in cells from patients with AF (by 60-65%), whilst the inward rectifier K(+) current (I(K1)) was increased, and the sustained outward current (I(KSUS)) was unaltered. Superfusion of cells from patients in sinus rhythm with nifedipine (10 micromol/l) moderately shortened repolarisation, but had no effect on the ERP (228+/-12 vs. 225+/-11 ms). 4-Aminopyridine (2 mmol/l) markedly prolonged repolarisation and the ERP (by 35%, P<0.05). However, the combination of these drugs had no effect on late repolarisation or refractoriness. CONCLUSION: Chronic AF in humans is associated with attenuation in adaptation of the atrial single cell ERP and MDP to fast rates, which may not be explained fully by accompanying changes in I(CaL) and I(TO).
Assuntos
Fibrilação Atrial/fisiopatologia , Função Atrial , Canais Iônicos , 4-Aminopiridina/farmacologia , Potenciais de Ação/efeitos dos fármacos , Idoso , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio , Estudos de Casos e Controles , Doença Crônica , Sinergismo Farmacológico , Estimulação Elétrica , Feminino , Humanos , Canais Iônicos/efeitos dos fármacos , Transporte de Íons/efeitos dos fármacos , Masculino , Potenciais da Membrana/efeitos dos fármacos , Pessoa de Meia-Idade , Nifedipino/farmacologia , Técnicas de Patch-Clamp , Bloqueadores dos Canais de Potássio/farmacologia , Canais de PotássioRESUMO
OBJECTIVES: Firstly, to compare effects of adenosine on membrane potential and refractoriness in AV nodal and atrial cells. Secondly, to assess the contribution of the effects of adenosine on IKAdo and ICaL to its effects on the functional electrophysiological properties in the two cell types. METHODS: The whole cell patch clamp technique was used to record action potentials and ion currents in AV nodal and left atrial myocytes isolated enzymatically from rabbit hearts. RESULTS: Adenosine (10 microM) caused similar hyperpolarisation and shortening of the action potential duration (APD) in both cell types: maximum diastolic potential was hyperpolarised from -59 +/- 3 to -66 +/- 2 and from -70 +/- 2 to -76 +/- 2 mV (mean +/- SEM) and APD90 was shortened by 31 +/- 4 and 30 +/- 7% in AV nodal (n = 14) and atrial cells (n = 8), respectively. Adenosine shortened the effective refractory period (ERP) in atrial cells, from 124 +/- 15 to 98 +/- 14 ms (n = 8). In contrast, ERP in AV nodal cells was not significantly affected (112 +/- 13 vs. 102 +/- 12 ms, n = 14), and post-repolarization refractoriness was prolonged. By contrast, current injection, to induce an equal degree of hyperpolarisation to that produced by adenosine, shortened APD and ERP in both cell types, suggesting an additional action of adenosine in AV nodal cells. Adenosine (10 microM) did not affect peak ICaL in AV nodal cells, but significantly altered the biexponential time course of recovery of ICaL from inactivation. The proportion of recovery in the fast phase (time constant, tau = 102 +/- 10 ms) was reduced from 71 +/- 3 to 55 +/- 5%, with shift to the slow phase (tau = 858 +/- 168 ms), without altering tau in either phase. A similar effect of adenosine was seen in left atrial cells. CONCLUSION: Adenosine caused hyperpolarisation, APD-shortening and slowing of recovery of ICaL from inactivation, in both AV nodal and atrial cells, but prolonged post-repolarisation refractoriness in AV nodal cells only. This differential effect of adenosine on refractoriness in the two cell types could not be explained by effects on IKAdo, but may be due to slowed reactivation of ICaL, which is the predominant inward current in AV nodal but not left atrial cells.
Assuntos
Potenciais de Ação/efeitos dos fármacos , Adenosina/farmacologia , Antiarrítmicos/farmacologia , Nó Atrioventricular , Canais Iônicos/efeitos dos fármacos , Animais , Canais de Cálcio/efeitos dos fármacos , Células Cultivadas , Estimulação Elétrica , Átrios do Coração , Potenciais da Membrana/efeitos dos fármacos , Técnicas de Patch-Clamp , Canais de Potássio/efeitos dos fármacos , CoelhosRESUMO
OBJECTIVE: The aims of this study were to establish an isolated working heart model for electrophysiological recordings from the epicardium and endocardium and to examine regional effects of changes in ion concentrations in normal and ischaemic conditions. METHODS: Monophasic action potential duration (MAPD90), effective refractory period (ERP) and conduction delay were measured simultaneously in the epicardium and endocardium of rabbit hearts paced at 3.3 Hz, subjected to 30 min of regional ischaemia and 15 min of reperfusion. The hearts were exposed before and throughout ischaemia and reperfusion to hypokalaemia (K+ = 2 mM), hypomagnesaemia (Mg2+ = 0.5 mM) or hyponatraemia (Na+ = 110 mM). RESULTS: In the control hearts, no regional electrophysiological differences were seen before ischaemia, but ischaemia-induced MAPD90 shortening and postrepolarisation refractoriness were greater in the epicardium than in the endocardium and conduction delay increased only in the epicardium. Hypokalaemia shortened ERP in the epicardium (but not endocardium) and increased conduction delay in all areas before ischaemia, but it had no effects during ischaemia. During reperfusion hypokalaemia increased the incidence of recurrent tachyarrhythmias. Hypomagnesaemia had no effect before ischaemia, increased epicardial (but not endocardial) MAPD90 shortening during ischaemia, although it had no pro-arrhythmic action. Hyponatraemia increased conduction delay in all areas before ischaemia and produced asystole or severe bradycardia in all hearts. During ischaemia, hyponatraemia decreased ERP shortening and inducibility of arrhythmias in the epicardium (but not endocardium). CONCLUSIONS: We conclude that the more pronounced effect of ischaemia upon the epicardium than the endocardium can be explained by the contact of the endocardium with intracavitary perfusate. We also conclude that changes in ion concentrations may have differential regional electrical effects in normal or ischaemic conditions.
Assuntos
Coração/fisiopatologia , Íons , Isquemia Miocárdica/fisiopatologia , Animais , Temperatura Corporal , Eletrofisiologia , Endocárdio/fisiopatologia , Magnésio/sangue , Masculino , Isquemia Miocárdica/sangue , Reperfusão Miocárdica , Perfusão , Pericárdio/fisiopatologia , Potássio/sangue , Coelhos , Sódio/sangueRESUMO
OBJECTIVES: Left ventricular hypertrophy (LVH) has been reported to produce differential electrophysiological effects in isolated epicardial and endocardial cells. This study aimed to examine regional electrophysiological effects of LVH in normal and ischaemic conditions in the whole heart. METHODS: LVH was secondary to perinephritis-induced hypertension. Monophasic action potential duration (MAPD(90)), effective refractory period (ERP) and conduction delay were measured in paced, isolated working rabbit hearts either at one right ventricular and two left ventricular sites (apical and basal epicardium) or at three left ventricular sites (apical and basal epicardium, apical endocardium). The hearts were subjected to 30 min of regional ischaemia and 15 min of reperfusion. RESULTS: In non-ischaemic conditions, LVH produced uniform prolongation of MAPD(90) and ERP in the left ventricular epicardium, but not in the endocardium. After coronary artery occlusion, LVH significantly increased ischaemia-induced transepicardial dispersion of repolarisation, but not refractoriness. LVH did not affect arrhythmogenesis in either non-ischaemic or ischaemic conditions. CONCLUSIONS: Differential effects of LVH on epicardial and endocardial electrophysiological parameters are also observed in the whole heart. In addition, the sensitivity of hypertrophied myocardium to ischaemia is increased and leads to an increase in ischaemia-induced dispersion of repolarisation. However, neither dispersion of refractoriness nor arrhythmogenesis are affected by LVH in non-ischaemic or ischaemic conditions in this experimental model.
Assuntos
Coração/fisiopatologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Isquemia Miocárdica/fisiopatologia , Potenciais de Ação , Análise de Variância , Animais , Endocárdio/fisiopatologia , Masculino , Reperfusão Miocárdica , Pericárdio/fisiopatologia , CoelhosRESUMO
OBJECTIVE: To study the intracellular pathways which mediate the inhibitory actions of adenosine on isoprenaline-stimulated calcium current (ICa) in atrioventricular (AV) nodal myocytes. METHODS: The whole-cell patch-clamp technique was used to record ICa from rabbit AV nodal cells, isolated by enzymatic and mechanical dispersion. RESULTS: Isoprenaline, 0.1 microM, increased peak ICa from 0.58 +/- to 1.23 +/- 0.1 nA, and this increase was reversibly inhibited by adenosine, 10 microM (83 +/- 6%), which we have previously shown to be mediated by nitric oxide (NO) production. A membrane-permeable analogue of cyclic GMP, 8-Br-cGMP (300 microM), an inhibitor of cGMP-stimulated phosphodiesterase, prevented the effect of adenosine on ICa-Methylene blue (10 microM), an inhibitor of NO-sensitive guanylyl cyclase and a generator of superoxide (.02-), did not prevent, but increased, the inhibiting action of adenosine (49.5 +/- 6.6%, P < 0.01). Methylene blue (50 microM) caused a reduction of ICa, with further inhibition when combined with adenosine. A .O(2-)-generating system, xanthine oxidase (0.02 U/ml) and purine (2.3 mM), also increased the inhibitory action of adenosine on ICa. Inhibition of ICa by adenosine in the presence of xanthine oxidase was not prevented by 8-Br-cGMP (300 microM) and was not influenced by pre-incubation of cells with a NO synthase inhibitor, L-NAME (0.5 mM). CONCLUSIONS: The inhibitory effect of adenosine on ICa in rabbit AV nodal myocytes can be mediated by two mechanisms--stimulation of cGMP-stimulated phosphodiesterase by NO-induced cGMP, and a mechanism which involves interaction with .O2- production.
Assuntos
Adenosina/farmacologia , Antiarrítmicos/farmacologia , Nó Atrioventricular/efeitos dos fármacos , ATPases Transportadoras de Cálcio/efeitos dos fármacos , GMP Cíclico/fisiologia , Óxido Nítrico/fisiologia , Superóxidos , 8-Bromo Monofosfato de Adenosina Cíclica/farmacologia , Agonistas Adrenérgicos beta/farmacologia , Animais , Separação Celular , Corantes/farmacologia , Isoproterenol/farmacologia , Azul de Metileno/farmacologia , Técnicas de Patch-Clamp , Coelhos , Xantina Oxidase/farmacologiaRESUMO
OBJECTIVES: To examine the cardiac electrophysiological effects of left ventricular hypertrophy (LVH) and to determine whether any observed differences are modified by global zero-flow ischaemia. METHODS: LVH was induced by perinephritic hypertension in New Zealand White rabbits. Transmembrane action potential recordings were made using conventional floating glass microelectrodes and effective refractory periods (ERP) determined by programmed stimulation in isolated arterially perfused interventricular septa during normal perfusion and a 30-min period of global ischaemia. The electrophysiological data were pooled into 6-min periods during ischaemia. RESULTS: The post-operative blood pressure was 76(2) mmHg (mean(s.e.m.)) and 113(2) mmHg (P < 0.0005) in the sham and perinephritic rabbits respectively. The left ventricular to body weight ratio was 0.27(0.01) g kg-1 in the sham and 0.36(0.02) g kg-1 in the perinephritic group (P < 0.005) representing 33% hypertrophy. In the isolated septa, prior to ischaemia, the hypertrophied group exhibited significant prolongations in action potential duration to 50% and 90% repolarisation (APD50, APD90) and ERP of 20%, 12% and 19% respectively (P < 0.005) without any differences in resting membrane potential (Em), upstroke velocity (dV/dtmax) or amplitude (APA) of the action potential. During ischaemia Em, APA and dV/dtmax progressively decreased to a similar extent in both groups. Ischaemia resulted in shortenings in APD50, APD90 and ERP in the hypertrophy group of 122(9) ms, 131(8) ms and 99 (6) ms respectively which were greater than those observed in the control group (84 (7) ms, 115 (7) ms and 50 (13) ms, P < 0.05). These differences resulted in loss of the preischaemic prolongation of repolarisation and refractoriness in the hypertrophy group. CONCLUSIONS: There was enhanced shortening of APD and ventricular refractoriness in hypertrophied muscle during global ischaemia. This could increase the dispersion of repolarization and refractoriness between normal and ischaemic hypertrophied muscle during regional ischaemia which may explain the increased susceptibility of hypertrophied hearts to arrhythmias.
Assuntos
Potenciais de Ação , Coração/fisiopatologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Animais , Processamento Eletrônico de Dados , Técnicas In Vitro , Isquemia Miocárdica/fisiopatologia , CoelhosRESUMO
OBJECTIVE: To study the actions of adenosine on the electrophysiology of spontaneously active, rod-shaped cells enzymatically isolated from rabbit atrioventricular (AV) node. METHODS: Calcium-tolerant myocytes were isolated from the region of the AV node by enzymatic and mechanical dispersion. They were rod- or spindle-shaped, with spontaneous activity at 35-37 degrees C, and had higher membrane resistances (776 +/- 283 M omega, n = 13), compared to atrial cells (41 +/- 18.2 M omega, n = 7; P < 0.001). Membrane potential, spontaneous action potentials and transmembrane ionic currents were studied using the whole-cell patch-clamp technique, in current-clamp and voltage-clamp mode. RESULTS: Adenosine (0.1-50 microM) slowed or abolished the spontaneous activity, with hyperpolarisation of the membrane potential. Voltage-clamp experiments showed that adenosine induced an inwardly rectifying time-independent current. The adenosine-induced current was shown to be carried by potassium ions by the effect of increasing external potassium, which altered the reversal potential in accordance with the calculated potassium equilibrium potential. The A1 adenosine receptor antagonist, CPDPX (8-cyclopentyl-1,3-dypropylxanthine), reversed the effects of adenosine and an A1 receptor agonist, R-PIA [R(-)N(6)-(2-phenylisopropyl)adenosine] had effects similar to adenosine. Adenosine also caused a small decrease in inward calcium current (ICa) in some AV nodal cells. CONCLUSIONS: These results indicate that adenosine acts at A1 adenosine receptors to suppress spontaneous activity, hyperpolarise membrane potential and induce a time-independent potassium current in AV nodal cells. These actions, combined with reduction in inward calcium current in some cells, may underlie the negative chronotropic and dromotropic actions of adenosine on rabbit AV nodal cells.
Assuntos
Adenosina/farmacologia , Nó Atrioventricular/metabolismo , ATPase Trocadora de Sódio-Potássio/efeitos dos fármacos , Animais , Nó Atrioventricular/efeitos dos fármacos , ATPases Transportadoras de Cálcio/efeitos dos fármacos , Células Cultivadas , Potenciais da Membrana/efeitos dos fármacos , Técnicas de Patch-Clamp , Fenilisopropiladenosina/farmacologia , Antagonistas de Receptores Purinérgicos P1 , Coelhos , Estimulação Química , Xantinas/farmacologiaRESUMO
This investigation aimed to determine whether contractile dysfunction of the myocardium could be produced upon generation of free radicals in the anaesthetised rat. The enzyme xanthine oxidase, combined with its substrate purine and an iron source, was used to generate free radicals in the venous circulation. The suspended form of xanthine oxidase, with substrate, produced a transient, significant depression in the contractile indices dP dt-1 max and dP dt-1 P-1 and arterial blood pressure, 1146 +/- 87 mm Hg s-1, 9 +/- 1 s-1, and 18 +/- 1 mm Hg, respectively. This could not be attenuated by the enzymatic free radical scavengers superoxide dismutase and catalase. Furthermore, the suspended xanthine oxidase alone or its vehicle were able to produce a similar effect to that of the complete free-radical-generating system. The maximum soluble dose of the crystalline form of the enzyme when employed in the generating system had no effect upon administration despite its production of superoxide radicals in vitro. These results suggest that the haemodynamic effects of the free-radical-generating system containing the suspended form of xanthine oxidase were due to the effects of its vehicle and that the free-radical-generating system containing the crystalline form of the enzyme did not produce sufficient free radicals in vivo to modify myocardial contractility.
Assuntos
Coração/fisiologia , Xantina Oxidase/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Catalase/farmacologia , Cloretos , Cristalização , Grupo dos Citocromos c/metabolismo , Ácido Edético/farmacologia , Compostos Férricos/farmacologia , Radicais Livres , Coração/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Masculino , Contração Miocárdica/efeitos dos fármacos , Oxirredução , Purinas/farmacologia , Ratos , Ratos Sprague-Dawley , Superóxido Dismutase/farmacologia , Xantina Oxidase/metabolismoRESUMO
1 The electrophysiological effects of Org 6001, a new orally active antidysrhythmic agent, have been compared with those of lignocaine on the human ventricular action potential in vitro.2 Org 6001 (4 to 16 mg/l) greatly reduced the maximum rate of depolarization (MRD) of the human ventricular action potential but had no effect on resting membrane potential or action potential amplitude.3 The action potential duration at the 50% repolarization level, but not at the 90% repolarization level, was significantly reduced by Org 6001. The absolute refractory period was unchanged.4 Lignocaine, at a concentration (4 mg/l) within the therapeutic range, had no significant effect on any measured parameter, either in muscle exposed to a normal (4.0 mM) or high (5.4 mM) extracellular potassium concentration ([K(+)](o)).5 Higher concentrations of lignocaine (8 to 16 mg/l) did, however, reduce MRD at both [K(+)](o) without changing resting membrane potential or action potential amplitude. The action potential duration was decreased slightly by these higher concentrations of lignocaine whilst the absolute refractory period was lengthened.6 Org 6001 was found to be more potent than lignocaine in reducing MRD but, unlike lignocaine, the absolute refractory period was not prolonged. These compounds, therefore, differed in their electrophysiological effects on human ventricular muscle although both are characterized as being class 1 antidysrhythmic drugs.
Assuntos
Androstanóis/farmacologia , Antiarrítmicos/farmacologia , Coração/efeitos dos fármacos , Lidocaína/farmacologia , 17-Cetosteroides/farmacologia , Potenciais de Ação/efeitos dos fármacos , Estimulação Elétrica , Humanos , Técnicas In Vitro , Potássio/farmacologiaRESUMO
1 Prostaglandin C(2) causes a prolonged fall in arterial blood pressure in the cat.2 At constant heart rate this fall in arterial pressure is accompanied by falls in stroke volume, left ventricular end diastolic pressure, and left ventricular dP/dt max.3 If mean aortic pressure and left ventricular end diastolic pressure are held constant as well as heart rate, prostaglandins C(2) and E(2) do not affect dP/dt max in the cat.4 In the dog, under similarly controlled conditions, prostaglandins C(2) and E(2) raise dP/dt max.5 We conclude that prostaglandins E(2) and C(2) have no direct inotropic action in the cat, but both have a direct positive inotropic action in the dog.
Assuntos
Hemodinâmica/efeitos dos fármacos , Prostaglandinas/farmacologia , Animais , Cateterismo Cardíaco , Gatos , Pressão Venosa Central/efeitos dos fármacos , Cães , Coração/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Especificidade da Espécie , Estimulação Química , Pressão Venosa/efeitos dos fármacosRESUMO
1. The effects of phentolamine (5-30 microM) and glibenclamide (10 microM) on action potential characteristics were examined in guinea-pig papillary muscle exposed to either hypoxia or levcromakalim (20 microM). 2. The hypoxia-induced abbreviation of action potential duration (APD) and effective refractory period (ERP) were attenuated but not abolished by glibenclamide (10 microM). Hypoxia reduced APD by 24 +/- 2 vs 65 +/- 4% in glibenclamide- and vehicle-treated tissue, respectively. 3. Phentolamine (10-30 microM) was less effective than glibenclamide in attenuating the hypoxic shortening of APD since APD was reduced by 38 +/- 10, 51 +/- 6% vs 65 +/- 4% in 10 and 30 microM phentolamine and vehicle-treated muscle, respectively. 4. Phentolamine, at concentrations of 10 and 30 microM, also reduced the upstroke velocity of the action potential and at 5 microM it increased the APD from 193 +/- 9 to 221 +/- 12 ms. 5. Glibenclamide completely abolished and phentolamine (30 microM) significantly attenuated levcromakalim-induced changes in duration and ERP. Levcromakalim reduced APD by 71 +/- 2 and 55 +/- 2% in control and phentolamine pretreated muscle, respectively. 6. It is concluded that phentolamine may block KATP channels at concentrations that also block sodium channels.
Assuntos
Benzopiranos/farmacologia , Coração/efeitos dos fármacos , Coração/fisiologia , Hipóxia/fisiopatologia , Fentolamina/farmacologia , Pirróis/farmacologia , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Trifosfato de Adenosina/fisiologia , Animais , Cromakalim , Interações Medicamentosas , Glucose/farmacologia , Glibureto/farmacologia , Cobaias , Hipóxia/tratamento farmacológico , Técnicas In Vitro , Cinética , Músculos Papilares/efeitos dos fármacos , Músculos Papilares/fisiologia , Canais de Potássio/efeitos dos fármacos , Canais de Potássio/fisiologiaRESUMO
1. The electrophysiological effects of adenosine and adenosine triphosphate (ATP) were examined in sheep Purkinje fibres, superfused in vitro with either a normal or a hypoxic, hyperkalaemic and acidotic physiological salt solution (PSS). The ability of adenosine to modify the effects of noradrenaline on action potential characteristics was also investigated. 2. The only statistically significant effects of adenosine (10(-6)-10(4) M) and of ATP (10(-6)-10(-4) M) on normal action potential characteristics were a slight dose-dependent shortening of the action potential by adenosine and a depolarization by ATP, 10(-4) M. 3. Superfusion with a hypoxic, hyperkalaemic and acidotic PSS caused marked reductions in resting membrane potential, upstroke and duration of the action potential. 4. Both adenosine and ATP attenuated the reduction in the rate of rise of the upstroke and the amplitude of the action potential caused by the modified PSS. 5. Adenosine did not alter the noradrenaline-induced effects on automaticity or on action potentials of normal or depressed Purkinje fibres. 6. Adenosine and ATP had electrophysiological effects on Purkinje fibres, exposed to conditions in vitro that mimic mild myocardial ischaemia, that were different from those observed on normally polarized fibres.
Assuntos
Trifosfato de Adenosina/farmacologia , Adenosina/farmacologia , Sistema de Condução Cardíaco/fisiologia , Ramos Subendocárdicos/fisiologia , Potenciais de Ação/efeitos dos fármacos , Animais , Eletrofisiologia , Hipóxia/fisiopatologia , Técnicas In Vitro , Isquemia/fisiopatologia , Norepinefrina/farmacologia , Ramos Subendocárdicos/efeitos dos fármacos , OvinosRESUMO
1. The effects of low oxygen tension on tone and on the responsiveness to contractile and relaxant agents were examined on circumflex coronary artery rings isolated from sheep. 2. When artery rings (2-2.5 mm o.d.) were set at their optimal resting tension, introduction of hypoxia (0% O2) caused a sustained contraction which was reversible on washing with oxygenated Krebs solution. In precontracted (40 mM KCl) arteries, hypoxia caused a similar response except that it was preceded by a transient relaxation. 3. The hypoxia-induced contraction was potentiated by the combination of phentolamine (1 microM) and propranolol (1 microM), markedly reduced by verapamil (10 microM) and either abolished or reduced by indomethacin (1 microM). Indomethacin itself caused a contraction. 4. Under hypoxic conditions, the contractile effects of U46619 (a stable thromboxane analogue) and 5-hydroxytryptamine (5-HT) and the vasodilator effects of noradrenaline, iloprost (a prostacyclin mimetic) and adenosine were markedly potentiated. In contrast, vasoconstriction to potassium or acetylcholine was depressed. 5. Changing the gases from 95% O2 to 12% O2 had no significant effect on the contractile effects of U46619. However, the maximum contractile effect of U46619 was significantly enhanced by changing the gases from 12% O2 to 0% O2. 6. Rings from a smaller branch (0.6-1.3 mm o.d.) of the circumflex coronary artery of the sheep, in the presence of hypoxia, exhibited qualitatively similar changes in the responsiveness to U46619, 5-HT and adenosine to those observed in the large artery. However, the effect of potassium was potentiated rather than depressed. 7. It is concluded that hypoxia-induced contraction may involve a modified release of cyclooxygenase products and be partly dependent upon the availability of extracellular calcium. 8. The change in the responsiveness of coronary arteries, under hypoxia, to both constrictor and dilator mediators may have clinical relevance to myocardial ischaemia and angina pectoris.
Assuntos
Hipóxia/fisiopatologia , Músculo Liso Vascular/efeitos dos fármacos , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico , Animais , Vasos Coronários/efeitos dos fármacos , Técnicas In Vitro , Indometacina/farmacologia , Contração Muscular/efeitos dos fármacos , Consumo de Oxigênio/efeitos dos fármacos , Fentolamina/farmacologia , Cloreto de Potássio/farmacologia , Propranolol/farmacologia , Endoperóxidos Sintéticos de Prostaglandinas/farmacologia , Serotonina/farmacologia , Ovinos , Verapamil/farmacologiaRESUMO
1. The effects of buprenorphine, given intravenously, on the incidence and severity of early acute coronary artery occlusion-induced arrhythmias were examined in anaesthetised rats. The electrophysiological effects of buprenorphine were also examined in sheep Purkinje fibres and rat papillary muscles, superfused in vitro with either a normal or a hypoxic, hyperkalaemic and acidotic physiological salt solution (PSS). 2. In anaesthetised rats subjected to acute coronary artery occlusion, pretreatment with buprenorphine (1 mg kg-1 i.v.) markedly reduced the incidence of ventricular extra-systoles during the initial 30 min post-occlusion period. The incidence of ventricular fibrillation (VF) was also significantly reduced from 56% to 10%. 3. At the antiarrhythmic dose (1 mg kg -1), buprenorphine also attenuated the sudden fall in systemic arterial blood pressure induced by acute coronary artery ligation. 4. In normal sheep Purkinje fibres and rat papillary muscles, buprenorphine (10(-6)-10(-5) M) significantly reduced the action potential height and maximum rate of depolarisation of phase zero (MRD) and prolonged the duration of the action potential. 5. Superfusion of sheep Purkinje fibres and rat papillary muscles with a hypoxic, hyperkalaemic and acidotic PSS resulted in marked reductions in resting membrane potential, upstroke and duration of the action potential. 6. In the presence of the modified compared with normal PSS, buprenorphine reduced the action potential height and MRD of both sheep Purkinje fibres and rat papillary muscles to a greater extent, although its ability to prolong the action potential duration was attenuated. 7. The antiarrhythmic effects of buprenorphine observed in vivo may be explained by its direct cardiac electrophysiological effects. Buprenorphine might be useful in relieving pain and in reducing the severity of arrhythmias in the early stages of acute myocardial infarction.