RESUMEN
BACKGROUND AND PURPOSE: Anandamide and sphingosine-1-phosphate (S1P) both regulate vascular tone in a variety of vessels. This study aimed to examine the mechanisms involved in the regulation of coronary vascular tone by anandamide and S1P, and to determine whether any functional interaction occurs between these receptor systems. EXPERIMENTAL APPROACH: Mechanisms used by anandamide and S1P to regulate rat coronary artery (CA) reactivity were investigated using wire myography. Interactions between S1P and the cannabinoid (CB)(2) receptor were determined using human embryonic kidney 293 (HEK293) cells that stably over-express recombinant CB(2) receptor. KEY RESULTS: Anandamide and S1P induced relaxation of the rat CA. CB(2) receptor antagonists attenuated anandamide-induced relaxation, while S1P-mediated relaxation was dependent on the vascular endothelium and S1P(3). Anandamide treatment resulted in an increase in the phosphorylation of sphingosine kinase-1 within the CA. Conversely, anandamide-mediated relaxation was attenuated by inhibition of sphingosine kinase. Moreover, S1P(3), specifically within the vascular endothelium, was required for anandamide-mediated vasorelaxation. In addition to this, S1P-mediated relaxation was also reduced by CB(2) receptor antagonists and sphingosine kinase inhibition. Further evidence that S1P functionally interacts with the CB(2) receptor was also observed in HEK293 cells over-expressing the CB(2) receptor. CONCLUSIONS AND IMPLICATIONS: In the vascular endothelium of rat CA, anandamide induces relaxation via a mechanism requiring sphingosine kinase-1 and S1P/S1P(3). In addition, we report that S1P may exert some of its effects via a CB(2) receptor- and sphingosine kinase-dependent mechanism, where subsequently formed S1P may have privileged access to S1P(3) to induce vascular relaxation.
Asunto(s)
Ácidos Araquidónicos/farmacología , Vasos Coronarios/fisiología , Lisofosfolípidos/farmacología , Alcamidas Poliinsaturadas/farmacología , Esfingosina/análogos & derivados , Animales , Ácidos Araquidónicos/administración & dosificación , Bloqueadores de los Canales de Calcio/administración & dosificación , Bloqueadores de los Canales de Calcio/farmacología , Fármacos Cardiovasculares/administración & dosificación , Fármacos Cardiovasculares/farmacología , Línea Celular , Dronabinol/análogos & derivados , Dronabinol/farmacología , Endocannabinoides , Humanos , Indoles/farmacología , Indometacina/administración & dosificación , Indometacina/farmacología , Lisofosfolípidos/administración & dosificación , Masculino , Alcamidas Poliinsaturadas/administración & dosificación , Ratas , Ratas Sprague-Dawley , Receptor Cannabinoide CB2/antagonistas & inhibidores , Esfingosina/administración & dosificación , Esfingosina/farmacología , VasodilataciónRESUMEN
1 Mast cells have classically been regarded as the 'bad guys' in the setting of acute myocardial ischaemia, where their released contents are believed to contribute both to tissue injury and electrical disturbances resulting from ischaemia. Recent evidence suggests, however, that if mast cell degranulation occurs in advance of ischaemia onset, this may be cardioprotective by virtue of the depletion of mast cell contents that can no longer act as instruments of injury when the tissue becomes ischaemic. 2 Many peptides, such as ET-1, adrenomedullin, relaxin and atrial natriuretic peptide, have been demonstrated to be cardioprotective when given prior to the onset of myocardial ischaemia, although their physiological functions are varied and the mechanisms of their cardioprotective actions appear to be diverse and often ill defined. However, one common denominator that is emerging is the ability of these peptides to modulate mast cell degranulation, raising the possibility that peptide-induced mast cell degranulation or stabilization may hold the key to a common mechanism of their cardioprotection. 3 The aim of this review was to consolidate the evidence implying that mast cell degranulation could play both a detrimental and protective role in myocardial ischaemia, depending upon when it occurs, and that this may underlie the cardioprotective effects of a range of diverse peptides that exerts physiological effects within the cardiovascular system.
Asunto(s)
Cardiotónicos , Cardiopatías/fisiopatología , Mastocitos/fisiología , Neuropéptidos/farmacología , Neuropéptidos/fisiología , Animales , Degranulación de la Célula , Cardiopatías/patología , Humanos , Isquemia Miocárdica/patología , Isquemia Miocárdica/fisiopatología , Miocardio/patologíaRESUMEN
BACKGROUND AND PURPOSE: The aim of this study was to investigate whether the previously reported anti-arrhythmic effect of endothelin-1 (ET-1) is mediated by degranulation of cardiac mast cells prior to myocardial ischaemia. EXPERIMENTAL APPROACH: Male Sprague-Dawley rats received either ET-1 (1.6 nmolxkg(-1)) in the presence or absence of disodium cromoglycate (DSCG; 20 mgxkg(-1)xh(-1)) prior to coronary artery occlusion (CAO). In separate experiments rats were given compound 48/80 (50 microgxkg(-1)) to compare the effects of ET-1 with those of a known mast cell degranulator. Ischaemia-induced ventricular arrhythmias were detected through continuous monitoring of a lead I electrocardiogram. After 30 min of CAO, the hearts were removed and mast cell degranulation determined by histological analysis. A parallel series of sham groups were performed to determine the direct effects of ET-1 and compound 48/80 on mast cell degranulation in the absence of ischaemia. KEY RESULTS: ET-1 and compound 48/80 both exerted profound anti-arrhythmic effects, significantly reducing the total number of ventricular ectopic beats (P < 0.001) and the incidence of ventricular fibrillation (P < 0.05). These anti-arrhythmic effects were abolished by concomitant DSCG infusion prior to CAO. In sham animals ET-1 and compound 48/80 both induced mast cell degranulation (P < 0.001), an effect which was abolished by DSCG, confirming their ability to induce degranulation of mast cells. CONCLUSIONS AND IMPLICATIONS: These results demonstrate for the first time that when given prior to ischaemia ET-1 mediates its anti-arrhythmic effects, at least in part, via cardiac mast cell degranulation.
Asunto(s)
Degranulación de la Célula , Endotelina-1/metabolismo , Frecuencia Cardíaca , Liberación de Histamina , Mastocitos/inmunología , Isquemia Miocárdica/inmunología , Fibrilación Ventricular/prevención & control , Complejos Prematuros Ventriculares/prevención & control , Animales , Antiarrítmicos/administración & dosificación , Presión Sanguínea , Degranulación de la Célula/efectos de los fármacos , Cromolin Sódico/administración & dosificación , Modelos Animales de Enfermedad , Electrocardiografía , Endotelina-1/administración & dosificación , Frecuencia Cardíaca/efectos de los fármacos , Liberación de Histamina/efectos de los fármacos , Inyecciones Intravenosas , Masculino , Mastocitos/efectos de los fármacos , Isquemia Miocárdica/complicaciones , Isquemia Miocárdica/fisiopatología , Ratas , Ratas Sprague-Dawley , Fibrilación Ventricular/etiología , Fibrilación Ventricular/inmunología , Fibrilación Ventricular/fisiopatología , Complejos Prematuros Ventriculares/inmunología , Complejos Prematuros Ventriculares/fisiopatología , p-Metoxi-N-metilfenetilamina/administración & dosificaciónRESUMEN
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.
Asunto(s)
Canales de Potasio de Tipo Rectificador Tardío/antagonistas & inhibidores , Epinefrina/farmacología , Bloqueadores de los Canales de Potasio/toxicidad , Torsades de Pointes/inducido químicamente , Potenciales de Acción/efectos de los fármacos , Animales , Cromanos/administración & dosificación , Cromanos/toxicidad , Relación Dosis-Respuesta a Droga , Electrocardiografía , Epinefrina/administración & dosificación , Cobayas , Masculino , Modelos Biológicos , Fenilefrina/farmacología , Piperidinas/administración & dosificación , Piperidinas/toxicidad , Bloqueadores de los Canales de Potasio/administración & dosificación , Canales de Potasio con Entrada de Voltaje/antagonistas & inhibidores , Piridinas/administración & dosificación , Piridinas/toxicidad , Sulfonamidas/administración & dosificación , Sulfonamidas/toxicidadRESUMEN
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.
Asunto(s)
Potenciales de Acción/efectos de los fármacos , Cromanos/toxicidad , Venenos de Cnidarios/toxicidad , Piperidinas/toxicidad , Piridinas/toxicidad , Sulfonamidas/toxicidad , Torsades de Pointes/inducido químicamente , Animales , Cromanos/administración & dosificación , Venenos de Cnidarios/administración & dosificación , Canales de Potasio de Tipo Rectificador Tardío/antagonistas & inhibidores , Canales de Potasio de Tipo Rectificador Tardío/metabolismo , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Electrocardiografía , Electrofisiología , Predicción , Síndrome de QT Prolongado/inducido químicamente , Masculino , Piperidinas/administración & dosificación , Canales de Potasio con Entrada de Voltaje/antagonistas & inhibidores , Canales de Potasio con Entrada de Voltaje/metabolismo , Piridinas/administración & dosificación , Conejos , Canales de Sodio/efectos de los fármacos , Sulfonamidas/administración & dosificaciónRESUMEN
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.
Asunto(s)
Linfocitos T CD4-Positivos/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Receptor PAR-2/fisiología , Animales , Aorta Torácica/citología , Aorta Torácica/efectos de los fármacos , Aorta Torácica/metabolismo , Linfocitos B/citología , Linfocitos B/efectos de los fármacos , Linfocitos B/metabolismo , Antígeno CD11b/análisis , Linfocitos T CD4-Positivos/citología , Linfocitos T CD4-Positivos/efectos de los fármacos , Adhesión Celular/efectos de los fármacos , Adhesión Celular/fisiología , Relación Dosis-Respuesta a Droga , Femenino , Citometría de Flujo , Técnicas In Vitro , Molécula 1 de Adhesión Intercelular/metabolismo , Mediciones Luminiscentes/métodos , Masculino , Ratones , Ratones Noqueados , Células Mieloides/citología , Células Mieloides/efectos de los fármacos , Células Mieloides/metabolismo , Selectina-P/metabolismo , Receptor PAR-2/genética , Receptor PAR-2/metabolismo , Bazo/citología , Bazo/efectos de los fármacos , Bazo/metabolismo , Superóxido Dismutasa/farmacología , Acetato de Tetradecanoilforbol/farmacología , Tripsina/farmacologíaRESUMEN
The effects of the endothelin ET(A), (BQ-123) and endothelin ET(A/B) (PD161721) receptor antagonists were investigated on ischaemia-induced arrhythmias and on the maximum following frequency. The study was carried out in Langendorff perfused rat hearts subjected to coronary artery occlusion in which the severity of arrhythmias, coronary perfusion pressure and heart rate were measured. The % incidence of ischaemia-induced irreversible ventricular fibrillation (ventricular fibrillation) was reduced significantly from 58%, in control rat hearts, to 0% (at 10(-7) and 10(-6) M PD161721 and 10(-6) M BQ-123 P<0.05). Maximum following frequency was measured in guinea-pig isolated atria. In the presence of normal extracellular [K(+)], BQ-123 and PD161721, at 10(-6) M, significantly decreased the maximum following frequency from 9.0+/-0.7 to 7.2+/-0.4 and from 8.3+/-0.4 to 6.7+/-0.3 Hz, respectively (P<0.05). These effects were not potentiated by raising the extracellular [K(+)] with the exception of 10(-9) M PD161721. In contrast, lignocaine's ability to reduce the maximum following frequency was greater in elevated (e.g. at 1.7x10(-4) M from 8.4+/-0.3 to 2.5+/-0.6 Hz) than in normal [K(+)] (from 9.0+/-0.3 to 4.9+/-0.5 Hz). In conclusion, both BQ-123 and PD161721 had an anti-fibrillatory effect in isolated rat hearts that may be due, at least in part, to an ability to reduce the maximum following frequency. This latter effect is unlikely to be due to Na(+) channel blockade since it was not markedly potentiated by elevation of extracellular [K(+)].
Asunto(s)
Antiarrítmicos/farmacología , Dioxinas/farmacología , Antagonistas de los Receptores de Endotelina , Péptidos Cíclicos/farmacología , Animales , Arritmias Cardíacas/etiología , Arritmias Cardíacas/fisiopatología , Arritmias Cardíacas/prevención & control , Función Atrial , Relación Dosis-Respuesta a Droga , Electrofisiología , Cobayas , Corazón/efectos de los fármacos , Corazón/fisiología , Atrios Cardíacos/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Técnicas In Vitro , Lidocaína/farmacología , Masculino , Contracción Muscular/efectos de los fármacos , Isquemia Miocárdica/complicaciones , Perfusión , Presión , Ratas , Ratas Sprague-DawleyRESUMEN
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).
Asunto(s)
Fibrilación Atrial/fisiopatología , Función Atrial , Canales Iónicos , 4-Aminopiridina/farmacología , Potenciales de Acción/efectos de los fármacos , Anciano , Bloqueadores de los Canales de Calcio/farmacología , Canales de Calcio , Estudios de Casos y Controles , Enfermedad Crónica , Sinergismo Farmacológico , Estimulación Eléctrica , Femenino , Humanos , Canales Iónicos/efectos de los fármacos , Transporte Iónico/efectos de los fármacos , Masculino , Potenciales de la Membrana/efectos de los fármacos , Persona de Mediana Edad , Nifedipino/farmacología , Técnicas de Placa-Clamp , Bloqueadores de los Canales de Potasio/farmacología , Canales de PotasioRESUMEN
We have shown previously that a small bolus dose of endothelin-1, given intravenously before coronary occlusion, exerts a marked antiarrhythmic effect in anaesthetised rats. The aim of the current study was to determine whether or not this is due to a direct effect of endothelin-1 on the heart by assessing the antiarrhythmic effect of endothelin-1 against occlusion-induced arrhythmias in rat isolated hearts. Rat isolated hearts were perfused in Langendorff mode (constant flow) and subjected to coronary artery occlusion for 30 min. Coronary perfusion pressure and a surface electrocardiogram (ECG) were monitored throughout the experiment. In the first series of studies, the effects of three 5-min infusions of endothelin-1 (0.1-10 nM), given prior to coronary occlusion, were assessed. A second series of hearts was given a single bolus dose of endothelin-1 (10 pmol) 5 min prior to ischaemia. A third series of experiments was performed using a modified (low K+) Krebs Henseleit solution to increase the incidence of ischaemia-induced ventricular fibrillation (VF). In these hearts, endothelin-1 (0.1 or 2 pmol) was administered as a bolus injection 5 min before ischaemia. Infusion of endothelin-1 prior to ischaemia did not modify the incidence or severity of arrhythmias at any of the concentrations used. Bolus administration of endothelin-1 (10 pmol) in hearts perfused with Kreb's Henseleit solution containing normal K+ (4.4 mM) was found to cause a small rise in coronary perfusion pressure, with no preceding depressor response. Under these conditions, endothelin-1 exerted only a very moderate reduction in arrhythmias, by reducing the arrhythmia count in the 21-30-min post-occlusion period. Furthermore, in hearts perfused with low K+ solution, bolus injection of endothelin-1, in a dose that either had no effect on coronary perfusion pressure (0.1 pmol) or produced a significant vasodilator effect with no significant pressor effect (2 pmol), had no effect on ventricular fibrillation. Thus, in concentrations that are sufficient to exert effects on the coronary vasculature, endothelin-1 fails to modify arrhythmias in an isolated heart preparation. These results suggest that the antiarrhythmic effects of endothelin-1 previously observed in vivo are not due to a direct effect on either the myocardium or the coronary blood vessels.
Asunto(s)
Arritmias Cardíacas/prevención & control , Endotelina-1/farmacología , Corazón/efectos de los fármacos , Isquemia Miocárdica/complicaciones , Animales , Arritmias Cardíacas/etiología , Enfermedad Coronaria/fisiopatología , Relación Dosis-Respuesta a Droga , Corazón/fisiopatología , Técnicas In Vitro , Masculino , Perfusión , Potasio/farmacología , Ratas , Ratas Sprague-Dawley , Taquicardia Ventricular/etiología , Taquicardia Ventricular/prevención & control , Factores de Tiempo , Fibrilación Ventricular/etiología , Fibrilación Ventricular/prevención & controlRESUMEN
The aim of this study was to investigate whether the endothelin-B- (ETB) receptor agonist sarafotoxin 6c (S6c) can protect against ischaemia-induced cardiac arrhythmias. Arrhythmias were induced by a 30 min period of coronary artery occlusion in pentobarbitone-anaesthetized male rats, or in Langendorff-perfused rat hearts. Rats or rat hearts were administered a bolus dose of vehicle or S6c (0.8 nmol/kg i.v. or 10(-8) M into the coronary circulation, respectively) 5 min before the onset of ischaemia. In vivo administration of S6c significantly reduced the incidence of ventricular fibrillation (VF) from 59% to 13% and the number of premature ventricular beats. This effect was associated with a transient fall in mean arterial blood pressure. In isolated hearts, S6c reduced significantly both the incidences of ventricular tachycardia (VT) and VF while having no statistically significant effect on coronary perfusion pressure. This is the first report to show that stimulation of ETB-receptors, with a bolus dose of S6c, has an antiarrhythmic effect on rat hearts both in vivo and in vitro, suggestive of a direct effect on the myocardium.
Asunto(s)
Arritmias Cardíacas/prevención & control , Isquemia Miocárdica/tratamiento farmacológico , Venenos de Víboras/farmacología , Animales , Endotelina-1/farmacología , Masculino , Ratas , Ratas Sprague-Dawley , Receptor de Endotelina B , Receptores de Endotelina/fisiologíaRESUMEN
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.
Asunto(s)
Corazón/fisiopatología , Hipertrofia Ventricular Izquierda/fisiopatología , Isquemia Miocárdica/fisiopatología , Potenciales de Acción , Análisis de Varianza , Animales , Endocardio/fisiopatología , Masculino , Reperfusión Miocárdica , Pericardio/fisiopatología , ConejosRESUMEN
The effects of study-test lags of between 0 and 32 items on conscious (C) and automatic (A) memory processes in a running word-completion task were investigated with event-related potentials (ERPs). The process dissociation procedure (PDP) can distinguish between C and A contributions to memory by comparing performance when subjects respond with either an old item (inclusion) or a new item (exclusion). C can be estimated by subtracting the probability of an intrusion of an old item during the exclusion task (due to A without C) from the probability of correctly producing an old item during the inclusion task (due to C and/or A). The behavioral results showed that C was stronger when the test item followed the studied word in the next trial or after a lag of one stimulus. The strength of A did not vary with lag. The ERP waveforms contained a broad parietal positive wave between 300 and 800 ms. This parietal wave distinguished between correctly recalled old and new words. The early portion of this old-new effect was significantly affected by lag. Subtracting waveforms to obtain a measure of C revealed an effect in the later portion of this wave, lateralized over the left hemisphere. A sustained frontal negativity occurred during all recordings and was larger during conscious retrieval. There was no consistent ERP effect related to automatic memory retrieval.
Asunto(s)
Concienciación/fisiología , Potenciales Evocados/fisiología , Recuerdo Mental/fisiología , Adulto , Conducta/fisiología , Mapeo Encefálico , Femenino , Humanos , Masculino , Factores de Tiempo , Conducta Verbal/fisiologíaRESUMEN
Nitrotyrosine and eNOS were detected immunocytochemically using specific antibodies in paraffin sections of lung from rats subjected to hypoxia for 2, 7, or 14 days. The staining intensity for eNOS was enhanced in the endothelium of both resistance and conduit pulmonary arteries at 2 days. Staining intensity for eNOS remained elevated at 7 and 14 days in conduit arteries, whereas it progressively increased further in resistance arteries. Nitrotyrosine staining was elevated to a similar degree in endothelium and adjacent vascular smooth muscle. In resistance pulmonary arteries, there was a progressive increase in nitrotyrosine, which matched the increase in eNOS. In conduit pulmonary arteries, nitrotyrosine increased only after 14 days of hypoxia. The results suggest that in chronic hypoxia the up-regulation of eNOS leads to the formation of peroxynitrite which has access to both endothelium and vascular smooth muscle.
Asunto(s)
Hipoxia/metabolismo , Pulmón/irrigación sanguínea , Óxido Nítrico Sintasa/metabolismo , Tirosina/análogos & derivados , Actinas/metabolismo , Animales , Arterias/metabolismo , Arterias/patología , Endotelio/metabolismo , Hipertrofia Ventricular Derecha/etiología , Hipoxia/complicaciones , Inmunohistoquímica , Pulmón/metabolismo , Pulmón/patología , Ratas , Tirosina/metabolismo , Resistencia VascularRESUMEN
During atrial fibrillation, ventricular rate is determined by atrioventricular nodal (AVN) conduction, which in part is dependent upon the refractoriness of single AVN cells. The aims of this study were to investigate the rate-dependency of the action potential duration (APD) and effective refractory period (ERP) in single myocytes isolated from the AV node and atrium of rabbit hearts, using whole cell patch clamping, and to determine the contribution of the 4-aminopyridine (4-AP)-sensitive current, I(TO1)to these relationships in the two cell types. AVN cells had a more positive maximum diastolic potential (-60+/-1 v-71+/-2 mV), lower V(max)(8+/-2 v 144+/-17 V/s) and higher input resistance [420+/-46 v 65+/-7 MOmega (mean+/-s.eP<0.05 n=9-33)], respectively, than atrial myocytes. Stepwise increases in rate from 75 beats/min caused activation failure and Wenckebach periodicity in AVN cells (at around 400 beats/min), but 1:1 activation in atrial cells (at up to 600 beats/min). Rate reduction from 300 to 75 beats/min shortened the ERP in both cell types (from 155+/-7 to 135+/-11 ms in AVN cells [P<0.05, n=6] and from 130+/-8 to 106+/-7 ms in atrial cells [P<0.05, n=10]). Rate increase from 300 to 480 and 600 beats/min shortened ERP in atrial cells, by 12+/-4% (n=8) and 26+/-7% (n=7), respectively (P<0.05). By contrast, AVN ERP did not shorten at rates >300 beats/min. In atrial cells, rate reduction to 75 beats/min caused marked shortening of APD(50)(from 51+/-6 to 29+/-6 ms, P<0. 05). 4-AP (1 m m) significantly prolonged atrial APD(50)at 75 beats/min (P<0.05, n=7), but not at 300 or 400 beats/min. In AVN cells, in contrast, there was less effect of rate change on APD, and 4-AP did not alter APD(50)at any rate. 4-AP also did not affect APD(90)or ERP in either cell type. In conclusion, a lack of ERP-shortening at high rates in rabbit single AVN cells may contribute to ventricular rate control. I(TO1)contributed to the APD(50)rate relation in atrial, but not AVN cells and did not contribute to the ERP rate relation in either cell type.
Asunto(s)
Potenciales de Acción , Nodo Atrioventricular/metabolismo , Miocardio/metabolismo , 4-Aminopiridina/farmacología , Potenciales de Acción/efectos de los fármacos , Animales , Función Atrial , Nodo Atrioventricular/efectos de los fármacos , Células Cultivadas , Estimulación Eléctrica , Electrofisiología , Atrios Cardíacos/efectos de los fármacos , Cinética , Masculino , ConejosRESUMEN
1. The aim of this study was to investigate the involvement of peroxynitrite, reactive metabolite originating from nitric oxide and superoxide, in preconditioning of the ischaemic myocardium in rat isolated hearts. 2. Isolated hearts perfused with Krebs-Henseleit solution were preconditioned either by 3 min of coronary artery occlusion (CAO) or by peroxynitrite administration at three different concentrations (0.1, 1, 10 microM) for 3 min, followed by 10 min reperfusion and 30 min of CAO. Peroxynitrite, at 1 microM concentration, decreased the incidence of VT from 100% (n=14) to 62% (n=13) and abolished the occurrence of VF (50% in the control group). 3. N-2-mercaptopropionylglycine (MPG, 1 microM - 10 mM) produced a concentration-dependent inhibition of peroxynitrite signals in luminol chemiluminescence and 67+/-1% inhibition was observed at 100 microM (n=7). MPG (at 300 microM, n=7) added to the perfusate 10 min prior to ischaemic preconditioning or peroxynitrite infusion and maintained until CAO, significantly reversed the beneficial effects of the ischaemic and peroxynitrite-treated groups. MPG administration in the peroxynitrite-treated group increased the incidence of VT from 62% (n=13) to 100% (n=10) and total VF from 0% (n=0) to 67% (n=10). Similarly, MPG elevated the incidence of VT from 50% (n=10) to 100% (n=8) in the ischaemic preconditioned group. On its own, MPG did not affect the severity of cardiac arrhythmias. 4. These results suggest that endogenously produced peroxynitrite plays a significant role in the antiarrhythmic effect of ischaemic preconditioning in the rat isolated hearts.
Asunto(s)
Arritmias Cardíacas/tratamiento farmacológico , Precondicionamiento Isquémico Miocárdico , Nitratos/uso terapéutico , Oxidantes/uso terapéutico , Animales , Antioxidantes/farmacología , Arritmias Cardíacas/etiología , Glicina/análogos & derivados , Glicina/farmacología , Precondicionamiento Isquémico Miocárdico/efectos adversos , Masculino , Nitratos/fisiología , Oxidantes/fisiología , Ratas , Ratas Wistar , Compuestos de Sulfhidrilo/farmacologíaRESUMEN
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.
Asunto(s)
Antiarrítmicos/farmacología , Arritmias Cardíacas/tratamiento farmacológico , Cardiopatías/fisiopatología , Corazón/anatomía & histología , Corazón/fisiología , Potenciales de Acción/fisiología , Animales , Anisotropía , Antiarrítmicos/uso terapéutico , Arritmias Cardíacas/patología , Arritmias Cardíacas/fisiopatología , Cardiomegalia/patología , Cardiomegalia/fisiopatología , Corazón/fisiopatología , Cardiopatías/patología , Humanos , Infarto del Miocardio/patología , Infarto del Miocardio/fisiopatología , Isquemia Miocárdica/patología , Isquemia Miocárdica/fisiopatología , Miocardio/patologíaRESUMEN
The present study examined the effect of nimodipine on a reference memory task and on the induction and maintenance of long-term potentiation (LTP) in the hippocampal dentate gyrus. Young rats, subcutaneously implanted with either a 30 mg nimodipine or placebo pellet, were trained on the Barnes circular platform task. Retention was tested 15 days following acquisition. Following behavioural testing, recording and stimulating electrodes were implanted in the granule cell layer of the dentate gyrus and the perforant path, respectively. Pre-pellet baseline evoked potentials were collected. Nimodipine or placebo pellets were again subcutaneously implanted, according to the original groupings, and post-pellet baseline evoked potentials were obtained. LTP was then induced in the granule cell population by perforant path tetanization and the decay of LTP was followed for 15 days. Nimodipine significantly decreased the number of trials to reach both the acquisition and the retention criterion on the circular platform task, but did not alter granule cell excitability, LTP threshold, or the magnitude of LTP. Sustained nimodipine administration, however, increased the decay rate of LTP of the population spike, but did not affect the decay rate for LTP of the EPSP. No significant correlations were obtained between behavioural and electrophysiological measures. These results provide further evidence against a simple direct relationship between LTP and spatial learning.
Asunto(s)
Bloqueadores de los Canales de Calcio/farmacología , Giro Dentado/efectos de los fármacos , Potenciación a Largo Plazo/efectos de los fármacos , Recuerdo Mental/efectos de los fármacos , Nimodipina/farmacología , Orientación/efectos de los fármacos , Animales , Mapeo Encefálico , Implantes de Medicamentos , Reacción de Fuga/efectos de los fármacos , Masculino , Ratas , Ratas Long-Evans , Retención en Psicología/efectos de los fármacosRESUMEN
Moxonidine has been shown to be antiarrhythmic during ischaemia in vivo. This study aimed to investigate its electrophysiological effects in isolated working rabbit hearts in vitro. Monophasic action potential duration, effective refractory period and conduction delay were measured at three ventricular sites. The hearts were treated before and during ischaemia and reperfusion with vehicle, moxonidine (0.01, 0.1 and 1 microM) or labetalol (1 microM). In all groups, ventricular fibrillation was always induced during ischaemia. Only 0.1 microM moxonidine decreased the incidence of sustained ventricular fibrillation from 86 to 17%, although it did not affect any electrophysiological parameters measured. Similarly, labetolol, an adrenoceptor blocker, facilitated spontaneous defibrillation without any electrophysiological effects. In conclusion, moxonidine directly facilitates spontaneous defibrillation of ventricular fibrillation during ischaemia. Since the same effect is observed with labetalol, it is possible that the defibrillatory action of moxonidine is related to its peripheral antiadrenergic activity, although other mechanisms cannot be excluded.
Asunto(s)
Antihipertensivos/farmacología , Imidazoles/farmacología , Isquemia Miocárdica/fisiopatología , Fibrilación Ventricular/tratamiento farmacológico , Potenciales de Acción/efectos de los fármacos , Animales , Arritmias Cardíacas/tratamiento farmacológico , Arritmias Cardíacas/fisiopatología , Modelos Animales de Enfermedad , Electrofisiología , Ventrículos Cardíacos/efectos de los fármacos , Ventrículos Cardíacos/patología , Hemodinámica/efectos de los fármacos , Imidazoles/uso terapéutico , Técnicas In Vitro , Labetalol/farmacología , Labetalol/uso terapéutico , Masculino , Isquemia Miocárdica/patología , Daño por Reperfusión Miocárdica/fisiopatología , Tamaño de los Órganos/efectos de los fármacos , ConejosRESUMEN
The aim of this study was to investigate the influence of maturation and gender on the anti-arrhythmic effect of myocardial ischaemic preconditioning in rats. Coronary artery occlusion was carried out in either rats anaesthetised with sodium pentobarbitone or in rat isolated hearts. Cardiac arrhythmias occurring in the 30 min post-occlusion period were assessed. In anaesthetised 3 month (m) old male rats ischaemic preconditioning, with a 3 min temporary coronary artery occlusion, significantly reduced the total number of ventricular ectopic beats (VEBs) from 2074 +/- 206 to 490 +/- 139 and the incidence of ventricular fibrillation (VF) from 40 to 0% during a subsequent 30 min occlusion (P < 0.05). In middle-aged male rats (16 m) the anti-arrhythmic effect of preconditioning was unaltered (VEBs were reduced from 1958 +/- 121 to 245 +/- 66 and VF from 70 to 0%). In 3 m old anaesthetised female rats the effect of ischaemic preconditioning was also evident (VEBs reduced from 961 +/- 170 to 154 +/- 48; P < 0.05). In non-preconditioned age-matched female animals the total number of VEBs (961 +/- 170), VF (0%) and mortality (0%) were significantly (P < 0.05) lower than in respective male animals. In female rats, attenuation of ischaemia-induced arrhythmic severity was most pronounced in the oestrus state. In hearts isolated from weight-matched male and female rats the incidence of ventricular tachycardia (81 vs 25%) and the total number of VEBs (351 +/- 73 vs 81 +/- 50) were significantly (P < 0.05) different. It is concluded that in rats neither maturation nor gender influence the anti-arrhythmic effect of ischaemic preconditioning. However, female rats exhibit a lower level of arrhythmic activity during sustained coronary artery occlusion than male rats both in vivo and in vitro.
Asunto(s)
Arritmias Cardíacas/fisiopatología , Precondicionamiento Isquémico Miocárdico , Caracteres Sexuales , Maduración Sexual , Factores de Edad , Animales , Peso Corporal , Estro , Femenino , Hemodinámica , Técnicas In Vitro , Masculino , Tamaño de los Órganos , Ratas , Ratas Sprague-DawleyRESUMEN
This study aimed to investigate the role of electrical dispersion in arrhythmogenesis by using K(ATP) channel modulating agents. Monophasic action-potential duration (MAPD90), effective refractory period (ERP), and conduction delay were measured at three ventricular sites in isolated working rabbit hearts. Cromakalim (10 microM), glibenclamide (3 microM), or 5-hydroxydecanoate (100 microM) were administered before and throughout 30 min of regional ischaemia and 15 min of reperfusion. Before ischaemia, cromakalim reduced MAPD90 and ERP in all areas and facilitated induction of ventricular fibrillation in five of 12 hearts. In these hearts, cromakalim increased interventricular ERP dispersion from 17 +/- 5 to 38 +/- 5 ms. During ischaemia, cromakalim decreased MAPD90 dispersion within the left ventricle from 84 +/- 5 to 44 +/- 4 ms, but did not affect ERP dispersion and arrhythmogenesis. 5-Hydroxydecanoate had no effect on MAPD90 and ERP shortening or dispersion during ischaemia and reperfusion and was not antiarrhythmic. Glibenclamide reduced forward flow to zero, preventing further electrophysiologic studies. In conclusion, in this model, an increase in interventricular ERP dispersion predisposes to ventricular fibrillation in normoxic conditions after cromakalim administration. However, a decrease in ischaemia-induced MAPD90 dispersion by cromakalim does not affect arrhythmogenesis. A lack of effect of 5-hydroxydecanoate on electrical dispersion during ischaemia is accompanied by a lack of antiarrhythmic activity.