RESUMEN
Roughly speaking, restitution is the dependence of recovery time of cardiac electrical activity on heart rate. Increased restitution slope is theorized to be predictive of sudden death after heart injury such as from coronary artery occlusion (ischemia). Adrenaline analogs are known to increase restitution slope in normal hearts, but their effects in failing hearts are unknown. Twenty-six rabbits underwent coronary ligation (n = 15) or sham surgery (n = 11) and implantation of a lead in the heart for recording electrocardiograms. Eight weeks later, unanesthetized rabbits were given 0.25-2.0 ml of 1 µmol/L isoprenaline intravenously, which increased heart rate. Heart rate was quantified by time between QRS peaks (RR) and heart activity duration by R to T peak time (QTp). Ligated rabbits (n = 6) had lower ejection fraction than sham rabbits (n = 7, p < 0.0001) indicative of heart failure, but similar baseline RR (269 ± 15 vs 292 ± 23 ms, p = 0.07), QTp (104 ± 17 vs 91 ± 9 ms, p = 0.1), and isoprenaline-induced minimum RR (204 ± 11 vs 208 ± 6 ms, p = 0.4). The trajectory of QTp vs TQ plots displayed hysteresis and regions of negative slope. The slope of the positive slope region was >1 in ligated rabbits (1.27 ± 0.66) and <1 in sham rabbits (0.35 ± 0.14, p = 0.004). The absolute value of the negative slope was greater in ligated rabbits (- 0.81 ± 0.52 vs - 0.35 ± 0.14, p = 0.04). Isoprenaline increased heart rate and slopes of restitution trajectory in failing hearts. The dynamics of restitution trajectory may hold clues for sudden death in heart failure patients.
RESUMEN
In vivo haemodynamic responses to human urotensin-II were determined in two models of pulmonary hypertension: rabbits with left ventricular dysfunction following coronary artery ligation and the hypoxic rat. Effects were also examined in the presence of the nitric oxide synthase inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME). Human urotensin-II increased pulmonary arterial pressure to a greater extent in ligated rabbits than their controls and L-NAME increased pulmonary pressure without significantly affecting these responses to human urotensin-II. Human urotensin-II raised right ventricular pressure slightly in control rats but not in hypoxic rats. Human urotensin-II did not constrict control rat isolated small pulmonary arteries and only induced a small constriction of these vessels in hypoxic rats. In conclusion, exogenous human urotensin-II exerts pulmonary pressor responses in vivo in rabbits and also induced small pulmonary pressor responses in control rats. Pulmonary pressor responses to urotensin-II were increased by pulmonary hypertension in rabbits but not in rats.
Asunto(s)
Hipertensión Pulmonar/fisiopatología , Arteria Pulmonar/efectos de los fármacos , Urotensinas/farmacología , Animales , Presión Sanguínea/efectos de los fármacos , Gasto Cardíaco/efectos de los fármacos , Modelos Animales de Enfermedad , Ecocardiografía , Frecuencia Cardíaca/efectos de los fármacos , Ventrículos Cardíacos/fisiopatología , Humanos , Hipoxia/fisiopatología , Técnicas In Vitro , Masculino , Infarto del Miocardio/fisiopatología , Arteria Pulmonar/fisiopatología , Circulación Pulmonar/efectos de los fármacos , Conejos , Ratas , Ratas Wistar , Vasoconstricción/efectos de los fármacosRESUMEN
The aims of this study were to determine if endothelin-1 (ET-1) under normal and ischaemic conditions exhibits a direct arrhythmogenic effect that is independent of its ability to cause coronary vasoconstriction, and to determine the contribution of the ET(A) and ET(B) receptor subtype. ET(A/B) (with ET-1) and ET(A) (ET-1 in the presence of BQ-788) receptor activation resulted in a significant reduction in both epi- and endocardial monophasic action potential duration (MAPD(90)). ET(A) receptor activation reduced both epi- and endocardial effective refractory period (ERP). This MAPD(90) and ERP shortening were associated with a reduction in coronary flow, myocardial contractility and induction of ventricular fibrillation (VF) during ERP measurement. The ET(B) agonist sarafotoxin (S6c) had no marked, or concentration-dependent, effect on MAPD(90), ERP, myocardial contractility or induction of arrhythmias. Neither ET-1 nor S6c, given prior to coronary artery occlusion, significantly changed the ischaemia-induced dispersion of MAPD(90), ERP or the % incidence of VF. In conclusion, neither ET(A) nor ET(B) receptor stimulation has a direct arrhythmogenic effect in isolated rabbit hearts under normal or ischaemic conditions. The ET-1-induced arrhythmogenic effect observed in nonischaemic hearts is likely to be the result of the associated coronary vasoconstriction caused by ET(A) receptor stimulation resulting in myocardial ischaemia.
Asunto(s)
Endocardio/efectos de los fármacos , Endotelina-1/farmacología , Isquemia Miocárdica/fisiopatología , Pericardio/efectos de los fármacos , Receptor de Endotelina A/agonistas , Receptor de Endotelina B/agonistas , Potenciales de Acción/efectos de los fármacos , Animales , Arritmias Cardíacas/inducido químicamente , Presión Sanguínea/efectos de los fármacos , Circulación Coronaria/efectos de los fármacos , Modelos Animales de Enfermedad , Endocardio/fisiología , Antagonistas de los Receptores de la Endotelina B , Técnicas In Vitro , Masculino , Contracción Miocárdica/efectos de los fármacos , Oligopéptidos/farmacología , Pericardio/fisiología , Piperidinas/farmacología , Conejos , Receptor de Endotelina A/fisiología , Receptor de Endotelina B/fisiología , Fibrilación Ventricular , Venenos de Víboras/farmacologíaRESUMEN
The role of 5-hydroxytryptamine (5-HT) in a rabbit model of pulmonary hypertension (PHT) secondary to left ventricular dysfunction was investigated. Following pulmonary artery catheterisation under anaesthesia, 5-HT (1-400 microg kg(-1) i.v.) was administered before and after either 5-HT(2A) receptor antagonism with ketanserin (0.5 mg kg(-1)) or infusion of the nitric oxide synthase inhibitor, l-NAME (30 micromol min(-1)). Eight week coronary artery ligated rabbits demonstrate increased mean pulmonary arterial pressure (PAP) compared to controls (17.0+/-0.5 versus 12.0+/-0.5 mmHg, P<0.001) accompanied by right ventricular hypertrophy. 5-HT alone produced a greater pulmonary pressor response in rabbits with PHT (increase of 7.5+/-1.2, n=12 c.f. 3.5+/-0.4 mmHg in shams, n=12, P<0.01). Ketanserin had no effect on basal PAP in either PHT or control rabbits but inhibited the response to 5-HT in both groups. The response to 5-HT following l-NAME was increased in both groups and was greater in rabbits with PHT (an increase of 20.1+/-2.9, n=6 c.f. 11.4+/-1.8 mmHg, n=6, P<0.05). These results suggest that the difference shown in the in vivo pulmonary response to exogenous 5-HT is mediated largely through 5-HT(2A) receptors in this model. However, activity of endogenous 5-HT at the 5-HT(2A) receptors is not responsible for maintaining the raised basal PAP through vasoconstriction in PHT rabbits once PHT has developed.
Asunto(s)
Hipertensión Pulmonar/fisiopatología , Músculo Liso Vascular/efectos de los fármacos , Arteria Pulmonar/efectos de los fármacos , Serotonina/fisiología , Disfunción Ventricular Izquierda/fisiopatología , Animales , Aorta , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Gasto Cardíaco/efectos de los fármacos , Modelos Animales de Enfermedad , Frecuencia Cardíaca/efectos de los fármacos , Frecuencia Cardíaca/fisiología , Hipertensión Pulmonar/inducido químicamente , Hipertensión Pulmonar/complicaciones , Hipertrofia Ventricular Izquierda/complicaciones , Hipertrofia Ventricular Izquierda/fisiopatología , Hipertrofia Ventricular Derecha/complicaciones , Hipertrofia Ventricular Derecha/fisiopatología , Ketanserina/farmacología , Masculino , Músculo Liso Vascular/fisiopatología , NG-Nitroarginina Metil Éster/farmacología , Tamaño de los Órganos/efectos de los fármacos , Arteria Pulmonar/fisiopatología , Conejos , Receptor de Serotonina 5-HT2A/efectos de los fármacos , Receptor de Serotonina 5-HT2A/fisiología , Serotonina/farmacología , Antagonistas de la Serotonina/farmacología , Volumen Sistólico/efectos de los fármacos , Volumen Sistólico/fisiología , Disfunción Ventricular Izquierda/complicacionesRESUMEN
BACKGROUND: Increased serotonin (5-hydroxytryptamine, 5-HT) transporter activity has been observed in human familial pulmonary hypertension. METHODS AND RESULTS: We investigated pulmonary hemodynamics and the development of hypoxia-induced pulmonary hypertension and pulmonary vascular remodeling in mice overexpressing the gene for the 5-HT transporter (5-HTT+ mice). Right ventricular pressure was elevated 3-fold in normoxic 5-HTT+ mice compared with their wild-type controls. Hypoxia-induced increases in right ventricular hypertrophy and pulmonary vascular remodeling were also potentiated in the 5-HTT+ mice. 5-HTT-like immunoreactivity, protein, and binding sites were markedly increased in the lungs from the 5-HTT+ mice. Hypoxia, however, decreased 5-HT transporter immunoreactivity, mRNA transcription, protein, and binding sites in both wild-type and 5-HTT+ mice. CONCLUSIONS: Increased 5-HT transporter expression causes elevated right ventricular pressures, and this occurs before the onset of right ventricular hypertrophy or pulmonary arterial remodeling. Hypoxia-induced remodeling is, however, increased in 5-HTT+ mice, whereas hypoxia inhibits 5-HTT expression. This provides a unique model that demonstrates differential mechanisms for familial pulmonary arterial hypertension and pulmonary arterial hypertension with hypoxemia.
Asunto(s)
Proteínas Portadoras/fisiología , Hipertensión Pulmonar/genética , Hipertrofia Ventricular Derecha/genética , Hipoxia/complicaciones , Glicoproteínas de Membrana/fisiología , Proteínas de Transporte de Membrana , Proteínas del Tejido Nervioso/fisiología , Arteria Pulmonar/patología , Animales , Sitios de Unión , Proteínas Portadoras/genética , Citalopram/metabolismo , Expresión Génica , Hemodinámica , Hipertensión Pulmonar/etiología , Hipertrofia Ventricular Derecha/etiología , Pulmón/metabolismo , Glicoproteínas de Membrana/genética , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos CBA , Proteínas del Tejido Nervioso/genética , ARN Mensajero/biosíntesis , Factores de Riesgo , Proteínas de Transporte de Serotonina en la Membrana Plasmática , Factores de TiempoRESUMEN
Chronic (8 weeks) coronary artery ligation caused marked left-ventricular dysfunction (LVD) in rabbits. The positive inotropic effect observed in vivo with intraventricular injection of saline in sham-operated (control) animals was reversed in rabbits with LVD. In vitro, a step increase in filling pressure from 10 to 15 cm H(2)O caused an immediate increase, followed by a slow increase, in left-ventricular peak systolic pressure (LVP(max)) and cardiac output (CO) over 5-7 min in sham-operated hearts. No significant slow positive inotropic effect was observed in hearts with LVD in response to a standard increase in filling pressure. Progressive increases in filling pressure increased (LVP(max)) and CO to a maximum value at 20 cm H(2)O in control hearts. In the LVD group, progressive increases in filling pressure caused a negative inotropic response and reduced CO. Hearts from the LVD group were significantly dilated compared with control hearts but no significant changes in myocardial compliance were observed in beating or quiescent hearts. These studies reveal an impaired inotropic response to increased ventricular filling in LVD rabbit hearts; this defect included the depression of the slow inotropic response to an increased end-diastolic volume. These changes appear not to be accompanied by altered passive mechanical properties.
Asunto(s)
Corazón/fisiopatología , Contracción Miocárdica/fisiología , Disfunción Ventricular Izquierda/fisiopatología , Animales , Presión Sanguínea/fisiología , Gasto Cardíaco/fisiología , Enfermedad Crónica , Masculino , Infarto del Miocardio/fisiopatología , Técnicas de Cultivo de Órganos , Conejos , Función Ventricular Izquierda/fisiologíaRESUMEN
Apex-to-base differences in the density of potassium currents have been recently described in isolated rabbit myocytes. The significance of those findings for arrhythmogenesis in the whole heart is not known. We aimed to examine electrophysiological effects of hypokalaemia/hypomagnesaemia in isolated working rabbit hearts. Monophasic action potential duration (MAPD(90)), effective refractory period (ERP) and conduction delay were measured at 3 left ventricular sites (basal epicardium, apical epicardium, apical endocardium) in control (K(+) = 4mmol/L, Mg(2+) = 1mmol/L) and hypokalaemia/hypomagnesaemia (K(+) = 2mmol/L, Mg(2+) = 0.5mmol/L) groups. It was found that hypokalaemia/hypomagnesaemia shortened ERP in the apical epicardial region (by 22 +/- 6ms), without any significant effect in the basal area. Consequently, hypokalaemia/hypomagnesaemia increased transepicardial dispersion of refractoriness (from 10 +/- 3 to 25 +/- 7ms, P <.05) and increased inducibility of ventricular fibrillation (from 10% to 100%, P <.05). Similar effects were seen in hearts with left ventricular hypertrophy secondary to perinephritis-induced hypertension. These results suggest that hypokalaemia/hypomagnesaemia is pro-arrhythmic in normal or hypertrophied hearts due to an increase in apex-to-base dispersion of refractoriness.
Asunto(s)
Arritmias Cardíacas/etiología , Hipopotasemia/fisiopatología , Magnesio/sangre , Periodo Refractario Electrofisiológico/fisiología , Potenciales de Acción , Animales , Electrofisiología , Hipertrofia Ventricular Izquierda/fisiopatología , Técnicas In Vitro , Masculino , ConejosRESUMEN
1. Using an in vivo model of pulmonary hypertension (PHT) secondary to left ventricular dysfunction (LVD), the pulmonary arterial response to the nitric oxide synthase (NOS) blocker L-NAME (30 micromol.min(-1) i.v.) and the subsequent responses to cumulatively administered endothelin-1 (ET-1) (0.001 -- 4 nmol.kg(-1) i.v.) or big ET-1 (0.1 -- 2.0 nmol.kg(-1) i.v.) were studied. Additionally, the effect of the non-selective ET-1 receptor antagonist, SB209670, was investigated. 2. Eight weeks after coronary artery ligation or sham operation, rabbits demonstrated increased mean pulmonary arterial pressure (PAP) accompanied by right ventricular hypertrophy. 3. Blockade of NOS caused a greater increase in basal PAP (increased by 7.7 +/- 1.1 mmHg c.f. 3.8 +/- 1.0 mmHg in controls, P<0.05) and uncovered a greater pulmonary pressor response to exogenous ET-1 in rabbits with PHT (increased by 10.2 +/- 2.3 mmHg c.f. 4.9 +/- 1.0 mmHg in controls, P<0.05). 4. Big ET-1 evoked a pulmonary pressor effect, in both groups of rabbits, that was increased following blockade of NOS and was more potent in rabbits with PHT. 5. The non-selective ET-1 receptor antagonist, SB209670, reduced basal PAP (from 16.9 mmHg to 15.9 mmHg, P < 0.05) in rabbits with PHT and blocked the response to ET-1 in the presence of L-NAME. 6. In conclusion, the results demonstrate that basal NO activity masks a pulmonary pressor response to exogenously administered ET-1. An increased responsiveness to ET-1 was shown in the pulmonary arterial bed of rabbits with PHT secondary to LVD, implicating a pathophysiological role for ET-1 in this model.