Activation of the sympathetic nervous system is a hallmark of heart failure (HF) and is positively correlated with disease progression. Catecholaminergic (C1) neurons located in the rostral ventrolateral medulla (RVLM) are known to modulate sympathetic outflow and are hyperactivated in volume overload HF. However, there is no conclusive evidence showing a contribution of RVLM-C1 neurons to the development of cardiac dysfunction in the setting of HF. Therefore, the aim of this study was to determine the role of RVLM-C1 neurons in cardiac autonomic control and deterioration of cardiac function in HF rats. A surgical arteriovenous shunt was created in adult male Sprague-Dawley rats to induce HF. RVLM-C1 neurons were selectively ablated using cell-specific immunotoxin (dopamine-β hydroxylase saporin [DβH-SAP]) and measures of cardiac autonomic tone, function, and arrhythmia incidence were evaluated. Cardiac autonomic imbalance, arrhythmogenesis and cardiac dysfunction were present in HF rats and improved after DβH-SAP toxin treatment. Most importantly, the progressive decline in fractional shortening observed in HF rats was reduced by DβH-SAP toxin. Our results unveil a pivotal role played by RVLM-C1 neurons in cardiac autonomic imbalance, arrhythmogenesis and cardiac dysfunction in volume overload-induced HF.

We have investigated the effects of the calcium-sensitizing inotropic agent EMD 57033 on Ca 2+ handling in intact and skinned rat ventricular myocytes. Intracellular Ca 2+ was monitored using fura 2. Myocytes were saponin-skinned, allowing study of sarcoplasmic reticulum (SR) function. In intact myocytes EMD 57033 (1–10 µ mol/l) produced a concentration-dependent decrease in the amplitude of the Ca 2+ transient and prolonged its declining phase, but had no effect on the rise time. In skinned myocytes, the amplitude of spontaneous Ca 2+ release from the SR was decreased by EMD 57033 (5 and 10 µ mol/l), although this agent had no significant effect on the frequency of spontaneous Ca 2+ release. In the presence of the cross-bridge inhibitor 2,3-butanedione monoxime (5 mmol/l), or in a low bathing Ca 2+ concentration (1 mmol/l), EMD 57033 (10 µ mol/l) had smaller effects on both the amplitude and time course of the Ca 2+ transient in intact cells than in the absence of 2,3-butanedione monoxime or in the presence of 2 and 5 mmol/l Ca 2+ respectively. These data suggest that the effects of EMD 57033 on Ca 2+ are due to changes in Ca 2+ binding to troponin C, secondary to cross-bridge formation. Thus, during positive inotropy, EMD 57033 is unlikely to provoke arrhythmias due to effects on SR Ca 2+ handling. In intact cells, its effects on Ca 2+ handling would be expected to protect against arrhythmias.

1. Exercise training reduces resting sympathetic activity, but the effects on sympathetic activation or withdrawal during baroreflex responses to blood pressure perturbations are controversial. The purpose of this study was to investigate the effects of training on both the vagal and sympathetic reflex heart rate responses to blood pressure changes. 2. Using 10 healthy males in a randomized cross-over design, we examined the effects of three 30 min cycling sessions at 70% of maximal capacity for 4 weeks on the steady-state reflex heart rate responses to perturbations in mean arterial pressure induced with injections of nitroprusside and phenylephrine. The method provides a sigmoidal relationship between changes in heart rate and blood pressure. The upper plateau (maximum tachycardia in response to blood pressure reduction) and lower plateau (maximum bradycardia in response to blood pressure elevation) are mainly mediated by the cardiac sympathetics and vagus, respectively. The slope of the relationship is a measure of reflex gain. 3. Training, which increased maximal oxygen consumption by 13 ± 2% (mean ± standard error of the difference), reduced supine and standing blood pressures by 3 ± 1 / 3 ± 1 mmHg ( P < 0.05) and 4 ± 1/2 ± 2 mmHg ( P < 0.05 for systolic), respectively, whereas resting heart rate was lowered by 6 ± 1 beats/min ( P < 0.05). Reflex sensitivity in the presence of functioning vagus and sympathetics was not altered with training, but the vagal component of sensitivity, as assessed after sympathetic blockade with propranolol, was significantly reduced. The maximal tachycardiac responses to blood pressure decreases were consistently reduced with training (sedentary, 106 beats/ min; trained, 97 ± 1 beats/min; P < 0.05). This attenuation was not evident in the presence of propranolol, suggesting a sympathetic origin. 4. Exercise training thus reduced the sympathetic contribution to reflex tachycardia induced by blood pressure reduction and diminished the vagal contribution to reflex sensitivity. These effects of training may be of relevance to individuals with elevated sympathetic activity who may be at risk of myocardial ischaemia, serious ventricular arrhythmias or sudden cardiac death.

1. Monophasic action potentials (MAPs) were recorded simultaneously from the endocardium and the epicardium in open-chested dogs ( n = 16) during bolus intravenous injections of potassium chloride at 0.1 mmol/kg and 0.2 mmol/kg. MAP duration was measured at 90% repolarization. Local conduction was measured as the delay between the pacing artefact and upstroke of the MAP. 2. The animals were anaesthetized with α-chloralose and urethane. Heart block was created by atrioventricular nodal ablation with 0.1% (v/v) formalin. Infra-nodal pacing was established. 3. Bolus injections of potassium chloride at 0.1 mmol/kg shortened MAP duration. The effect was maximal at 15 s after the injection [epicardium: 171.5 ± 3.0 (control) and 148.9 ± 5.2 ms at 15 s ( P < 0.001); endocardium: 178.7 ± 4.4 (control) and 165.6 ± 5.3 ms ( P < 0.001)]. The shortening on the epicardium was significantly greater than on the endocardium ( P < 0.05). 4. Local conduction time showed no significant change [epicardium: 37.8 ± 1.8 (control) and 41.2 ± 2.4 at 15 s; endocardium: 41.1 ± 1.6 (control) and 45.0 ± 3.4 at 15 s]. 5. After β-adrenoceptor blockade, MAP duration shortened, exhibiting a maximum effect at 20 s after a bolus injection of potassium chloride at 0.1 mmol/kg [epicardium: 184.7 ± 7.1 (control) and 130.7 ± 9.0 ms at 20 s ( P < 0.001); endocardium 192.0 ± 7.4 (control) and 148.6 ± 10.8 ms at 20 s ( P < 0.001)]. The greater shortening observed on the epicardial surface did not reach statistical significance. 6. Local conduction time after β-adrenoceptor blockade was prolonged, reaching a maximum at 20 s [epicardium: 41.2 ± 4.8 (control) and 65.9 ± 8.6 ms at 20 s: endocardium: 47.5 ± 7.4 (control) and 87.3 ± 13.1 ms at 20 s]. 7. Doubling of the dose of potassium chloride to 0.2 mmol/kg was usually terminal and often showed bizarre electrophysiological responses with striking regional differences. 8. Our results show that bolus injections of potassium chloride exert a differential influence on the time course of epicardial and endocardial repolarization by an effect on MAP duration rather than on local conduction time. After β-adrenoceptor blockade the effect of a bolus injection of potassium chloride on MAP duration was greater and conduction time was increased.

1. Sufficient isolated extrasystoles were recorded during a period of quiet breathing in nine patients to test the null hypothesis that there is no within-breath influence of respiration on the triggering of extrasystoles. 2. In five patients a highly significant respiratory modulation of the firing of extrasystoles was seen. The frequency distribution of extrasystoles during the respiratory cycle appeared to be approximately sinusoidal. 3. The phase relations varied with respiratory frequency, and the peak incidence occurred relatively later in the cycle when breaths were shorter: always at about 2 s after the start of inspiration. 4. An autonomic reflex mechanism, equivalent to that causing sinus arrhythmia, appears to be the most likely explanation.

1. The isolated perfused non-working rat heart, subjected to low coronary flow, has been used to study the effects of myocardial ischaemia on both the mechanical and metabolic performance of the heart. 2. In this preparation, adrenaline initially increased developed tension and heart rate, followed shortly thereafter by marked deterioration in mechanical performance to levels below those observed in the control state. These latter responses occurred simultaneously with stimulation of endogenous myocardial lipolysis. The rate of release of non-esterified fatty acids was positively correlated with both the decline in developed tension and the rise in resting tension. 3. The anti-lipolytic agent nicotinic acid had no effect on the initial mechanical responses of the heart to adrenaline but prolonged the period of enhanced tension development after adrenaline and reduced the degree of later deterioration in performance, in addition to blocking lipolytic stimulation. 4. Hearts from rats fed on a diet rich in animal fat contained larger triglyceride reserves and exhibited greater rates of non-catecholamine-stimulated lipolysis than hearts from normally fed rats. During ischaemic perfusion such hearts showed a more marked rise in resting tension and decline in heart rate than hearts from normally fed animals. Such hearts also had an increased incidence of arrhythmias and a slight reduction in developed tension. The initial responses of these hearts from fat-fed rats to adrenaline were also depressed as compared with normal hearts. Hearts from fat-fed rats showed a greater tendency to deteriorate in performance after adrenaline, particularly with falling heart rates and the onset of ventricular fibrillation. 5. We suggest that these results indicate that myocardial lipolysis makes a significant contribution to the adrenaline-induced deterioration in performance seen in these ischaemically perfused rat hearts.