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A model of cellular cardiac-neural coupling that captures the sympathetic control of sinoatrial node excitability in normotensive and hypertensive rats
Hypertension is associated with sympathetic hyperactivity. To represent this neural-myocyte coupling, and to elucidate the mechanisms underlying sympathetic control of the cardiac pacemaker, we developed a new (to our knowledge) cellular mathematical model that incorporates signaling information from cell-to-cell communications between the sympathetic varicosity and sinoatrial node (SAN) in both normotensive (WKY) and hypertensive (SHR) rats. Features of the model include 1), a description of pacemaker activity with specific ion-channel functions and Ca 2+ handling elements; 2), dynamic β-adrenergic modulation of the excitation of the SAN; 3), representation of ionic activity of sympathetic varicosity with NE release dynamics; and 4), coupling of the varicosity model to the SAN model to simulate presynaptic transmitter release driving postsynaptic excitability. This framework captures neural-myocyte coupling and the modulation of pacemaking by nitric oxide and cyclic GMP. It also reproduces the chronotropic response to brief sympathetic stimulations. Finally, the SHR model quantitatively suggests that the impairment of cyclic GMP regulation at both sides of the sympathetic cleft is crucial for development of the autonomic phenotype observed in hypertension. © 2011 Biophysical Society.
Defining the neurocircuitry of exercise hyperpnoea.
One hundred years ago in this journal, Krogh and Lindhard published a seminal paper highlighting the importance of the brain in the control of breathing during exercise. This symposium report reviews the historical developments that have taken place since 1913, and attempts to place the detailed neurocircuitry thought to underpin exercise hyperpnoea into context by focusing on key structures that might form the command network. With the advent of enhanced neuroimaging and functional neurosurgical techniques, a unique window of opportunity has recently arisen to target potential circuits in humans. Animal studies have identified a priori sites of interest in mid-brain structures, in particular the subthalamic locomotor region (subthalamic nucleus, STN) and the periaqueductal grey (PAG), which have now been recorded from in humans during exercise. When all data are viewed in an integrative manner, the PAG, in particular the lateral PAG, and aspects of the dorsal lateral PAG, appear to be key communicating circuitry for 'central command'. Moreover, the PAG also fulfils many requirements of a command centre. It has functional connectivity to higher centres (dorsal lateral prefrontal cortex) and the basal ganglia (in particular, the STN), and receives a sensory input from contracting muscle, but, importantly, it sends efferent information to brainstem nuclei involved in cardiorespiratory control.
Cardiac sympathetic dysfunction in the prehypertensive spontaneously hypertensive rat.
Recent studies in prehypertensive spontaneously hypertensive rats (SHR) have shown larger calcium transients and reduced norepinephrine transporter (NET) activity in cultured stellate neurons compared with Wistar-Kyoto (WKY) controls, although the functional significance of these results is unknown. We hypothesized that peripheral sympathetic responsiveness in the SHR at 4 wk of age would be exaggerated compared with the WKY. In vivo arterial pressure (under 2% isoflurane) was similar in SHRs (88 ± 2/50 ± 3 mmHg, n = 18) compared with WKYs (88 ± 3/49 ± 4 mmHg, n = 20). However, a small but significant (P < 0.05) tachycardia was observed in the young SHR despite the heart rate response to vagus stimulation (3 and 5 Hz) in vivo being similar (SHR: n = 12, WKY: n = 10). In isolated atrial preparations there was a significantly greater tachycardia during right stellate stimulation (5 and 7 Hz) in SHRs (n = 19) compared with WKYs (n = 16) but not in response to exogenous NE (0.025-5 μM, SHR: n = 10, WKY: n = 10). There was also a significantly greater release of [(3)H]NE to field stimulation (5 Hz) of atria in the SHR (SHR: n = 17, WKY: n = 16). Additionally, plasma levels of neuropeptide Y sampled from the right atria in vivo were also higher in the SHR (ELISA, n = 12 for both groups). The difference in [(3)H]NE release between SHR and WKY could be normalized by the NET inhibitor desipramine (1 μM, SHR: n = 10, WKY: n = 8) but not the α2-receptor antagonist yohimbine (1 μM, SHR: n = 7, WKY: n = 8). Increased cardiac sympathetic neurotransmission driven by larger neuronal calcium transients and reduced NE reuptake translates into enhanced cardiac sympathetic responsiveness at the end organ in prehypertensive SHRs.
Remodeling of the cardiac pacemaker L-type calcium current and its beta-adrenergic responsiveness in hypertension after neuronal NO synthase gene transfer.
Hypertension is associated with abnormal neurohumoral activation. We tested the hypothesis that beta-adrenergic hyperresponsiveness in the sinoatrial node (SAN) of the spontaneously hypertensive rat occurs at the level of the L-type calcium current because of altered cyclic nucleotide-dependent signaling. Furthermore, we hypothesized that NO, a modulator of cGMP and cAMP, would normalize the beta-adrenergic phenotype in the hypertensive rat. Chronotropic responsiveness to norepinephrine (NE), together with production of cAMP and cGMP, was assessed in isolated atrial preparations from age-matched hypertensive and normotensive rats. Right atrial/SAN pacemaking tissue was injected with adenovirus encoding enhanced green fluorescent protein (control vector) or neuronal NO synthase (nNOS). In addition, L-type calcium current was measured in cells isolated from the SAN of transfected animals. Basal levels of cGMP were lower in hypertensive rat atria. These atria were hyperresponsive to NE at all of the concentrations tested, with elevated production of cAMP. This was accompanied by increased basal and norepinephrine-stimulated L-type calcium current. Using enhanced green fluorescent protein, we observed transgene expression within both tissue sections and isolated pacemaking cells. Adenoviral nNOS increased right atrial nNOS protein expression and cGMP content. NE-stimulated cAMP concentration and L-type calcium current were also attenuated by adenoviral nNOS, along with the chronotropic responsiveness to NE in hypertensive rat atria. Decreased calcium current after cardiac nNOS gene transfer contributes to the normalization of beta-adrenergic hyperresponsiveness in the SAN from hypertensive rats by modulating cyclic nucleotide signaling.
Noradrenergic cell specific gene transfer with neuronal nitric oxide synthase reduces cardiac sympathetic neurotransmission in hypertensive rats.
Nitric oxide-cGMP pathway can inhibit cardiac norepinephrine (NE) release. Sympathetic hyper-responsiveness in hypertension may result from oxidative stress impairing this pathway. We tested the hypothesis that the gene transfer of neuronal NO synthase (nNOS) could restore sympathetic balance in the spontaneously hypertensive rat (SHR). An adenovirus (5x10(10) particles) constructed with a noradrenergic neuron-specific promoter (PRS x8) encoding nNOS (Ad.PRS-nNOS) or enhanced green fluorescence protein (Ad.PRS-eGFP) was targeted to the right atrial wall by percutaneous injection in age-matched male SHRs and Wistar-Kyoto (WKY) rats. Five days after transduction, right atria were removed, and evoked [(3)H] norephinephrine (NE) release, NOS activity, and cGMP were measured. In the Ad.PRS-eGFP treated group, tissue levels of cGMP were significantly lower in the SHR compared with the WKY atria. NE release was also greater in the SHR, and soluble guanylate cyclase inhibition did not alter evoked [(3)H] NE release in the Ad.PRS-eGFP-treated SHR. All atria treated with Ad.PRS-nNOS had enhanced nNOS activity when compared with Ad.PRS-eGFP atria. Ad.PRS-nNOS in WKY rats reduced NE release compared with the Ad.PRS-eGFP group. Guanylate cyclase inhibition enhanced NE release in both Ad.PRS-nNOS- and Ad.PRS-eGFP-treated WKY atria. Ad.PRS-nNOS restored cGMP levels in the SHR to those seen in the WKY atria. In the SHR, Ad.PRS-nNOS also attenuated NE release compared with Ad.PRS-eGFP group. This was reversed by guanylate cyclase inhibition. We conclude that artificial upregulation of sympathetic nNOS via gene transfer with a noradrenergic promoter may provide a novel approach for correcting peripheral sympathetic hyperactivity in hypertension.
Organization of ventricular fibrillation in the human heart: experiments and models.
Sudden cardiac death is a major health problem in the industrialized world. The lethal event is typically ventricular fibrillation (VF), during which the co-ordinated regular contraction of the heart is overthrown by a state of mechanical and electrical anarchy. Understanding the excitation patterns that sustain VF is important in order to identify potential therapeutic targets. In this paper, we studied the organization of human VF by combining clinical recordings of electrical excitation patterns on the epicardial surface during in vivo human VF with simulations of VF in an anatomically and electrophysiologically detailed computational model of the human ventricles. We find both in the computational studies and in the clinical recordings that epicardial surface excitation patterns during VF contain around six rotors. Based on results from the simulated three-dimensional excitation patterns during VF, which show that the total number of electrical sources is 1.4 +/- 0.12 times greater than the number of epicardial rotors, we estimate that the total number of sources present during clinically recorded VF is 9.0 +/- 2.6. This number is approximately fivefold fewer compared with that observed during VF in dog and pig hearts, which are of comparable size to human hearts. We explain this difference by considering differences in action potential duration dynamics across these species. The simpler spatial organization of human VF has important implications for treatment and prevention of this dangerous arrhythmia. Moreover, our findings underline the need for integrated research, in which human-based clinical and computational studies complement animal research.
Targeting cardiac sympatho-vagal imbalance using gene transfer of nitric oxide synthase.
Heightened sympathetic excitation and diminished parasympathetic suppression of heart rate, cardiac contractility and vascular tone are all associated with cardiovascular diseases such as hypertension and ischemic heart disease. This phenotype often exists before these disease states have been established and is a strong correlate of mortality in the population. However, the causal role of the autonomic phenotype in the development and maintenance of hypertension and myocardial ischemia remains a subject of debate, as are the mechanisms responsible for regulating sympathovagal balance. Emerging evidence suggests oxidative stress and reactive oxygen species (such as nitric oxide (NO) and superoxide) play important roles in the modulation of autonomic balance, but so far the most important sites of action of these ubiquitous signaling molecules are unclear. In many cases, these mediators have opposing effects in separate tissues rendering conventional pharmacological approaches non-efficacious. Novel techniques have recently been used to augment these signaling pathways experimentally in a targeted fashion to central autonomic nuclei, cardiac neurons, and myocytes using gene transfer of NO synthase. This review article discusses these recent advances in the understanding of the roles of NO and its oxidative metabolites on autonomic imbalance in models of cardiovascular disease.
Experiment-model interaction for analysis of epicardial activation during human ventricular fibrillation with global myocardial ischaemia
We describe a combined experiment-modelling framework to investigate the effects of ischaemia on the organisation of ventricular fibrillation in the human heart. In a series of experimental studies epicardial activity was recorded from 10 patients undergoing routine cardiac surgery. Ventricular fibrillation was induced by burst pacing, and recording continued during 2.5 min of global cardiac ischaemia followed by 30 s of coronary reflow. Modelling used a 2D description of human ventricular tissue. Global cardiac ischaemia was simulated by (i) decreased intracellular ATP concentration and subsequent activation of an ATP sensitive K + current, (ii) elevated extracellular K + concentration, and (iii) acidosis resulting in reduced magnitude of the L-type Ca 2+ current I Ca,L. Simulated ischaemia acted to shorten action potential duration, reduce conduction velocity, increase effective refractory period, and flatten restitution. In the model, these effects resulted in slower re-entrant activity that was qualitatively consistent with our observations in the human heart. However, the flattening of restitution also resulted in the collapse of many re-entrant waves to several stable re-entrant waves, which was different to the overall trend we observed in the experimental data. These findings highlight a potential role for other factors, such as structural or functional heterogeneity in sustaining wavebreak during human ventricular fibrillation with global myocardial ischaemia. © 2011 Elsevier Ltd.