Peripheral cardiac sympathetic hyperactivity in cardiovascular disease: role of neuropeptides

Abstract

High levels of sympathetic drive in several cardiovascular diseases including postmyocardial infarction, chronic congestive heart failure and hypertension are reinforced through dysregulation of afferent input and central integration of autonomic balance. However, recent evidence suggests that a significant component of sympathetic hyperactivity may also reside peripherally at the level of the postganglionic neuron. This has been studied in depth using the spontaneously hypertensive rat, an animal model of genetic essential hypertension, where larger neuronal calcium transients, increased release and impaired reuptake of norepinephrine in neurons of the stellate ganglia lead to a significant tachycardia even before hypertension has developed. The release of additional sympathetic cotransmitters during high levels of sympathetic drive can also have deleterious consequences for peripheral cardiac parasympathetic neurotransmission even in the presence of β-adrenergic blockade. Stimulation of the cardiac vagus reduces heart rate, lowers myocardial oxygen demand, improves coronary blood flow, and independently raises ventricular fibrillation threshold. Recent data demonstrates a direct action of the sympathetic cotransmitters neuropeptide Y (NPY) and galanin on the ability of the vagus to release acetylcholine and control heart rate. Moreover, there is as a strong correlation between plasma NPY levels and coronary microvascular function in patients with ST-elevation myocardial infarction being treated with primary percutaneous coronary intervention. Antagonists of the NPY receptors Y1 and Y2 may be therapeutically beneficial both acutely during myocardial infarction and also during chronic heart failure and hypertension. Such medications would be expected to act synergistically with β-blockers and implantable vagus nerve stimulators to improve patient outcome.

Keywords: autonomic nervous system; cardiac; hypertension; myocardial infarction; neuropeptide Y.

Fig. 1.

The peripheral cardiac sympathetic phenotype of the spontaneously hypertensive rat (SHR). A: calcium transients (measured using Fura 2-AM) within cultured neurons from the stellate ganglia in response to cellular depolarization (100 mmol/l KCl) are larger in the SHR compared with age-matched Wistar-Kyoto (WKY) controls. This can be observed at 4 wk of age when the SHR is normotensive and without left ventricular hypertrophy and when hypertension is well established at 16 wk of age [modified from Li et al. (60) with permission]. B: increased release of [³H]norepinephrine (NE) from isolated atria during stimulation at 5 Hz is also observed within the SHR compared with WKY at both developmental stages [from Shanks et al. (103) and republished from Herring et al. (41) with permission from Elsevier]. C: a reduction in the activity of the NE transporter (NET), slowing the rate at which NE is cleared from the synaptic cleft is observed in the SHR at both 4 and 16 wk of age. NET activity is measured using a novel fluorescent assay in cultured neurons from the stellate ganglia. Desipramine (DMI) can block all fluorescence increase confirming uptake specificity to NET [from Shanks et al. (101)]. D: heart rate response to stimulation of the right stellate ganglia in isolated atrial preparations is significantly greater in the SHR compared with age matched WKY at both 16 wk (1–7 Hz) and 4 wk of age (5 and 7 Hz) [from Shanks et al. (103) and republished from Herring et al. (41) with permission from Elsevier].

Fig. 2.

Cardiac sympathovagal cross talk. Evidence for the release of the neuromodulators neuropeptide-Y (NPY) and galanin (GAL) from cardiac sympathetic nerves and their action on cardiac vagal function. A: after a period of prolonged (2 min), high-frequency (10 Hz) stimulation of the right stellate ganglion, both NPY and GAL release can be detected in the perfusate of an isolated atrial preparation (using ELISA) sampled at 5, 10, 15, and 20 min postsympathetic nerve stimulation (SNS) [republished from Herring et al. (39) with permission from Elsevier]. B: release of [³H]acetycholine (ACh) from isolated atria during stimulation at 5 Hz is also reduced in the presence of NPY [modified from Herring et al. (41) with permission from Elsevier] and GAL [modified from Herring et al. (39) with permission from Elsevier]. C: after a period of prolonged high-frequency stimulation of the right stellate ganglion in the presence of a β-blocker (10 μmol/l metoprolol), the ability of stimulation of the right vagus nerve (5 Hz) to reduce heart is also significantly impaired at 5, 10, 15, and 20 min post-SNS [modified from Herring et al. (39) with permission from Elsevier].

Fig. 3.

Sympathovascular cross talk during ST-elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (PPCI): a role of neuropeptide-Y (NPY)? A: schematic diagram of an epicardial coronary artery stent, inserted during emergency PPCI treatment of a STEMI. Once the occluded epicardial coronary artery (white arrow, bottom left) has been opened and stented (shown in the angiogram in the bottom right), blood flow is not always completely restored. High plasma levels of the vasoconstrictor NPY can be detected pre and post-PPCI and for up to 48 h in those patients where angiographic reflow is not restored. B: high plasma NPY levels are also associated with low coronary flow reserve (<1.5) and a high index of microcirculatory resistance (>33) post-STEMI. C: ST elevation on the electrocardiogram (shown in bottom) remains despite opening and stenting of the epicardial coronary artery in those patients with higher plasma NPY levels at all time points post-PPCI [republished from Cuculi et al. (22) with permission from BMJ Publishing Group].