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Background: Activation of neurohormonal systems contributes to the progression of heart failure (HF). The mechanism(s) whereby these systems become activated is(are) not fully explained. We determined whether vagal cardiopulmonary baroreflex control of renal sympathetic nerve activity is abnormal in dogs with left ventricular (LV) dysfunction in the absence of clinical HF, and the relationship of abnormalities in baroreflexes to the development of the neurohumoral excitatory state., Methods: LV end-systolic and end-diastolic dimensions (echocardiography), arterial baroreflex sensitivity (slope of ΔRR/Δsystolic BP during phenylephrine or nitroglycerin bolus), and neurohumoral profiles (plasma norepinephrine, renin activity, and arginine vasopressin) were measured serially in conscious dogs (n=24) with progressive LV dysfunction due to rapid ventricular pacing. LV dimensions were used to define groups with mild, moderate, and marked LV dilatation (LVD; increase in LV end-diastolic volume <15%, 15-30%, and >30% of control, respectively). Changes in renal nerve activity (RNA) were recorded in response to increases in pulmonary capillary wedge pressure (PCWP) induced by volume infusion in anesthetized, sinoaortic-denervated dogs., Results: Cardiopulmonary baroreflex sensitivity (slope of %ΔRNA/ΔPCWP) for mild LVD (-17.8%/mmHg) was the same as controls (-17.7%/mmHg). However, the slopes of moderate (-5.8%/mmHg) and severe LVD (-1.9%/mmHg) were decreased significantly compared with controls (P < .05). Arterial baroreflex sensitivity was preserved at all stages of LVD. Plasma norepinephrine, renin activity, and arginine vasopressin remained unchanged after 4, 7, and 11 days of pacing., Conclusions: Vagal cardiopulmonary baroreflex control of renal sympathetic nerve activity is blunted early in the development of LVD. These abnormalities precede neurohumoral excitation and abnormal arterial baroreflexes and become apparent when LV end-diastolic volume starts to increase., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Parasympathetic control of the heart via the vagus nerve is the primary mechanism that regulates beat-to-beat control of heart rate. Additionally, the vagus nerve exerts significant effects at the AV node, as well as effects on both atrial and ventricular myocardium. Vagal control is abnormal in heart failure, occurring at early stages of left ventricular dysfunction, and this reduced vagal function is associated with worse outcomes in patients following myocardial infarction and with heart failure. While central control mechanisms are abnormal, one of the primary sites of attenuated vagal control is at the level of the parasympathetic ganglion. It remains to be seen whether or not preventing or treating abnormal vagal control of the heart improves prognosis.

Nicotinic acetylcholine receptors (nAChR) are assembled from a pool of nine alpha-subunits and three beta-subunits into functional pentamers in peripheral autonomic neurons. The contribution of different subunits to native, physiologically important nAChR for synaptic transmission in autonomic ganglia is unclear. Here, we examined the importance of the alpha7-subunit for parasympathetic innervation of the heart. Normal (C57BL/6J), alpha7-deficient (Chrna7), and wild-type littermate mice were implanted with telemetry devices, and, under conscious, unsedated conditions, ECG recordings were obtained at baseline and after atropine, propranolol, and hexamethonium bromide administration. Spectral analysis of heart rate variability [power spectral analysis (PSA)] was performed for the evaluation of resting autonomic tone to the heart. At the completion of conscious studies, animals were anesthetized and underwent electrical stimulation of the vagus nerve (VS) while R-R intervals were recorded. Heart rate at baseline and after atropine, propranolol, or hexamethonium was similar in all three groups of animals. PSA curves were similar between normal, wild-type, and Chrna7 mice. VS showed no difference between control and Chrna7 mice throughout the range of stimulation (5-20 Hz). Mice deficient in the alpha7-nAChR subunit do not display differences in resting autonomic tone to the heart at baseline or under conditions of single and combined autonomic blockade. VS showed no difference in heart rate responses between normal and alpha7-deficient mice. These data support previous findings in vitro and highlight the important differences in function between nicotinic receptor subtypes because alpha3-deficient mice display major autonomic dysfunction. We conclude that the alpha7-subunit does not contribute critically to resting parasympathetic control of the heart.

Decreased synaptic transmission in parasympathetic ganglia contributes to abnormal parasympathetic function in heart failure (HF). Because nicotinic ACh receptors (nAChR) mediate synaptic transmission at the ganglion and upregulate in response to chronic exposure to agonist in vitro, we tested the hypothesis that repeated exposures of ganglionic neurons to a nAChR agonist can prevent a loss of parasympathetic control in HF. Two sets of experiments were performed. In set 1, unpaced control dogs and dogs undergoing pacing-induced HF were treated with a repeated intravenous nicotinic agonist during the development of HF. Under conditions of sympathetic blockade, R-R responses to a bolus injection of 200 microg 1,1-dimethyl-4-phenylpiperazinium iodide (DMPP; nicotinic agonist) were found to be increased five times over the untreated group after 6 wk. In experimental set 2, dogs treated with weekly DMPP injections and in HF were anesthetized and underwent electrical stimulation of the right vagus nerve, which showed sinus cycle length responses >10 times that of controls (P < 0.05). Complete ganglionic blockade with hexamethonium abolished all responses, confirming that synaptic transmission was mediated entirely by nAChRs in both controls and HF. Despite decreased ganglionic function leading to reduced parasympathetic control of the heart in HF, repeated exposure with a nicotinic agonist during the development of HF results in not only preserved but also supranormal effects of parasympathetic stimulation on the sinus node.