Molecular Mechanisms of Dysautonomia During Heart Failure. Focus On “Heart Failure-Induced Changes of Voltage-Gated CA2+ Channels and Cell Excitability in Rat Cardiac Postganglionic Neurons”

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baroreceptive input, baroreceptor drive, respiratory motor control, nitroprusside

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We tested the hypothesis, motivated in part by a coordinated computational cough network model, that alterations of mean systemic arterial blood pressure (BP) influence the excitability and motor pattern of cough. Model simulations predicted suppression of coughing by stimulation of arterial baroreceptors. In vivo experiments were conducted on anesthetized spontaneously breathing cats. Cough was elicited by mechanical stimulation of the intrathoracic airways. Electromyograms (EMG) of inspiratory parasternal, expiratory abdominal, laryngeal posterior cricoarytenoid (PCA), and thyroarytenoid muscles along with esophageal pressure (EP) and BP were recorded. Transiently elevated BP significantly reduced cough number, cough-related inspiratory, and expiratory amplitudes of EP, peak parasternal and abdominal EMG, and maximum of PCA EMG during the expulsive phase of cough, and prolonged the cough inspiratory and expiratory phases as well as cough cycle duration compared with control coughs. Latencies from the beginning of stimulation to the onset of cough-related diaphragm and abdominal activities were increased. Increases in BP also elicited bradycardia and isocapnic bradypnea. Reductions in BP increased cough number; elevated inspiratory EP amplitude and parasternal, abdominal, and inspiratory PCA EMG amplitudes; decreased total cough cycle duration; shortened the durations of the cough expiratory phase and cough-related abdominal discharge; and shortened cough latency compared with control coughs. Reduced BP also produced tachycardia, tachypnea, and hypocapnic hyperventilation. These effects of BP on coughing likely originate from interactions between barosensitive and respiratory brainstem neuronal networks, particularly by modulation of respiratory neurons within multiple respiration/cough-related brainstem areas by baroreceptor input.

cough is initiated by stimulation of mechano- and chemosensitive sensory endings of cough receptors and also may be influenced by a cough-related subgroup of rapidly adapting “irritant” receptors and C fibers within tracheobronchial and laryngeal mucosa (23, 24, 148). However, the pattern of coughing (the number of coughs and their strength and timing; Refs. 67, 149) is profoundly affected by other peripheral and central afferent inputs (17, 49), particularly during pathological processes such as infection, inflammation, and allergic reactions (28, 118). Stimuli within the larynx (141) and nose (109, 110) enhance cough induced from the tracheal-bronchial region. Stimulation of cardiac receptors (140), chemoreceptors (138), and pulmonary as well as bronchial C fibers in anesthetized animals (139) reduces coughing. Afferent signaling from muscles, joints, skin, and possibly the viscera may also alter the expression of cough (66, 67, 118).

Coughing induces vigorous intrathoracic and intra-abdominal pressure oscillations and changes of sympathetic and parasympathetic nervous activities (27, 67, 145) that significantly affect the cardiovascular system including dynamic changes of blood pressure (BP) and regional blood flow (60, 67). Coughing is associated with peaks in systemic arterial blood pressure during systole and cough expulsions followed by post-tussive hypotension (unpublished observations; Refs. 67, 127). This relationship involves central reflex mechanisms (27, 127, 145); it is observed also in neuromuscular-blocked decerebrate animals (unpublished observations). However, very little is known about the effects of systemic BP and baroreceptor afferent input on the excitability and patterning of cough. Available data were mostly obtained with stimulation of multiple sensory afferents resulting in expression of the chemoreflex (96, 140), and the results suggested either no changes (139, 140) or only transient alterations of the cough reflex (96) during reduced BP.

The respiratory neuronal network is a crucial component in the generation of cough and the transmission of its central motor pattern to the respiratory muscles (54, 119, 123125). There is a close relationship between the control of the respiratory and cardiovascular systems. It is well established that an increase in blood pressure resulting in the baroreflex (83, 98, 135) can prolong expiration, significantly reduce breathing frequency, and reduce inspiratory drive by an action on selected populations of brainstem respiratory neurons (2, 35, 72, 76, 107) sensitive to afferent impulses originating from baroreceptors. Thus baroreceptor reflex feedback mechanisms that modulate breathing may also limit cough intensity and/or number. Hence, changes in cough excitability and/or the pattern of coughing due to the stimulation of baroreceptors (and alternatively by their unloading) are consistent with the multifunctional role of the respiratory pattern generator in controlling cough and breathing.

Motivated by this consideration, we undertook a computational modeling study of the respiratory/cough neuronal network and in vivo experiments to test the role of blood pressure changes in modulation of cough motor pattern. The study also allowed us to address a more general hypothesis that this model could be used to predict, not just motor patterns and neuronal responses of the brainstem respiratory network, but regulation of this system as well. Models simulating concurrent cough and baroreceptor perturbations of breathing predicted that an increase of mean systemic arterial BP would alter the motor pattern and excitability of the cough reflex.

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Citation / Publisher Attribution

Journal of Applied Physiology, v. 111, issue 3, p. 861-873