Mechanisms of carotid body chemoreflex dysfunction during heart failure

Schultz, Harold D.; Marcus, Noah J.; Rio, Rodrigo Del

doi:10.1113/expphysiol.2014.079517

Cited by 61 publications

(60 citation statements)

References 32 publications

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“…This finding raises the possibility that ROS-induced endothelial dysfunction could, via “stagnant hypoxia”, affect carotid chemosensitivity apart from the direct effects of ROS on glomus cell function. An analogous effect has been observed in an experimental model of heart failure (see Schultz (Schultz et al, 2015). Our laboratory has previously shown, in cerebral and skeletal muscle resistance arteries, that CIH impairs endothelium-dependent hypoxic vasodilation (Phillips et al, 2004).…”

Section: Discussionsupporting

confidence: 71%

Oxidative stress augments chemoreflex sensitivity in rats exposed to chronic intermittent hypoxia

Morgan

Bates

Río

et al. 2016

Respiratory Physiology & Neurobiology

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Chronic exposure to intermittent hypoxia (CIH) elicits plasticity of the carotid sinus and phrenic nerves via reactive oxygen species (ROS). To determine whether CIH-induced alterations in ventilation, metabolism, and heart rate are also dependent on ROS, we measured responses to acute hypoxia in conscious rats after 14 and 21 d of either CIH or normoxia (NORM), with or without concomitant administration of allopurinol (xanthine oxidase inhibitor), combined allopurinol plus losartan (angiotensin II type 1 receptor antagonist), or apocynin (NADPH oxidase inhibitor). Carotid body nitrotyrosine production was measured by immunohistochemistry. CIH produced an increase in the ventilatory response to acute hypoxia that was virtually eliminated by all three pharmacologic interventions. CIH caused a robust increase in carotid body nitrotyrosine production that was greatly attenuated by allopurinol plus losartan and by apocynin but unaffected by allopurinol. CIH caused a decrease in metabolic rate and a reduction in hypoxic bradycardia. Both of these effects were prevented by allopurinol, allopurinol plus losartan, and apocynin.

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Section: Discussionsupporting

confidence: 71%

Oxidative stress augments chemoreflex sensitivity in rats exposed to chronic intermittent hypoxia

Morgan

Bates

Río

et al. 2016

Respiratory Physiology & Neurobiology

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“…In turn, chemoreflex dysfunction contributes to sympathetic hyperactivity, hyperventilation and the associated breathing instability typically found in HFrEF subjects (Schultz et al, 2015). Accordingly, Di Vanna and collaborators demonstrated that the activity of muscle sympathetic nerves in response to central and peripheral chemoreceptor stimulation is exacerbated in patients with HFrEF (Di Vanna et al, 2007) (Table 1).…”

Section: Hyperadrenergic State In Heart Failurementioning

confidence: 99%

“…Oxidative stress is known to activate the carotid body in HF (Schultz et al, 2015). We now know that both circulating and local tissue levels of the pro-oxidant angiotensin II peptide are elevated in HF (Li et al, 2006).…”

Section: Hyperadrenergic State In Heart Failurementioning

confidence: 99%

Contribution of Autonomic Reflexes to the Hyperadrenergic State in Heart Failure

et al. 2017

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Heart failure (HF) is a complex syndrome representing the clinical endpoint of many cardiovascular diseases of different etiology. Given its prevalence, incidence and social impact, a better understanding of HF pathophysiology is paramount to implement more effective anti-HF therapies. Based on left ventricle (LV) performance, HF is currently classified as follows: (1) with reduced ejection fraction (HFrEF); (2) with mid-range EF (HFmrEF); and (3) with preserved EF (HFpEF). A central tenet of HFrEF pathophysiology is adrenergic hyperactivity, featuring increased sympathetic nerve discharge and a progressive loss of rhythmical sympathetic oscillations. The role of reflex mechanisms in sustaining adrenergic abnormalities during HFrEF is increasingly well appreciated and delineated. However, the same cannot be said for patients affected by HFpEF or HFmrEF, whom also present with autonomic dysfunction. Neural mechanisms of cardiovascular regulation act as “controller units,” detecting and adjusting for changes in arterial blood pressure, blood volume, and arterial concentrations of oxygen, carbon dioxide and pH, as well as for humoral factors eventually released after myocardial (or other tissue) ischemia. They do so on a beat-to-beat basis. The central dynamic integration of all these afferent signals ensures homeostasis, at rest and during states of physiological or pathophysiological stress. Thus, the net result of information gathered by each controller unit is transmitted by the autonomic branch using two different codes: intensity and rhythm of sympathetic discharges. The main scope of the present article is to (i) review the key neural mechanisms involved in cardiovascular regulation; (ii) discuss how their dysfunction accounts for the hyperadrenergic state present in certain forms of HF; and (iii) summarize how sympathetic efferent traffic reveal central integration among autonomic mechanisms under physiological and pathological conditions, with a special emphasis on pathophysiological characteristics of HF.

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“…Therefore, 5-HT and ET-1 may have a stronger effect on [Ca 2+ ] i in chronic hypoxia conditions and activate NSC to augment the chemosensitivity of glomus cells. Similar effects may occur in models of heart failure where the AngII and endothelin signaling is augmented, causing an enhanced CB chemoreflex (Schultz et al, 2015). …”

Section: Discussionmentioning

confidence: 74%

Voltage- and receptor-mediated activation of a non-selective cation channel in rat carotid body glomus cells

Wang

Hogan

Kim

2017

Respiratory Physiology & Neurobiology

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Recent study showed that hypoxia activates a Ca2+-sensitive, Na+-permeable non-selective cation channel (NSC) in carotid body glomus cells. We studied the effects of mitochondrial inhibitors that increase Ca2+ influx via Ca2+ channel (Cav), and receptor agonists that release Ca2+ from endoplasmic reticulum (ER) on NSC. Mitochondrial inhibitors (NaCN, FCCP, H2S, NO) elevated [Ca2+]i and activated NSC. Angiotensin II and acetylcholine that elevate [Ca2+]i via the Gq-IP3 pathway activated NSC. However, endothelin-1 (Gq) and 5-HT (Gq) showed little or no effect on [Ca2+]i and did not activate NSC. Adenosine (Gs) caused a weak rise in [Ca2+]i but did not activate NSC. Dopamine (Gs) and γ-aminobytyric acid (Gi) were ineffective in raising [Ca2+]i and failed to activate NSC. Store-operated Ca2+ entry (SOCE) produced by depletion of Ca2+ stores with cyclopiazonic acid activated NSC. Our results show that Ca2+ entry via Cav, ER Ca2+ release and SOCE can activate NSC. Thus, NSC contributes to both voltage- and receptor-mediated excitation of glomus cells.

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Mechanisms of carotid body chemoreflex dysfunction during heart failure

Cited by 61 publications

References 32 publications

Oxidative stress augments chemoreflex sensitivity in rats exposed to chronic intermittent hypoxia

Oxidative stress augments chemoreflex sensitivity in rats exposed to chronic intermittent hypoxia

Contribution of Autonomic Reflexes to the Hyperadrenergic State in Heart Failure

Voltage- and receptor-mediated activation of a non-selective cation channel in rat carotid body glomus cells

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