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Potential Contribution of Carotid Body-Induced Sympathetic and Renin-Angiotensin System Overflow to Pulmonary Hypertension in Intermittent Hypoxia

  • Pulmonary Hypertension (JR Klinger, Section Editor)
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Abstract

Purpose of Review

Obstructive sleep apnea (OSA), featured by chronic intermittent hypoxia (CIH), is an independent risk for systemic hypertension (HTN) and is associated with pulmonary hypertension (PH). The precise mechanisms underlying pulmonary vascular remodeling and PH in OSA are not fully understood. However, it has been suggested that lung tissue hypoxia, oxidative stress, and pro-inflammatory mediators following CIH exposure may contribute to PH.

Recent Findings

New evidences obtained in preclinical OSA models support that an enhanced carotid body (CB) chemosensory reactiveness to oxygen elicits sympathetic and renin-angiotensin system (RAS) overflow, which contributes to HTN. Moreover, the ablation of the CBs abolished the sympathetic hyperactivity and HTN in rodents exposed to CIH. Accordingly, it is plausible that the enhanced CB chemosensory reactivity may contribute to the pulmonary vascular remodeling and PH through the overactivation of the sympathetic-RAS axis. This hypothesis is supported by the facts that (i) CB stimulation increases pulmonary arterial pressure, (ii) denervation of sympathetic fibers in pulmonary arteries reduces pulmonary remodeling and pulmonary arterial hypertension (PAH) in humans, and (iii) administration of angiotensin-converting enzyme (ACE) or blockers of Ang II type 1 receptor (ATR1) ameliorates pulmonary remodeling and PH in animal models.

Summary

In this review, we will discuss the supporting evidence for a plausible contribution of the CB-induced sympathetic-RAS axis overflow on pulmonary vascular remodeling and PH induced by CIH, the main characteristic of OSA.

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Abbreviations

ACE:

Angiotensin-converting enzyme

AHI:

Apnea/hypopnea index

Ang II:

Angiotensin II

ATR1:

Angiotensin II receptor type 1

ATR2:

Angiotensin II receptor type 2

BP:

Arterial blood pressure

BRS:

Baroreceptor reflex sensitivity

CB:

Carotid body

CIH:

Chronic intermittent hypoxia

CPAP:

Continuous positive airway pressure

CSN:

Carotid sinus nerve

CVO:

Circumventricular organs

ET-1:

Endothelin-1

ETB:

Endothelin type B receptor

HTN:

Systemic hypertension

HIFs:

Hypoxia-induced factors

IL-6:

Interleukin 6

IL-1β:

Interleukin 1β

ICAM:

Intercellular adhesion molecule 1

MnSOD:

Manganese-dependent superoxide dismutase

MCP-1:

Monocyte chemoattractant protein-1

MSNA:

Muscle sympathetic nerve activity

NA:

Nucleus ambiguous

NF-kB:

Transcription nuclear factor κB

NTS:

Nucleus of the tractus solitarious

NADPH:

Nicotinamide adenine dinucleotide phosphate

NOX2:

NADPH oxidase 2

NOX4:

NADPH oxidase 4

3-NT:

3-Nitrotyrosine

OSA:

Obstructive sleep apnea

PASMC:

Pulmonary arterial smooth muscle cells

PAH:

Pulmonary arterial hypertension

PH:

Pulmonary hypertension

PVN:

Paraventricular nucleus

RAS:

Renin-angiotensin system

ROS:

Reactive oxygen species

RVSP:

Right ventricular systolic pressure

RVH:

Right ventricular hypertrophy

RVLM:

Rostral ventrolateral medulla

SFO:

Subfornical organ

SHR:

Spontaneous hypertensive rats

TNF-α:

Tumor necrosis factor

VCAM:

Vascular cell adhesion molecule

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Funding

This work was supported by grant 1150040 from the National Fund for Scientific and Technological Development of Chile (FONDECYT).

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  1. Laboratorio de Neurobiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Alameda 340, Santiago, Chile

    Rodrigo Iturriaga & Sebastian Castillo-Galán

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  1. Rodrigo Iturriaga
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Correspondence to Rodrigo Iturriaga.

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Iturriaga, R., Castillo-Galán, S. Potential Contribution of Carotid Body-Induced Sympathetic and Renin-Angiotensin System Overflow to Pulmonary Hypertension in Intermittent Hypoxia. Curr Hypertens Rep 21, 89 (2019). https://doi.org/10.1007/s11906-019-0995-y

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