Sympathoexcitation following intermittent hypoxia in rat is mediated by circulating angiotensin II acting at the carotid body and subfornical organ

Abstract

Circulating angiotensin II (Ang II) is vital for arterial pressure elevation following intermittent hypoxia in rats, although its importance in the induction of sympathetic changes is unclear. We tested the contribution of the renin-angiotensin system to the effects of acute intermittent hypoxia (AIH) in anaesthetized and ventilated rats. There was a 33.7 ± 2.9% increase in sympathetic nerve activity (SNA), while sympathetic chemoreflex sensitivity and central sympathetic-respiratory coupling increased by one-fold following AIH. The sympathetic effects of AIH were prevented by blocking angiotensin type 1 receptors with systemic losartan. Intermittent systemic injections of Ang II (Int.Ang II) elicited similar sympathetic responses to AIH. To identify the neural pathways responsible for the effects of AIH and Int.Ang II, we performed bilateral carotid body denervation, which reduced the increase in SNA by 56% and 45%, respectively. Conversely, pharmacological inhibition of the subfornical organ (SFO), an established target of circulating Ang II, reduced the increase in SNA following AIH and Int.Ang II by 65% and 59%, respectively, although it did not prevent the sensitization of the sympathetic peripheral chemoreflex, nor the increase in central sympathetic-respiratory coupling. Combined carotid body denervation and inhibition of the SFO eliminated the enhancement of SNA following AIH and Int.Ang II. Repeated systemic injections of phenylephrine caused an elevation in SNA similar to AIH, and this effect was prevented by a renin inhibitor, aliskiren. Our findings show that the sympathetic effects of AIH are the result of RAS-mediated activations of the carotid bodies and the SFO.

PACAP-PAC1 Receptor Activation Is Necessary for the Sympathetic Response to Acute Intermittent Hypoxia

“…This activity is dependent on TRPV1 and P2X receptors. Other long term effects of intermittent hypoxia appear to involve reactive oxygen species (Prabhakar et al, 2012), angiotensin (Kim et al, 2018), and serotonin (Ling et al, 2001) to name a few. Intermittent stimulation of the RVLM also causes a persistent sympathoexcitation (Kakall et al, 2018), but what has remained elusive is the identity of the final central output driving the increase in sympathetic activity.…”

Mouth breathing impairs the development of temporomandibular joint at a very early stage

“…Nasal obstruction and hypoxia are both stimuli for the growth and development of rats throughout the process. Moreover, prolonged hypoxia can cause significant pathological changes in organs such as the skull, eyes, kidney, cardiovascular system, and gastrointestinal tract (Damman, Bloks, & Daha, 2015; Jakus, Jakus, Aračić, Stipić, & Vilović, 2017; Kim, Fong, Pilowsky, & Abbott, 2018; Klemm, Hurst, & Dias Blak, 2019; Wang et al., 2013; Yuan et al., 2018). However, at the very early stage, hypoxia is not as significant in remodeling the condyles of rats as mouth breathing.…”

G-Protein-Coupled Receptor (GPCR) Signaling in the Carotid Body: Roles in Hypoxia and Cardiovascular and Respiratory Disease

“…Repetitive application of Ang II can also promote sensory long-term facilitation (sLTF) of chemoafferent nerve activity, an effect reliant on activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and ROS generation [ 89 ]. AT 1 -receptor signaling is also key to causing CB sensory long-term facilitation (sLTF) and persistent sympathoexcitation following acute intermittent hypoxia, in a protein kinase C (PKC), ROS-dependent manner [ 94 , 95 ]. Whether or not the response to prolonged Ang II desensitizes due to receptor phosphorylation, β-arrestin recruitment and internalization is yet to be studied in the CB.…”