Carotid body and subfornical organ AT1R‐mediated sympathoexcitation following repetitive hypoxia requires intrarenal ischemia in rats

Abstract

Recurrent hypoxemia induced by acute intermittent hypoxia (AIH) elevates sympathetic nerve activity (SNA); a pre‐clinical neural manifestation before the onset of resistant hypertension. Blocking angiotensin type 1 receptors (AT1R) in the rodent brain prevents arterial pressure (AP) elevation after chronic intermittent hypoxia (CIH), but becomes ineffective once the vascular pathology establishes. Hence, understanding how angiotensin II (AngII) recruits neural circuits for enhancing sympathetic tone is important. We produce AIH‐induced elevations in SNA and chemoreceptor‐mediated reflex sensitivity, while AP remains unchanged (i.e. a ‘pre‐hypertensive’ phase). The sympathetic effects of AIH were alleviated by pre‐treating animals with losartan that target AT1R. We demonstrate that CB denervation reduces the elevated sympathetic tone by 56% following AIH, whereas subfornical organ (SFO) inhibition by GABAA receptor agonist, isoguvacine, reduces the effect by 65%. Combined CB ablation and SFO inhibition abrogates the enhanced SNA after AIH. Extracellular single unit recording demonstrates that 43% of SFO neurons (26/60) recorded increases firing rate in response to AngII and hypoxia. Type I SFO neurons (n=16) immediately responds to both AngII and hypoxia upon the onset of the stimulus. Type II SFO neurons (n=10) produce a delayed response that manifests 228 ± 22 and 233 ± 23 secs after AngII and hypoxia respectively. Type III neurons (n=9) respond specifically to hypoxia, while type IV (n=16) neurons are unresponsive to both stimuli, and type V (n=9) neurons display attenuated activity to both AngII and hypoxia. To confirm that peripheral RAS activity increases during hypoxia, we hypothesised that renal perfusion is reduced during hypoxia that leads to an elevation in plasma renin. We use laser speckle imaging and doppler flowmetry to demonstrate that hypoxia causes intense renal ischemia. A comparable ischemic effect can be pharmacologically induced by α1‐adrenergic receptor‐mediated vasoconstriction in the kidney using phenylephrine. Intermittent injections of phenylephrine augments SNA, and this effect is abolished by pre‐treating the animals with a renin‐inhibitor, aliskiren. To confirm that renal ischemia is the pathophysiological cause for evoking increased SNA in AIH, aliskiren was injected prior to AIH and this prevented the increase in SNA. Together, our results suggest that renal ischemia induced by hypoxia leads to an activation of AT1Rs in the CB/SFO pathways to subsequently enhance sympathetic efferent activity. It appears that the kidney‐brain connection is crucial for the induction of increased SNA during AIH, and possibly for the generation of elevated AP in CIH.Support or Funding InformationNational Health and Medical Research Council of Australia Fellowship [PMP; 1024489], [NHMRC Project Grants: 1065485, 1082215] and the Heart Research Institute. S.B.G.A. is supported by the National Health and Medical Research Council of Australia (Grant GNT1052674) and the University of Sydney. S.J.K. is supported by an Australian Postgraduate Award [APA SC0042] from the University of Sydney and a Heart Research Institute scholarship.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.