Acute Intermittent Hypoxia Induces Chemoreflex-Independent Sympathetic Plasticity and Improves Cardiovascular Function in a Rodent Model of Spinal Cord Injury
Bibliographic record
Abstract
Background: Cardiovascular complications are one of the leading causes of morbidity and mortality in people with spinal cord injury (SCI). Activation of spinal sympathetic circuitry is critical to offset cardiovascular dysregulation and disease in those with high-level SCI. Acute intermittent hypoxia (AIH) elicits plasticity (i.e., a gradual increase in nerve activity post-AIH exposure) in phrenic and non-phrenic spinal motor circuitry and improves motor function — yet the cardiovascular benefits of AIH after SCI are largely unexplored. Aims: Determine mechanisms (Aim 1) and potential benefits (Aim 2) of AIH-induced sympathetic plasticity post-SCI. Hypothesis: We hypothesized that AIH elicits chemoreflex-dependent sympathetic plasticity and improves cardiovascular function in rats with SCI. Methods: For Aim 1, 40 adult (10-12 weeks) male Wistar rats were subjected to a spinal cord contusion injury (T3, 300 kdyn) and randomly assigned to 5 groups of 8 each: AIH alone, AIH after carotid body denervation (CBX, no peripheral chemoreflex), time control with no intervention (TC), simulated hemorrhage (to mimic AIH-induced hypotension), and AIH plus phenylephrine (to prevent hypotension during hypoxic episodes). Two weeks post-SCI recovery, rats were anesthetized with urethane (~2.1g.kg −1 i.v.) and underwent femoral venous and arterial catheterizations to monitor blood pressure (BP), sample arterial blood gases, and enable intravenous fluid and drug delivery. Additionally, splanchnic sympathetic nerve activity (sSNA) was recorded using a suction electrode at baseline and for up to 90-min following each experimental paradigm. AIH consisted of 10 x 1 min episodes of F i O 2 = 0.1 (balanced N 2 ) interspersed with 2 min of F i O 2 = 1. Hexamethonium bromide (30 mg.kg −1 ) was infused to subtract noise levels from each recording, after which rats were euthanized with chloral hydrate. For Aim 2, 19 additional rats were subjected to the same injury model and time post-injury and allocated to 2 groups: AIH ( n = 11) and TC ( n = 8). These rats were instrumented with left-ventricular (LV) and arterial catheters and assessed simultaneously for cardiac and peripheral hemodynamic function at baseline and 90-min post-AIH/TC. Results: Aim 1) When expressed as % change from baseline, sSNA increased at 90-min post-treatment in AIH (93±67%, P = 0.02) and CBX (193±182%, P < 0.001), but not TC rats (50±45%, P = 0.40). Preventing BP reduction during hypoxic episodes with i.v. phenylephrine blocked the increase in sSNA 90-min post-AIH (12±66%, P > 0.99). Mimicking the AIH-induced BP reduction with simulated hemorrhage (10 x 1-min BP reductions of ~20-25 mmHg equal to those during AIH, interspersed by 2-min of euvolemia), increased sSNA 90-min post-intervention (106±86%, P = 0.01). Aim 2) The changes in maximal LV pressure (AIH = 11±8 mmHg vs. TC = 2±5 mmHg, P = 0.05) and mean arterial pressure (AIH = 8±7 mmHg vs. TC = 0±4 mmHg, P = 0.05) were greater at 90-min post-AIH treatment. Conclusions: We conclude that AIH elicits sympathetic plasticity and improves cardiovascular function post-SCI. Since AIH-induced sympathetic plasticity remains in the presence of a bilateral CBX, is replicated by episodic simulated hemorrhage, and is blocked by phenylephrine, AIH-induced sympathetic plasticity is independent of carotid (peripheral) chemoreflex activation, and is closely linked to episodic hypotension. We suggest that AIH-induced sympathetic plasticity arises from episodic reductions in spinal/medullary cardiovascular centers blood flow (and oxygen delivery) post-SCI. International Spinal Research Trust and Natural Sciences, Engineering Research Council of Canada, International Collaboration on Repair Discoveries. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".