Heat Therapy Does Not Restore Functional Sympatholysis Impairments in HFpEF Rodents

Attenuation of sympathetic vasoconstriction during exercise (i.e., functional sympatholysis) plays a key role in the regulation of arterial blood pressure, peripheral O 2 delivery, and exercise tolerance. During skeletal muscle contractions, functional sympatholysis constrains the fall in interstitial oxygen pressures (PO 2 is) within the microcirculation. This is important because PO 2 is provides the sole driving force for oxygen diffusion into the myocyte (as per Fick’s law) thus supporting oxidative phosphorylation. In pathological conditions such as heart failure with preserved ejection fraction (HFpEF), impaired functional sympatholysis contributes to reduced exercise tolerance, making it a potential target for therapeutic intervention. Recent evidence indicates that repeated heat therapy in HFpEF rats promotes central and peripheral adaptations that impact positively muscle PO 2 is and exercise tolerance. However, it remains unclear whether heat therapy can ameliorate the impaired functional sympatholysis response in HFpEF rats. Purpose: To assess the effects of repeated heat therapy on functional sympatholysis (quantified via norepinephrine administration on resting and contracting skeletal muscle PO 2 is) in HFpEF rats. We hypothesized that the impaired functional sympatholysis response (i.e., blunted reductions in contracting muscle PO 2 is upon norepinephrine superfusion) in HFpEF rats would be ameliorated with heat therapy. Methods: PO 2 is was determined via phosphorescence quenching in the exposed spinotrapezius of anesthetized healthy (Sprague-Dawley, n=14) and HFpEF rats (Zucker fatty and spontaneously hypertensive rats, ZSF1, n=20) at rest and during electrically-induced submaximal muscle contractions (0.5 Hz, 3-6 V) for 6 minutes in response to norepinephrine (5 x 10 -4 M). Healthy rats served as a proof of concept for impaired functional sympatholysis in HFpEF rats and were not subjected to heat therapy. HFpEF rats underwent either 8 weeks (6 days/week) of heat therapy (HT, 39°C; n=10) or control (CON; 22°C; n= 10) treatment. The tail (caudal) artery was cannulated for measurements of mean arterial pressure (MAP). Functional sympatholysis was determined as the difference between the norepinephrine-induced changes in PO 2 is at rest and during the contraction steady-state (i.e., 2 min following the onset of muscle contractions) using the %PO 2 is fall with norepinephrine normalized to MAP (ΔPO 2 is/MAP; %/mmHg). Results: Consistent with our hypothesis, functional sympatholysis was impaired in HFpEF rats (rest:-0.85±0.04, contractions:-0.93±0.02) compared to healthy rats (rest:-0.49±0.06, contractions:-0.24±0.04, p<0.05). However, contrary to our hypothesis, heat therapy did not improve functional sympatholysis in HFpEF (rest:-0.61±0.08, contractions:-0.85±0.02, p>0.05). Moreover, while HFpEF rats showed an exacerbated noradrenergic response at rest compared to healthy rats (-0.85±0.04 vs. -0.49±0.06, respectively, p<0.05), heat therapy in HFpEF restored those responses (-0.61±0.08, p>0.05 vs. healthy). Conclusions: Functional sympatholysis is impaired in a preclinical HFpEF model. Although heat therapy did not improve functional sympatholysis in HFpEF rats, it restored the noradrenergic response in resting skeletal muscle. Partially Funded by Purdue University This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.