Noradrenergic regulation of skeletal muscle oxygen pressures: Impact of heart failure with preserved ejection fraction and heat therapy

Attenuation of sympathetic vasoconstriction during exercise (functional sympatholysis) contributes to skeletal muscle oxygen delivery-utilization matching. However, the extent to which muscle contractions impact noradrenergic regulation of interstitial oxygen pressures ( <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:semantics> <mml:msub><mml:msub><mml:mi>P</mml:mi> <mml:msub><mml:mi>O</mml:mi> <mml:mn>2</mml:mn></mml:msub> </mml:msub> <mml:mi>is</mml:mi></mml:msub> <mml:annotation>${P_{{{\mathrm{O}}_2}}}_{{\mathrm{is}}}$</mml:annotation></mml:semantics> </mml:math> ; the driving force for blood-myocyte oxygen flux) is unknown. We tested the hypotheses that (1) muscle contractions would attenuate the noradrenaline-induced reduction in muscle <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:semantics> <mml:msub><mml:msub><mml:mi>P</mml:mi> <mml:msub><mml:mi>O</mml:mi> <mml:mn>2</mml:mn></mml:msub> </mml:msub> <mml:mi>is</mml:mi></mml:msub> <mml:annotation>${P_{{{\mathrm{O}}_2}}}_{{\mathrm{is}}}$</mml:annotation></mml:semantics> </mml:math> compared to rest (thus indicating functional sympatholysis) in healthy rats, and (2) functional sympatholysis would be impaired in rats with heart failure with preserved ejection fraction (HFpEF) but ameliorated with heat therapy. Skeletal muscle <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:semantics> <mml:msub><mml:msub><mml:mi>P</mml:mi> <mml:msub><mml:mi>O</mml:mi> <mml:mn>2</mml:mn></mml:msub> </mml:msub> <mml:mi>is</mml:mi></mml:msub> <mml:annotation>${P_{{{\mathrm{O}}_2}}}_{{\mathrm{is}}}$</mml:annotation></mml:semantics> </mml:math> was determined via phosphorescence quenching in anaesthetized healthy (Sprague-Dawley, n = 14) and HFpEF rats (obese ZSF1, n = 20) at rest and during contractions following noradrenaline superfusion (5 × 10^-4 M). HFpEF rats underwent 8 weeks of heat therapy (HEAT, n = 10) or control treatment (CON; n = 10). Functional sympatholysis was evaluated based on the noradrenaline-induced changes in <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:semantics> <mml:msub><mml:msub><mml:mi>P</mml:mi> <mml:msub><mml:mi>O</mml:mi> <mml:mn>2</mml:mn></mml:msub> </mml:msub> <mml:mi>is</mml:mi></mml:msub> <mml:annotation>${P_{{{\mathrm{O}}_2}}}_{{\mathrm{is}}}$</mml:annotation></mml:semantics> </mml:math> at rest and during contractions normalized to mean arterial pressure (Δ <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:semantics> <mml:msub><mml:msub><mml:mi>P</mml:mi> <mml:msub><mml:mi>O</mml:mi> <mml:mn>2</mml:mn></mml:msub> </mml:msub> <mml:mi>is</mml:mi></mml:msub> <mml:annotation>${P_{{{\mathrm{O}}_2}}}_{{\mathrm{is}}}$</mml:annotation></mml:semantics> </mml:math> /MAP; %/mmHg). Consistent with our hypothesis, muscle contractions attenuated the noradrenaline-evoked <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:semantics> <mml:msub><mml:msub><mml:mi>P</mml:mi> <mml:msub><mml:mi>O</mml:mi> <mml:mn>2</mml:mn></mml:msub> </mml:msub> <mml:mi>is</mml:mi></mml:msub> <mml:annotation>${P_{{{\mathrm{O}}_2}}}_{{\mathrm{is}}}$</mml:annotation></mml:semantics> </mml:math> reductions in healthy rats (rest: -0.50 ± 0.23, contractions: -0.25 ± 0.16; P < 0.05). Compared to healthy rats, the noradrenergic response at rest was exacerbated in HFpEF-CON (-0.85 ± 0.13; P < 0.05) but restored in HFpEF-HEAT (-0.61 ± 0.25; P > 0.05). During contractions, the noradrenergic response was not different between HFpEF-CON and HFpEF-HEAT (-0.94 ± 0.07 and -0.86 ± 0.09, respectively; P > 0.05). Moreover, the magnitude of sympatholysis was lower in both HFpEF-CON and HFpEF-HEAT compared to healthy. Taken together, these results indicate that heat therapy failed to improve functional sympatholysis in HFpEF rats but restored the noradrenergic response in resting skeletal muscle.