Skeletal and respiratory muscle blood flow redistribution during submaximal exercise in pulmonary hypertensive rats

Pulmonary hypertension (PH) is a chronic, progressive disease characterized by pulmonary vascular remodelling, dyspnoea and exercise intolerance. Key facets of dyspnoea and exercise intolerance include skeletal and respiratory muscle contractile and metabolic disturbances; however, muscle perfusion during exercise has not been investigated. We hypothesized that diaphragm blood flow ( <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:semantics><mml:mover><mml:mi>Q</mml:mi> <mml:mo>̇</mml:mo></mml:mover> <mml:annotation>$\dot{Q}$</mml:annotation></mml:semantics> </mml:math> ) would be increased and locomotory muscle <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:semantics><mml:mover><mml:mi>Q</mml:mi> <mml:mo>̇</mml:mo></mml:mover> <mml:annotation>$\dot{Q}$</mml:annotation></mml:semantics> </mml:math> would be decreased during submaximal treadmill running in PH rats compared to healthy controls. Female Sprague-Dawley rats were injected (i.p.) with monocrotaline to induce PH (n = 16), or a vehicle control (n = 15). Disease progression was monitored via echocardiography. When moderate disease severity was confirmed, maximal oxygen uptake ( <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:semantics> <mml:msub><mml:mover><mml:mi>V</mml:mi> <mml:mo>̇</mml:mo></mml:mover> <mml:msub><mml:mi>O</mml:mi> <mml:msup><mml:mn>2</mml:mn> <mml:mi>max</mml:mi></mml:msup> </mml:msub> </mml:msub> <mml:annotation>${{\dot{V}}_{{{{\mathrm{O}}}_{{{2}^{{\mathrm{max}}}}}}}}$</mml:annotation></mml:semantics> </mml:math> ) tests were performed. Rats were given >24 h to recover, and then fluorescent microspheres were infused during treadmill running (20 m/min, 10% grade; ∼40-50% maximal speed attained during the <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:semantics> <mml:msub><mml:mover><mml:mi>V</mml:mi> <mml:mo>̇</mml:mo></mml:mover> <mml:msub><mml:mi>O</mml:mi> <mml:msup><mml:mn>2</mml:mn> <mml:mi>max</mml:mi></mml:msup> </mml:msub> </mml:msub> <mml:annotation>${{\dot{V}}_{{{{\mathrm{O}}}_{{{2}^{{\mathrm{max}}}}}}}}$</mml:annotation></mml:semantics> </mml:math> test) to determine tissue <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:semantics><mml:mover><mml:mi>Q</mml:mi> <mml:mo>̇</mml:mo></mml:mover> <mml:annotation>$\dot{Q}$</mml:annotation></mml:semantics> </mml:math> . In PH rats compared with healthy controls, <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:semantics> <mml:msub><mml:mover><mml:mi>V</mml:mi> <mml:mo>̇</mml:mo></mml:mover> <mml:msub><mml:mi>O</mml:mi> <mml:msup><mml:mn>2</mml:mn> <mml:mi>max</mml:mi></mml:msup> </mml:msub> </mml:msub> <mml:annotation>${{\dot{V}}_{{{{\mathrm{O}}}_{{{2}^{{\mathrm{max}}}}}}}}$</mml:annotation></mml:semantics> </mml:math> was lower (84 (7) vs. 67 (11) ml/min/kg; P < 0.001), exercising diaphragm <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:semantics><mml:mover><mml:mi>Q</mml:mi> <mml:mo>̇</mml:mo></mml:mover> <mml:annotation>$\dot{Q}$</mml:annotation></mml:semantics> </mml:math> was 35% higher and soleus <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:semantics><mml:mover><mml:mi>Q</mml:mi> <mml:mo>̇</mml:mo></mml:mover> <mml:annotation>$\dot{Q}$</mml:annotation></mml:semantics> </mml:math> was 28% lower. Diaphragm <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:semantics><mml:mover><mml:mi>Q</mml:mi> <mml:mo>̇</mml:mo></mml:mover> <mml:annotation>$\dot{Q}$</mml:annotation></mml:semantics> </mml:math> was negatively correlated with soleus <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:semantics><mml:mover><mml:mi>Q</mml:mi> <mml:mo>̇</mml:mo></mml:mover> <mml:annotation>$\dot{Q}$</mml:annotation></mml:semantics> </mml:math> and <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:semantics> <mml:msub><mml:mover><mml:mi>V</mml:mi> <mml:mo>̇</mml:mo></mml:mover> <mml:msub><mml:mi>O</mml:mi> <mml:msup><mml:mn>2</mml:mn> <mml:mi>max</mml:mi></mml:msup> </mml:msub> </mml:msub> <mml:annotation>${{\dot{V}}_{{{{\mathrm{O}}}_{{{2}^{{\mathrm{max}}}}}}}}$</mml:annotation></mml:semantics> </mml:math> in PH rats. Furthermore, there was regional <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:semantics><mml:mover><mml:mi>Q</mml:mi> <mml:mo>̇</mml:mo></mml:mover> <mml:annotation>$\dot{Q}$</mml:annotation></mml:semantics> </mml:math> redistribution in the diaphragm in PH compared to healthy rats, which may represent or underlie diaphragmatic weakness in PH. These findings suggest the presence of a pathological respiratory muscle blood flow steal phenomenon in PH and that this may contribute to the exercise intolerance reported in patients. KEY POINTS: Pulmonary hypertension (PH) impairs exercise tolerance, which is associated with skeletal and respiratory muscle dysfunction. Increased work of breathing in PH may augment diaphragm blood flow and lower locomotory muscle blood flow during exercise, hindering exercise tolerance. Our findings demonstrate that respiratory muscle blood flow is increased while the locomotory muscle is decreased in PH compared to healthy rats during exercise, suggesting that blood flow is preferentially redistributed to sustain ventilatory demand. Furthermore, blood flow is regionally redistributed within the diaphragm in PH, which may underlie diaphragm dysfunction. Greater respiratory muscle work at a given workload in PH commands higher respiratory muscle blood flow, impairing locomotory muscle oxygen delivery and compromising exercise tolerance, which may be improved by therapeutics which target the diaphragm vasculature.