Dual ETA‐ETB receptor antagonism improves metabolic syndrome‐induced heart failure with preserved ejection fraction

Figures

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  FIGURE 1. Blood pressure and heart rate. Twenty‐four hour measurements of diastolic and systolic blood pressure (upper panel) as well as heart rate (lower panel) assessed by telemetry in conscious untreated Zucker fa/fa rats (open circles), and in Zucker fa/fa macitentan‐treated rats before (Day 0) and after 1, 7 and 90 days macitentan administration (black circles). Black bars indicate lights off. Each point is the mean of 6 animals.

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  FIGURE 2. Right ventricular function. Upper panel. Right ventricular (RV) ejection fraction (EF), RV end‐diastolic volume (RV EDV), RV end‐systolic volume (RV ESV) and cardiac output obtained by MRI in 13 week‐old lean (n = 11; white bars) and Zucker fa/fa rats either untreated (n = 14; grey bars) or treated for 7 days with macitentan (n = 14; down‐hatched bars). Lower panel. RV EF, RV EDV, RV ESV and cardiac output obtained by MRI in 24 week‐old lean (n = 8; white bars), and Zucker fa/fa rats either untreated (n = 10; grey bars) or treated for 90 days with macitentan (n = 10; down‐hatched bars). *: P < 0.05 versus lean; †: P < 0.05 versus untreated Zucker fa/fa.

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  FIGURE 3. Right ventricular haemodynamics. Right ventricular (RV) end‐systolic pressure (ESP), RV end‐diastolic pressure (EDP), as well as RV dP/dtmax and dP/dtmin and RV relaxation constant Tau determined in 24 week‐old lean rats (n = 9; white bars), and Zucker fa/fa rats either untreated (n = 9; grey bars) or treated for 90 days with macitentan (n = 7; down‐hatched bars). *: P < 0.05 versus lean; †: P < 0.05 versus untreated Zucker fa/fa.

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  FIGURE 4. Left ventricular function analysis by MRI. Upper panel. Left ventricular (LV) ejection fraction (EF), LV end‐diastolic volume (LV EDV), LV end‐systolic volume (LV ESV) and cardiac output obtained by MRI in 13 week‐old lean (n = 9; white bars) and Zucker fa/fa rats either untreated (n = 11; grey bars) or treated for 7 days with macitentan (n = 13; down‐hatched bars).Lower panel. LV EF, LV EDV, LV ESV and cardiac output obtained by MRI in 24 week‐old lean (n = 9; white bars) and Zucker fa/fa rats either untreated (n = 11; grey bars) or treated for 90 days with macitentan (n = 12; down‐hatched bars).*: P < 0.05 versus lean; †: P < 0.05 versus untreated Zucker fa/fa.

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  FIGURE 5. Left ventricular haemodynamics. Upper panel. Left ventricular (LV) end‐systolic pressure (ESP), LV end‐systolic pressure‐volume relationship (ESPVR), LV end‐diastolic pressure (EDP) and LV end‐diastolic pressure‐volume relationship (EDPVR) determined in 13 week‐old lean rats (n = 6; white bars) and Zucker fa/fa rats either untreated (n = 9; grey bars) or treated for 7 days with macitentan (n = 9; down‐hatched bars). Lower panel LV ESP, LV ESPVR, LV EDP and LV EDPVR determined in 24 week‐old lean rats (n = 6; white bars), and Zucker fa/fa rats either untreated (n = 9; grey bars) or treated for 90 days with macitentan (n = 9; down‐hatched bars). *: P < 0.05 versus lean; †: P < 0.05 versus untreated Zucker fa/fa.

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  FIGURE 6. Right ventricular and left ventricular coronary endothelium‐dependent relaxation. Upper panel. Right ventricular (RV) (upper panel) and left ventricular (LV) (lower panel) coronary relaxation induced by acetylcholine in 13 and 24 week‐old lean rats (n = 6 and n = 4, respectively; white circles) and Zucker fa/fa rats either untreated (n = 4 and n = 6, respectively; black circles) or treated for 7 or 90 days, respectively, with macitentan (n = 5 and n = 8 respectively black triangles). Lower panel. Left ventricular (LV) (lower panel) coronary relaxation induced by acetylcholine in 13‐ and 24‐week‐old lean rats (n = 4 and n = 4, respectively; white circles) and Zucker fa/fa rats either untreated (n = 6 and n = 6, respectively; black circles) or treated for 7 or 90 days, respectively, with macitentan (n = 8 and n = 7, respectively black triangles). *: P < 0.05 versus lean; †: P < 0.05 versus untreated Zucker fa/fa.