Familial hypercholesterolemia impairs exercise-induced systemic vasodilation due to reduced NO bioavailability

Area of Science:

• Cardiovascular Physiology
• Endothelial Function
• Metabolic Disorders

Background:

• Hypercholesterolemia is known to impair endothelial function, affecting pathways like nitric oxide (NO) and phosphodiesterase 5 (PDE5).
• This impairment is expected to reduce vasodilation during exercise, impacting blood flow regulation.

Purpose of the Study:

• To investigate the specific effects of hypercholesterolemia on endothelial function and exercise-induced vasodilation.
• To compare the roles of endothelial NO synthase (eNOS) and PDE5 in hypercholesterolemic swine during rest and exercise.

Main Methods:

• Utilized chronically instrumented Yucatan (Control) and Rapacz familial hypercholesterolemic (FH) swine.
• Administered inhibitors for eNOS (nitro-l-arginine) and PDE5 (EMD360527) at rest and during treadmill exercise.
• Measured systemic and pulmonary vascular conductance responses to various stimuli, including ATP, nitroprusside, and exercise.

Main Results:

• Exercise-induced and ATP-mediated vasodilation were blunted in FH swine compared to controls.
• Vasoconstrictor responses to eNOS inhibition were attenuated in FH swine.
• Vasodilator responses to PDE5 inhibition were reduced in FH swine, suggesting altered PDE5 activity.
• Pulmonary circulation showed attenuated ATP responses but maintained responses to eNOS and PDE5 inhibition in FH swine.

Conclusions:

• Hypercholesterolemia significantly reduces exercise-induced vasodilation in the systemic circulation.
• The primary mechanism involves decreased nitric oxide bioavailability, partially offset by reduced PDE5 activity.
• Endothelial dysfunction in hypercholesterolemia impacts systemic vasodilation differently than pulmonary vasodilation.