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Reduced NO Bioavailability Hampers Exercise Induced Vasodilation in Familial Hypercholesterolemic Swine
Author(s) -
Beer Vincent J,
Merkus Daphne,
Bender Shawn B,
Tharp Darla L,
Ivey Jan R,
Bowles Dougla K,
Duncker Dirk J,
Laughlin M Harold
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.1138.25
Subject(s) - vasodilation , bioavailability , medicine , enos , endocrinology , nitric oxide , pharmacology , nitric oxide synthase
Hypercholesterolemia impairs endothelial function (e.g. the NO‐cGMP‐ phosphodiesterase 5 (PDE5) pathway), limits shear stress induced vasodilation, and is thereby expected to reduce exercise induced vasodilation. To assess the actual effects of hypercholesterolemia on endothelial function and exercise induced vasodilation, we compared the effects of eNOS and PDE5 inhibition in chronically instrumented Yorkshire (Y) and Rapacz Familial Hypercholesterolemic (FH) swine, at rest and during exercise. Exercise induced systemic vasodilation, i.e. the increase in systemic vascular conductance index (SVCi = SVC per Kg bodyweight), was markedly reduced in FH swine (27±5%) compared to Y swine (119±4%). As a result, during exercise mean arterial pressure remained constant in Y swine while it significantly increased in FH swine (from 91±6 to 110±8 mmHg). The vasoconstrictor effect of eNOS inhibition, with Nitro‐L‐Arginine, was attenuated in FH compared to Y swine, both at rest and during exercise. Furthermore, the vasodilator effect of PDE5 inhibition, with EMD360527, was also markedly reduced in FH compared to Y swine. In conclusion, hypercholesterolemia hampers exercise‐induced vasodilation via reduced NO bioavailability. The reduced NO bioavailability results in a decreased activation of the NO‐cGMP pathway, as evidenced by a blunted vasodilator response to PDE5 inhibition.