Familial hypercholesterolemia impairs exercise-induced systemic vasodilation due to reduced NO bioavailability
Familial hypercholesterolemia impairs exercise-induced systemic vasodilation due to reduced NO bioavailability
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DOI：
10.1152/japplphysiol.00619.2013
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发表时间：
2013-12-01
影响因子：
3.3
通讯作者：
Laughlin, M. Harold
中科院分区：
文献类型：
--
作者：
de Beer, Vincent J.;Merkus, Daphne;Laughlin, M. Harold
高胆固醇血症损害内皮功能[例如，一氧化氮（NO）-环GMP-磷酸二酯酶5（PDE 5）途径]限制剪切应力诱导的血管舒张，因此预期减少运动诱导的血管舒张。为了评估高胆固醇血症对内皮功能和运动诱导的血管舒张的实际影响，我们比较了在静息和跑步机运动期间，在慢性仪器化的尤卡坦（对照）和Rapacz家族性高胆固醇血症（FH）猪中内皮NO合酶（eNOS）和PDE 5抑制的影响。与对照组相比，FH组由ATP（相对于硝普钠）和运动引起的体循环血管传导性增加减弱。与对照组相比，FH组在休息和运动时对硝基-L-精氨酸（NLA）抑制eNOS的血管收缩反应减弱。此外，与对照猪相比，FH中对硝普钠的血管扩张反应略有增强，而对EMD 360527抑制PDE 5的血管扩张反应则降低。最后，在肺循环中，FH导致对ATP的血管舒张反应减弱，同时维持对NLA和EMD 360527的反应。总之，高胆固醇血症减少运动引起的全身血管舒张，但不减少肺循环。这种减少似乎是NO生物利用度降低的主要结果，其通过较低的PDE 5活性来减轻。
Hypercholesterolemia impairs endothelial function [e.g., the nitric oxide (NO)-cyclic GMP-phosphodiesterase 5 (PDE5) pathway], limits shear stress-induced vasodilation, and is therefore 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 endothelial NO synthase (eNOS) and PDE5 inhibition in chronically instrumented Yucatan (Control) and Rapacz familial hypercholesterolemic (FH) swine, at rest and during treadmill exercise. The increases in systemic vascular conductance produced by ATP (relative to nitroprusside) and exercise were blunted in FH compared with Control swine. The vasoconstrictor response to eNOS inhibition, with nitro-L-arginine (NLA), was attenuated in FH compared with Control swine, both at rest and during exercise. Furthermore, whereas the vasodilator response to nitroprusside was enhanced slightly, the vasodilator response to PDE5 inhibition, with EMD360527, was reduced in FH compared with Control swine. Finally, in the pulmonary circulation, FH resulted in attenuated vasodilator responses to ATP, while maintaining the responses to both NLA and EMD360527. In conclusion, hypercholesterolemia reduces exercise-induced vasodilation in the systemic but not the pulmonary circulation. This reduction appears to be the principal result of a decrease in NO bioavailability, which is mitigated by a lower PDE5 activity.