Abstract 500: Reactive Oxygen Species and Insufficiency of Nitric Oxide Mediate Enhanced Microvascular Contractility and Impaired Endothelium Dependent Relaxation in Mice With Renal Failure
Background: Cardiovascular disease (CVD) is common and major cause of death and disability in chronic kidney disease (CKD). Since CVD starts with endothelial dysfunction, we tested the hypothesis that reactive oxygen species (ROS) and insufficient nitric oxide (NO) contributed to microvascular contractility and endothelial dysfunction in C57BL/6 mice with normotensive reduced renal mass (RRM) 5/6 nephrectomy, a model of progressive CKD.
Methods and Results: Mesenteric arterioles (MAs) were isolated from mice 3 months after sham-operation (Sham) or RRM (n=6/group) and were mounted on Mulvany-Halperin wire myograph, preconstricted with norepinephrine and relaxed with acetylcholine (ACh) for: endothelium-dependent relaxation (EDR); endothelium-dependent relaxation factor (EDRF; NOS-dependent relaxation); endothelium-dependent hyperpolarizing factor (EDHF; K+-channel dependent relaxation) and endothelium-independent relaxation (EIR; sodium nitroprusside). Contractions were tested to endothelium-dependent contracting factor (EDCF; ACh-induced contraction with blocked relaxation pathways); phenylephrine (PE); U-46,619 (thromboxane-prostanoid receptor agonist) and endothelin-1 (ET-1). NO activity (DAF-FM fluorescence) and ROS generation (tempo-9-AC fluorescence) were measured by fluorescence microscopy. Data are mean ±SEM. The MAs from RRM mice had diminished EDR (54 ±5 vs. 77±3%; P<0.01) and EDRF (13±5 vs. 27±4%; P<0.01) with reduced NO activity (0.18 ± 0.05 vs. 0.36± 0.04 ΔUnits; P<0.05), but unchanged EDHF (30±4 vs. 38±4%; NS). These vessels from RRM mice developed an EDCF (14±1 vs. 8±1%; P<0.05) and ACh-induced increased in ROS (0.17±0.03 vs. 0.06±0.02 ΔUnits; P<0.05). Contractile responses were enhanced to U-46,619 (107±4 vs. 87±6, P<0.05) and ET-1 (108±7 vs. 89±4, P<0.05), but not to PE (87±6 vs. 77±8%, NS).
Conclusion: mice with RRM developed defective microvascular EDR, EDRF with reduced NO activity and enhanced new ACh-induced EDCF, contractilities to thromboxane and endothelin with increased ROS generation. These microvascular disturbances may contribute to the later development of thrombosis, vascular remodeling and dysfunction in patients with CKD.
*D. Wang and C.Wang: Equal contribution
- © 2013 by American Heart Association, Inc.