2005 Fiscal Year Final Research Report Summary
The investigation of inducing factors of cardiovascular events in early stage of chronic kidney disease
| Project/Area Number |
16590716
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Circulatory organs internal medicine
|
|---|
| Research Institution | Keio University |
|---|
Principal Investigator |
HAYASHI Koichi Keio University, School of Medicine, Assistant Professor, 医学部, 専任講師 (80164937)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
WAKINO Shu Keio University, School of Medicine, Assistant, 医学部, 助手 (50265823)
KANDA Takeshi Keio University, School of Medicine, Assistant, 医学部, 助手 (80317114)
|
|---|
| Project Period (FY) |
2004 – 2005
|
| Keywords | chronic kidney disease / coronary endothelial dysfunction / ADMA / DDAH / eNOS / atRA |
|---|
| Research Abstract |
Background-Cardiovascular events are accelerated in chronic kidney disease (CKD). Although deranged nitric oxide (NO) pathways and asymmetric dimethylarginine (ADMA) cause endothelial dysfunction, no direct evidence for coronary artery endothelial dysfunction in CKD has been documented.
Methods and Results-Male dogs were rendered CKD by hemi-nephrectomy (1/2Nx) or five-sixth nephrectomy (5/6Nx). After four weeks, renal ablation reduced glomerular filtration rate (GFR, control ; 71±6, 1/2Nx ; 39±3, 5/6Nx ; 21±6ml/min) and elevated plasma ADMA (control ; 2.6±0.2, 1/2Nx ; 3.1±0.5, 5/6Nx ; 3.5±0.3μmol/L). Coronary circulatory responses to acetylcholine (ACh) revealed marked increases in coronary blood flow (CBF) in control group (83±17% increment), but blunted responses in 1/2Nx (34±8% increment) and 5/6Nx (20±4% increment). The ACh-induced changes in epicardial arteriolar diameter, using needle-lens probe charge-coupled device videomicroscopy, showed similar results. The responsiveness to sodium nitroprusside did not differ among three groups. The ACh-induced increases in CBF were correlated with plasma ADMA (r^2=0.26) but not with GFR. Plasma NOx levels decreased in 1/2Nx and 5/6Nx, and the mRNA expressions of dimethylarginine dimethylaminohydrolase (DDAH)-II, ADMA-degrading enzyme, and endothelial NO synthase (eNOS) in coronary arteries were downregulated in 1/2Nx and 5/6Nx. Finally, 4-week treatment with all-trans retinoic acid restored the impaired endothelium-dependent vasodilation and reversed the expression of eNOS but not DDAH.
Conclusions-Coronary endothelial function is impaired in the early-stage CKD. The dysfunction is attributed to eNOS downregulation and the increased ADMA resulting from the DDAH-II downregulation in coronary arteries. Furthermore, the manipulation of NO pathways may constitute a therapeutic strategy for the prevention of coronary dysfunction in CKD.
|
