Impaired endothelial function in isolated human uremic resistance arteries.
BACKGROUND
Patients with chronic renal failure (CRF) face a markedly increased risk of cardiovascular death. CRF is frequently complicated by hypertension and changes in both the heart (left ventricular hypertrophy) and the vasculature (endothelial dysfunction and accelerated atherosclerosis). The mechanisms underlying changes in vascular function and specifically endothelial dysfunction are unclear. This present study therefore examined subcutaneous resistance artery function in vitro, comparing adult uremic patients and controls using wire myography.


METHODS
Subcutaneous fat biopsies were obtained from 12 patients with CRF (median serum creatinine 735 micromol/L) at the time of renal transplantation or peritoneal dialysis catheter insertion, and from eight controls without renal disease at the time of abdominal surgery. Resistance arteries were mounted on a wire myograph. Their contractile ability was tested with high potassium depolarization, and endothelial integrity was tested by relaxation to acetylcholine. Cumulative concentration-response curves were then constructed for norepinephrine, endothelin-1, acetylcholine, and sodium nitroprusside (SNP).


RESULTS
Following preconstriction with norepinephrine, vessels from uremic patients vasodilated less well to acetylcholine compared with vessels from controls [maximum % relaxation 77% (range 41, 97) vs. 98% (78, 100), P < 0.001]. The vasodilation to SNP was similar [95% (63, 100) vs. 94% (71, 100), P = 0.751]. There was a trend toward increased maximum pressure (kPa) achieved with both norepinephrine and endothelin-1 in vessels from uremic patients, and the contractions to both of these agents were more prolonged in the uremic vessels.


CONCLUSIONS
The pattern of normal vasodilation to SNP but reduced vasodilation to acetylcholine is consistent with endothelial dysfunction due to impaired nitric oxide (NO) production in uremic vessels. Similar results have been demonstrated in vivo in uremia, one suggested mechanism being accumulation of endogenous inhibitors of NO synthase such as asymmetric dimethylarginine (ADMA). This in vitro study suggests that a short-lived circulating factor is not entirely responsible and that there may be an inherent abnormality in endothelial function in uremia, although the exact pathophysiology remains unclear. Endothelial dysfunction may predispose the patient to accelerated atherosclerosis and may be involved in the pathogenesis of hypertension in end-stage renal failure.
Morris
S T
ST
The Renal Unit, Western Infirmary, Glasgow, Scotland, United Kingdom. st.morris@virgin.net
McMurray
J J
JJ
Spiers
A
A
Jardine
A G
AG
D000109:Acetylcholine / Q000494:pharmacology; D000328:Adult; D000368:Aged; D001158:Arteries / Q000503:physiopathology*; D004305:Dose-Response Relationship, Drug; D019332:Endothelin-1 / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology*; D006801:Humans; D066298:In Vitro Techniques; D007676:Kidney Failure, Chronic / Q000503:physiopathology; D008875:Middle Aged; D009213:Myography; D009599:Nitroprusside / Q000494:pharmacology; D009638:Norepinephrine / Q000494:pharmacology; D014511:Uremia / Q000503:physiopathology*; D014655:Vascular Resistance; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology
D019332:Endothelin-1; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D009599:Nitroprusside; D000109:Acetylcholine; D009638:Norepinephrine