Impaired endothelium-dependent vasodilatation in uraemia

Patients with chronic renal failure (CRF) have a substantially increased risk of cardiovascular death, the proposed mechanisms being arrhythmias (left ventricular hypertrophy) and accelerated atherosclerosis. The vascular endothelium protects against the development of atherosclerosis principally by releasing vasoactive substances such as nitric oxide (NO) and endothelium-derived hyperpolarizing factor. In CRF there is accumulation of endogenous inhibitors of NO synthesis. In this present study we assessed endothelium-dependent vasodilatation in patients with advanced uraemia.

Sixteen uraemic patients (pre-dialysis and continuous ambulatory peritoneal dialysis) and 18 controls were studied. Forearm plethysmography was used to measure forearm blood flow and the changes induced by carbachol (endothelium-dependent vasodilator) and sodium nitroprusside (SNP; endothelium-independent vasodilator). The order of drugs infused was randomized between subjects. Dose response curves were constructed for each agent and area under the curve (AUC) calculated (arbitrary units).

Overall, vasodilatation to SNP and carbachol was similar between uraemic patients and controls. However, it became apparent that there was a marked order effect for the drugs infused, such that infusion of SNP as the first agent blunted the subsequent response to carbachol. When only those patients and controls who received carbachol followed by SNP were studied (10 in each group), the response to carbachol in uraemic patients was attenuated compared to controls: AUC (median(range)) for uraemic patients 529.0 (150.9-834.7) compared to AUC for controls 703.9 (583.5-1576.6); P=0. 028. Vasodilatation to SNP was, however, similar between groups: AUC for uraemic patients 1475.0 (857.8-4717.1) compared to AUC for controls 1328.1 (216.6-3311.4); P=0.545.

This study has demonstrated a marked drug order effect not previously described for forearm plethysmography. When the order effect was taken into account, this study demonstrated reduced vasodilatation to carbachol in uraemic patients with a preserved response to SNP. This pattern indicates impaired endothelium-dependent vasodilatation in uraemic patients, a defect that may predispose this group to accelerated atherosclerosis.