Inflammatory Cytokines Impair Endothelium-Dependent Dilatation in Human Veins In Vivo

BACKGROUND: Endothelial dysfunction occurs in many diseases associated with increased cardiovascular risk. We examined the effects of pro-inflammatory cytokines on endothelial function. METHODS AND RESULTS: Subjects lay with one hand placed on an angled support. The diameter of a vein was recorded by measuring the linear displacement of a probe placed on the skin overlying the vein when the pressure in a congesting cuff placed around the upper arm was deflated from 40 to 0 mm Hg. A length of the vein was isolated by two wedges. TNF-alpha (1 ng), IL-1beta (1 ng), or IL-6 (100 pg) were instilled for 1 hour, either individually or together. At the end of the hour, the wedges were removed and the vein reconnected with the circulation. Dose-response curves (bradykinin: 2, 4, and 8 pmol/min; arachidonic acid: 0.2, 2, and 20 nmol/min; and glyceryl trinitrate 1, 2, and 4 pmol/min) were constructed before and 1, 6, 24, and 48 hours after instillation. In another study, hydrocortisone (100 mg) was given 2 hours before the study. In a different study, subjects were given oral aspirin (75 mg or 1 g) 2 hours before the study. TNF-alpha and IL-1beta alone but not IL-6 attenuated the dilatation to bradykinin and arachidonic acid; the response was greatest at 1 hour with recovery occurring by 6 hours. Combination of IL-1beta and TNF-alpha prolonged the endothelial dysfunction, resulting in recovery at 24 hours. Hydrocortisone and high-dose aspirin prevented endothelial dysfunction. CONCLUSIONS: The results demonstrate that pro-inflammatory cytokines induce transient and reversible endothelial dysfunction and indicate that cyclooxygenase activity may contribute to the genesis of the effect. If other vessels behave similarly, this may provide further insight into the mechanisms precipitating acute cardiovascular events after inflammatory disorders.