Modulation of vascular tone by endothelin-1 in healthy and septic sheep

Endothelin-1 (ET-1), a potent endogenous vasodilator, is implicated in the regulation of vascular tone. In sepsis, hypotension occurs despite elevated ET-1 levels. We determined the influence of ET-1 on vascular tone by ET-1 receptor blockade with bosentan, a mixed ET_A and ET_B receptor antagonist. Sheep received an 44-hr infusion of 6×10⁶ colony-forming-units/kg/h Pseudomonas aeruginosa (S, n=5) or carrier solution (H, n=5). After 32h, 10 mg/kg bosentan was injected. Statistical analysis with ANOVA. Data are shown as mean±SEM. CI: cardiac index in l/min/m², MAP: mean arterial pressure in mmHg, SVRI: systemic vascular resistance 0h 32h 32.5h (+B) index in CI H 4.7±0.5 4.5±0.4 5.0±0.3 dyne·s/cm⁵/m², S 4.9±0.3 8.1±0.5* 9.1±0.4 *p<0.05 vs. 0h, MAP H 95±3 94±3 86±3† † vs. 32h. S 93±4 88±3 67±3† Bosentan caused SVRI H 1579±225 1610±227 1294±124† vasodilation in S 1436±137 802±59* 519±39† both groups indicating that ET-1 contributes to vascular tone both in health and sepsis. The greater decrease in SVRI in sepsis (35±5%) compared to healthy animals (18±3%, p<0.05) suggests increased activity of ET-1 which, however, is counteracted by vasodilatory mediators that are also released during sepsis.