RELEASE OF EDRF AND NO IN EX-VIVO PERFUSED AORTA - INHIBITION BY IN-VIVO ESCHERICHIA-COLI ENDOTOXEMIA

Previous studies have yielded contradictory results about interrelatio ns between endotoxin and endothelium-derived relaxing factor (EDRF). W e tested the hypothesis that in vivo endotoxemia inhibits basal and/or agonist-mediated release of EDRF and nitric oxide (NO). EDRF bioactiv ity, NO production, and NO synthase (NOS) activity were measured in ao rta from guinea pigs following 16 h of Escherichia coli endotoxemia (4 mg/kg endotoxin ip). Endothelium-dependent relaxation of aortic rings was studied under standard isometric conditions. Endotoxemia resulted in an 89% reduction in basal EDRF bioactivity and a 62% reduction in basal NO production in perfused aorta. EDRF bioactivity and NO product ion in response to the receptor-dependent agonists acetylcholine and A DP were significantly reduced in perfused aorta from endotoxemic anima ls. In contrast, endotoxin did not significantly inhibit EDRF bioactiv ity and NO production by the receptor-independent agonist A-23187. Aor tic rings from endotoxemic animals likewise showed decreased vasodilat or responses to acetylcholine and ADP but not to A-23187. Inducible (C a2+ independent) NOS activity was not significantly different in contr ol and endotoxin-treated animals. These findings indicate that prolong ed endotoxemia resulted in diminution of release of EDRF, consistent w ith the interpretation that endotoxemia decreases basal and agonist-st imulated EDRF bioactivity and NO production with loss of endothelium-d ependent vasodilator reserves during gram-negative sepsis.