Role for endogenous endothelin in the regulation of plasma volume and albumin escape during endotoxin shock in conscious rats

1 To explore the role of endogenous endothelin (ET) in the regulation of vascular functions, we studied the effects endothelin receptor blockade on blood pressure, plasma volume and albumin escape during endotoxin shock in conscious, chronically catheterized rats. Red blood cell volume and plasma volume were determined by using chromium-51-tagged erythrocytes and iodine-125-labelled albumin, respectively. 2 Intravenous injection of lipopolysaccharide (LPS, 10 mg kg(-1)) resulted in hypotension, haemoconcentration, and increased total-body albumin escape, which is reflected by a 30% reduction in plasma volume. Plasma ET-1 concentrations increased 2.1 fold and 5.4 fold at 30 and 120 min post-LPS, respectively. 3 LPS-induced losses in plasma volume and albumin escape were significantly attenuated by pretreatment of animals with the dual ETA/ETB receptor antagonist bosentan (17.4 mu mol kg(-1), i.v. 15 min prior to LPS) or the ETA receptor antagonist FR 139317 (3.8 mu mol kg(-1), i.v.) during both the immediate and delayed phases of endotoxin shock. The inhibitory actions of bosentan and FR 139317 were similar. Both antagonists augmented the hypotensive action of LPS. 4 Administration of bosentan or FR 139317 70 min after injection of LPS also attenuated further losses in plasma volume and increases in total body and organ albumin escape rates with the exception of the lung and kidney. 5 These results indicate a role for endogenous endothelin in mediating losses in plasma volume and albumin escape elicited by LPS predominantly through activation of ETA receptors, and suggest that by attenuating these events, ETA or dual ETA/ETB receptor blockers may be useful agents in the therapy of septic shock.