Effects of the novel selective endothelin ETA receptor antagonist, SB 234551, on the cardiovascular responses to endotoxaemia in conscious rats

1 In conscious, freely moving, mate, Long Evans rats, regional haemodynamic responses to exogenous endothelin-1 (ET-1; 25, 50 and 250 pmol kg(-1) i.v. ) were assessed in the presence of vehicle, or the selective ETA-receptor a ntagonist, SB 234551. On the following day, the effects of SB 234551 on the haemodynamic responses to lipopolysaccharide (LPS) infusion (150 pg kg(-1) h(-1), i.v.) were determined. 2 When SB 234551 was given i.v. by primed infusion at a dose of 0.3 mg kg(- 1) bolus, 0.3 mg kg(-1) h(-1) infusion, it caused selective inhibition of t he vasoconstrictor effects of exogenous endothelin-1, whereas at a dose of 1 mg kg(-1), 1 mg kg(-1) h(-1), SB 234551 also inhibited some of the vasodi lator effects of endothelin-1. 3 Infusion of LPS, in the presence of vehicle, caused a short-lived (1-2 h) hypotension, tachycardia, and vasodilatation in renal, superior mesenteric and hindquarters vascular beds. Thereafter, blood pressure, heart rate and mesenteric vascular conductance returned to baseline values, but renal vas odilatation persisted, and there was vasoconstriction in the hindquarters. 4 In the presence of SB 234551 (0.3 mg kg(-1), 0.3 mg kg(-1) h(-1)), the ea rly (1-2 h) cardiovascular responses to LPS infusion were unaffected, but t he subsequent recovery of mean arterial blood pressure was impaired, due to developing vasodilatation in the mesenteric and, to a lesser extent, hindq uarters., vascular beds. SB 234551 had no effect on the renal haemodynamic responses to LPS infusion. 5 The results confirm an important, regionally-selective, vasoconstrictor r ole for endogenous endothelin in this model of endotoxaemia.