Effects of dexamethasone and SB 209670 on the regional haemodynamic responses to lipopolysaccharide in conscious rats

1 Male (350-450 g) Long Evans rats were chronically instrumented to permit regional haemodynamics to be monitored in the conscious state. In the first experiment, either saline (0.4 ml h(-1)) or dexamethasone (3 mg kg(-1), 125 mu g kg(-1) h(-1)) was infused continuously for 24 h, before co-infusion of lipopolysaccharide of (LPS, 150 mu g kg(-1) h(-1)) for 24 h. Dexamethasone prevented the delayed (5-24 h) fall in mean arterial blood pressure (MAP) and the renal and hindquarters vasodilatation seen with LPS infusion alone, but not the initial (about 2 h) fall in MAP or renal vasodilatation. However, at this dose, dexamethasone itself caused a significant rise in MAP and regional vasoconstrictions. 2 In the second experiment, dexamethasone at a lower dose (12.5 mu g kg(-1) h(-1)) had only slight presser and vasoconstrictor effects. However, in its presence, infusion of LPS caused a substantial and progressive rise in MAP (maximum at 8 h, +32+/-3 mmHg) together with persistent mesenteric and hindquarters vasoconstriction and a transient renal vasodilatation. 3 In the third experiment, the non-selective endothelin antagonist, SE 209670 (600 mu g kg(-1) h(-1)), blocked the slight presser and regional vasoconstrictor effects of the lower dose of dexamethasone. Furthermore, in the presence of dexamethasone and SE 209670, infusion of LPS caused marked, but transient hypotension (nadir at 5 h, -24+/-2 mmHg) and renal and mesenteric vasodilatation. 4 At the end of all experimental protocols, sequential administration of the AT(1)-receptor antagonist, losartan, followed by the V-1-receptor antagonist, (+)-(CH2)(5)-O-Me-Tyr, vasopressin, caused effects indicating a variable involvement of angiotensin and vasopressin in the maintenance of cardiovascular status. 5 Collectively, the results indicate that, in the conscious rat, dexamethasone interacts with vasoconstrictor and vasodilator mechanisms, and hence its influence on the haemodynamic responses to LPS cannot be attributed, simply, to inhibition of the activity of inducible nitric oxide synthase and/or cyclo-oxygenase-2.