Effects of the novel selective endothelin ET(A) receptor antagonist, SB 234551, on the cardiovascular responses to endotoxaemia in conscious rats

Abstract

1. In conscious, freely moving, male, 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 ET(A)-receptor antagonist, SB 234551. On the following day, the effects of SB 234551 on the haemodynamic responses to lipopolysaccharide (LPS) infusion (150 microg 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 the 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 vasodilator 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 vasodilatation 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 early (1 - 2 h) cardiovascular responses to LPS infusion were unaffected, but the subsequent recovery of mean arterial blood pressure was impaired, due to developing vasodilatation in the mesenteric and, to a lesser extent, hindquarters, vascular beds. SB 234551 had no effect on the renal haemodynamic responses to LPS infusion. 5. The results confirm an important, regionally-selective, vasoconstrictor role for endogenous endothelin in this model of endotoxaemia.

Figure 1

Changes in cardiovascular variables in response to endothelin-1 (ET-1) in conscious rats receiving vehicle (n=8) or SB 234551 (0.3 mg kg⁻¹; 0.3 mg kg⁻¹ h⁻¹ (n=8)). Values are mean and vertical bars show s.e.mean. ^*P<0.05 vs baseline (Friedman's test); ^#P<0.05 between the integrated responses (Mann–Whitney U-test).

Figure 2

Changes in cardiovascular variables in rats infused with LPS (150 μg kg⁻¹ h⁻¹ starting at time 0 h) in the presence of vehicle (n=8) or SB 234551 (1 mg kg⁻¹; 1 mg kg⁻¹ h⁻¹ (n=4)). Values are mean and vertical bars show s.e.mean. ^*P<0.05 vs baseline (Friedman's test).

Figure 3

Changes in cardiovascular variables in rats infused with LPS (150 μg kg⁻¹ h⁻¹ start at time 0 h) in the presence of vehicle (n=8) or SB 234551 (0.3 mg kg⁻¹; mg kg⁻¹ h⁻¹ (n=8)). Values are mean and vertical bars show s.e.mean. ^*P<0.05 vs baseline (Friedman's test); ^#P<0.05 between the integrated responses (Mann–Whitney test).