Subtypes of endothelin receptors that mediate venous effects of endothelin-1 in anaesthetized rats

Abstract

1. The subtypes of endothelin receptors that mediate the effects of endothelin-1 (ET-1) on mean arterial pressure (MAP), heart rate (HR), mean circulatory filling pressure (MCFP), arterial resistance (R_A), cardiac output (CO) and venous resistance (R_V) were characterized in 9 groups of pentobarbitone-anaesthetized rats via the injection of ET-1 in the absence and presence of bosentan (Ro 47-0203, ET_A- and ET_B-receptor antagonist), PD 142893 (ET_A- and ET_B-receptor antagonist) or FR 139317 (ET_A-receptor antagonist), as well as injection of the ET_B-receptor agonist, IRL 1620.

2. Cumulative i.v. bolus injections of ET-1 or IRL 1620 (0.5, 1 and 2 nmol kg⁻¹) dose-dependently increased MAP (ET: by 22, 34 and 44; IRL: 8, 17 and 28 mmHg), R_A (ET: 62, 108 and 162; IRL: 51, 63 and 86% over baseline), R_V (ET: 70, 132 and 179; IRL: 81, 89 and 98% over baseline) and MCFP (ET: 1.1, 1.8 and 1.9; IRL: 0.9, 1.0 and 1.2 mmHg) and reduced CO (ET: −18, −35 and −44; IRL: −24; −26; −25% below baseline). Equimolar doses of ET-1 and IRL 1620 caused similar initial transient depressor responses. Saline did not modify any haemodynamic variables in the time-control group.

3. Bosentan (10 mg kg⁻¹, i.v.) inhibited ET-induced increases in MAP, R_V, R_A and MCFP and decrease in CO. PD 142893 (22 mg kg⁻¹, i.v.) abolished ET-induced changes on MAP, R_V, R_A and CO, but did not alter effects on MCFP. Bosentan alone did not cause haemodynamic changes, but PD 142893 alone elevated MCFP (0.9±0.3 mmHg at 1 h after injection) and did not alter other variables. Both antagonists abolished the initial depressor effects of ET-1.

4. FR 139317 (1 mg kg⁻¹, i.v.) partially inhibited the increases in MAP, R_V, R_A and MCFP and decreases in CO elicited by ET-1, but did not alter the transient depressor response of ET-1.

5. The results show that both ET_A- and ET_B-receptors mediate the arterial and venous constrictor effects of ET-1. Bosentan is more efficacious than PD 142893 in inhibiting the venous effects of ET-1.

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