SUBTYPES OF ENDOTHELIN RECEPTORS THAT MEDIATE VENOUS EFFECTS OF ENDOTHELIN-1 IN ANESTHETIZED RATS

1 The subtypes of endothelin receptors that mediate the effects of end othelin-l (ET-l) on mean arterial pressure (MAP), heart rate (HR), mea n circulatory filling pressure (MCFP), arterial resistance (RA), cardi ac output (GO) and venous resistance (R-v) were characterized in 9 gro ups of pentobarbitone-anaesthetized rats via the injection of ET-1 in the absence and presence of bosentan (Ro 47-0203, ETA-and ETB-receptor antagonist), PD 142893 (ETA-and ETB-receptor antagonist) or FR 139317 (ETA-receptor antagonist), as well as injection of the ETB-receptor a gonist, IRL 1620. 2 Cumulative i.v. bolus injections of ET-1 or IRL 16 20 (0.5, 1 and 2 nmol kg(-1)) dose-dependently increased MAP (ET: by 2 2, 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 a nd 98% over baseline) and MCFP (ET: 1.1, 1.8 and 1.9; IRL: 0.9, 1.0 an d 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 i nitial transient depressor responses. Saline did not modify any haemod ynamic variables in the lime-control group. 3 Bosentan (10 mg kg(-1), i.v.) inhibited ET-induced increases in MAP, R-v, R-A and MCFP and dec rease in CO. PD 142893 (22 mg kg(-1), i.v.) abolished ET-induced chang es on MAP, R-v, R-A and CO, but did not alter effects on MCFP. Bosenta n alone did not cause haemodynamic changes, but PD 142893 alone elevat ed MCFP (0.9+/-0.3 mmHg at 1 h after injection) and did not alter othe r variables. Both antagonists abolished the initial depressor effects of ET-1. 4 FR 139317 (1 mg kg(-1), i.v.) partially inhibited the incre ases in MAP, R-v, R-A and MCFP and decreases in CO elicited by ET-1, b ut did not alter the transient depressor response of ET-1. 5 The resul ts show that both ETA- and ETB-receptors mediate the arterial and veno us constrictor effects of ET-1. Bosentan is more efficacious than PD 1 42893 in inhibiting the venous effects of ET-1.