Mediation of endothelin‐1‐induced inhibition of platelet aggregation via the ETB receptor

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Abstract
1 The effects of FR139317 (ETA antagonist) or PD145065 (non-selective ETA/ETB antagonist) on endothelin-1 (ET-1)-induced changes in blood pressure and inhibition of ex vivo platelet aggregation were investigated in the anaesthetized rabbit. 2 ET-1 (1 nmol kg−1, i.a. bolus) caused a sustained increase in mean arterial pressure (MAP) (peak increase 47 ± 5 mmHg, n = 8). Intravenous infusion of FR139317 at 0.2 (n = 4) or 0.6 mg kg−1 min−1 (n = 4) inhibited the ET-1 pressor response by 83 or 89%, respectively. Infusion of PD 145065 at 0.2 (n = 4) or 0.6 mg kg−1 min−1 (n = 4) inhibited the ET-1-induced increase in MAP by 79 or 75%, respectively. 3 The transient depressor response (−16 ± 3 mmHg) which preceded the rise in blood pressure induced by ET-1 (1 nmol kg−1, i.a., n = 8) was enhanced by an intravenous infusion of FR139317 (0.6 mg kg−1 min−1) to −35 ± 5 mmHg (P < 0.05, n = 4). This enhancement was abolished by indomethacin (5 mg kg−1, i.v.) pretreatment (−17 ± 1 mmHg, n = 4). PD145065 (0.2 mg kg−1 min−1, i.v.) attenuated the ET-1-induced fall in blood pressure to −9 ± 1 mmHg (n = 4), while a higher dose of this antagonist (0.6 mg kg−1 min−1, i.v.) completely abolished the ET-1-mediated depressor response. 4 ET-1 (1 nmol kg−1, n = 8) inhibited ex vivo platelet aggregation by 96% at 5 min after injection of the peptide. FR139317 (0.2 or 0.6 mg kg−1 min−1, i.v.) or PD145065 (0.2 mg kg−1 min−1, i.v.) did not affect the inhibition of ex vivo platelet aggregation in response to ET-1. In contrast, intravenous infusion of PD145065 (0.6 mg kg−1 min−1) abolished the anti-aggregatory effects of ET-1. 5 Thus, FR139317 inhibits the pressor, but not the depressor actions of ET-1 and has no effect on the ET-1-induced inhibition of ex vivo platelet aggregation. In contrast, PD145065 antagonizes the pressor and depressor responses to ET-1 and abolishes the anti-aggregatory effects of the peptide. 6 These results strongly suggest that ET-1-induced vasoconstriction in the anaesthetized rabbit is primarily mediated via the ETA receptor while the depressor and antiaggregatory actions of ET-1 are due to activation of the ETB receptor.