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Mediation of endothelin‐1‐induced inhibition of platelet aggregation via the ET B receptor
Author(s) -
McMurdo Lorraine,
Lidbury Paul S.,
Thiemermann Christoph,
Vane John R.
Publication year - 1993
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1993.tb13602.x
Subject(s) - antagonist , chemistry , bolus (digestion) , endothelin receptor , platelet , blood pressure , in vivo , endocrinology , ex vivo , endothelin 3 , endothelins , endothelin 1 , medicine , pharmacology , receptor , in vitro , biology , biochemistry , microbiology and biotechnology
1 The effects of FR139317 (ET A antagonist) or PD145065 (non‐selective ET A /ET B 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 ET A receptor while the depressor and antiaggregatory actions of ET‐1 are due to activation of the ET B receptor.