1 The present study has determined the receptors mediating the vascular responses (pressor and depressor actions and vascular permeability effect) to endothelin-1 (ET-1) in the conscious rat by using the novel non-peptide ET(A)/ET(B) receptor antagonist, bosentan (Re 47-0203, 4-tert-butyl-N-[6-(2 hydroxyethoxy)- 5-(2-methoxy-phenoxy)-2,2'-bipyrimidine-4-yl]benzene-sulphonamide), the ET(A) receptor-selective antagonist, FR 139317 and the ET(B) receptor-selective peptide agonist, IRL 1620. 2 Bolus injection of ET-1 (1 nmol kg(-1), i.v.) resulted in a prolonged presser effect (maximum increase in mean arterial blood pressure (MABP) was 47+/-3 mmHg, n = 6) preceded by a transient depressor response (maximum decrease in MABP was 17+/-1 mmHg). Both these responses were inhibited by bosentan (1-20 mg kg(-1), i.v. bolus) in a dose-dependent manner. The maximum inhibition of ET-induced depressor and presser responses did not exceed 53 and 87%, respectively. FR 139317 (2.5 mg kg(-1), i.v.) attenuated the presser response to ET-1 by 75% without affecting the depressor response. Furthermore, FR 139317, but not bosentan, prolonged the depressor action of ET-1. Corresponding to changes in blood pressure, a small transient tachycardia (Delta heart rate 15+/-5 beats min(-1)) followed by a sustained bradycardia (Delta heart rate -48+/-10 beats min(-1), n = 6) was observed following injection of 1 nmol kg(-1) ET-1. FR 139317 and bosentan (10 mg kg(-1)) inhibited ET-1-induced bradycardia by 79% and 71%, respectively. ET-1-induced tachycardia was significantly attenuated by bosentan, but not FR 139317. 3 The ET(B) receptor agonist, IRL 1620 (0.1-2 mol kg(-1), i.v.) produced biphasic dose-dependent changes in MABP with an initial transient fall followed by a prolonged presser action. The maximum decrease and increase in MABP were 11+/-2 and 19+/-3 mmHg, respectively (n = 5). These changes in MABP were accompanied by a transient tachycardia (Delta heart rate 9+/-3 beats min(-1)) and prolonged bradycardia (Delta heart rate -17+/-11 beats min(-1)), respectively. Pretreatment of the animals with FR 139317 (2.5 mg kg(-1), i.v.) did not affect IRL 1620 (1 nmol kg(-1))-induced changes in MABP and heart rate, whereas both the depressor and presser actions of IRL 1620 and the accompanying tachycardia and bradycardia were almost completely inhibited by bosentan (10 mg kg(-1)). 4 ET-1 (1 nmol kg(-1)) enhanced albumin extravasation in the upper and lower bronchi, spleen, kidney, stomach and duodenum (up to 246%) as measured by the extravasation of Evans blue dye. FR 139317 (2.5 mg kg(-1)) completely inhibited ET-1-induced protein extravasation in the stomach and duodenum, whereas 40-75% inhibition was observed in the other vascular beds studied. The permeability effect of ET-1 was almost completely inhibited by bosentan (10 mg kg(-1)) in all vascular beds studied. 5 IRL 1620 (0.4 or 1 nmol kg(-1), i.v.) enhanced albumin extravasation (up to 219%) in the upper and lower bronchi, spleen and kidney in a dose-dependent manner. Unlike ET-1, IRL 1620 failed to increase albumin extravasation in the stomach and duodenum. 6 The present study demonstrates in the conscious rat that ET(A) and ET(B) receptors are responsible for mediating the majority of the presser response to ET-1 and suggest that a small component of the ET-1 presser response might be mediated via a non-ET(A), non-ET(B) receptor, whereas ET(B) and perhaps a non-ET(A), non-ET(B) receptor may mediate the depressor action of ET-1. Furthermore, the ET-1 induced albumin extravasation is mediated solely via ET(A) receptors in the stomach and duodenum, whereas both ET(A) and ET(B) receptors are involved in the permeability effect of ET-1 in the bronchial, splenic and renal vascular beds.
