1 The present study characterizes the receptors responsible for endothelin-l-induced release of thromboxane A2 from the guinea pig lung and of endothelium-derived nitric oxide from the rabbit perfused kidney, by the use of the selective ETA receptor antagonist, BQ-123, and a novel selective ETB receptor antagonist, BQ-788. 2 In the guinea pig perfused lung, endothelin-1 (ET-1) (5 nM) induced a marked increase of thromboxane A2 which was reduced by 17 ± 5.0, 70 ± 1.0 and 93 ± 1.2% by BQ-788 infused at concentrations of 1, 5 and 10nM respectively. In contrast, BQ-123 (0.1 and 1.O0M) had little or no effect on the ET-1-induced release of thromboxane A2. 3 In the same perfused model, the selective ETB agonist, IRL 1620 (50 nM), stimulated the release of thromboxane A2, but not prostacyclin. The eicosanoid-releasing properties of IRL 1620 were abolished by BQ-788 at 10 nM, yet were unaffected by BQ-123 (1 ItM). 4 In the rabbit perfused kidney, BQ-788 (10 nM) potentiated the increase of perfusion pressure induced by endothelin-1 (1, 5 and 10 nM) by approximately 90%, but not that induced by angiotensin II (1 IAM).Furthermore, the selective ETB receptor antagonist did not reduce the release of prostacyclin triggered by either peptide. 5 In another series of experiments, pretreatment of the perfused kidney with a nitric oxide synthase inhibitor, L-NAME (100 1tM), potentiated the pressor responses to both endothelin-l and angiotensin II.Under L-NAME treatment, BQ-788 did not further potentiate the pressor response to endothelin-1. 6 Our results illustrate the predominant role of ETB receptor activation in the release of thromboxane A2 and nitric oxide triggered by endothelin-l in the guinea pig perfused lung and rabbit kidney respectively.
Endothelin-1 (ET-1) is a potent endogenous vasoconstrictor peptide formed through a specific conversion of its intermediate precursor, big ET-1, by an endothelin-converting enzyme (ECE). The present study evaluates the capacity of the ECE to convert the three big endothelins (big ET-1, big ET-2, and big ET-3), by comparing the pressor responses to these peptides with those induced by their respective metabolites (ET-1, -2, and -3) in the rat in vivo, anesthetized either with a mixture of ketamine/xylazine or with urethane. The mean basal arterial pressure under urethane anesthesia was not significantly different from that of ketamine/xylazine-treated animals (90/15 mg/kg; intramuscularly), although the basal heart rate was significantly higher in the former animals (urethane: 407 +/- 10 beats/min, ketamine/xylazine: 276 +/- 4 beats/min, P < .01; n = 8 to 17). In ketamine/xylazine and hexamethonium-treated rats (5-min infusion, 10 mg/kg intravenously), intravenous injection of ET-1 (1 nmol/kg) and big ET-1 (1 nmol/kg) induced potent vasopressor effects which lasted for more than 20 min. ET-2 (1 nmol/kg) produced similar pressor responses while big ET-2 (1-37) and big ET-2 (1-38) were twofold less potent than ET-2 (P < .05; n = 3 to 4). Big ET-3 induced a pressor effect only at 4 nmol/kg and was found to be at least 10 times less potent than ET-3. In animals anesthetized with urethane (1.5 g/kg intraperitoneally), the pressor responses induced by the endothelins and their intermediate precursors, as well as the pressor responses to angiotensin II and norepinephrine, were reduced by more than 60% (P < .01) when compared to ketamine/xylazine-treated animals. Big ET-3 was found inactive under urethane anesthesia. Ganglion blockade by hexamethonium did not affect the response to ET-1, big ET-1, ET-3, or big ET-3 in rats anesthetized with either ketamine/xylazine or urethane. On the other hand, big ET-2 (1-38), in contrast to ET-2 or big ET-1, did not release prostacyclin from the rat perfused lung, thus indicating that big ET-2 (1-38) is poorly converted in the pulmonary vasculature, and that the phosphoramidon-sensitive ECE responsible for the pressor effects of big ET-2 is localized elsewhere in the systemic circulation. Our results also show that the choice of anesthetics is crucial for the proper monitoring of the pressor responses to endothelins as well as other pressor agents. Nonetheless, even in what we consider as optimal conditions of anesthesia (threshold dose for the pressor response to ET-1 in ketamine/xylazine-treated rats: 0.01 nmol/kg), big ET-3 remains far less active than big ET-1 as a pressor peptide in the rat, suggesting a preferential processing of the latter by the ECE.
1 In the present study, we have pharmacologically characterized two novel mixed endothelin ET A /ET B receptor antagonists, namely BQ-928 and BQ-238, in ET A and ET B preparations, the rabbit carotid artery (RbCA) and the rabbit pulmonary artery (RbPA), respectively. These two antagonists were compared to established ET A (BQ-123 and BMS 182874), ET B (BQ-788) and mixed ET A /ET B (SB 209670) receptor antagonists. 2 In the RbCA, the ET A monoreceptor preparation, BQ-238 and BQ-928 had apparent a nities (pA 2 ) of 7.42+0.22 and 7.22+0.18, respectively, BQ-788 being inactive in this preparation. In the ET B monoreceptor preparation, the RbPA (when IRL-1620 was used as an ET B receptor agonist), the pA 2 for BQ-238 was 7.05+0.14 and for BQ-928 was 8.43+0.04. BQ-123 and BMS 182874 were inactive in this preparation. Similar to SB 209670, BQ-238 but not BQ-928 had a higher a nity for the ET A than the ET B receptor. 3 All of the antagonists were tested for their ability to block and reverse endothelin-1-induced vasoconstrictions in the rabbit perfused kidney. In this preparation endothelin-1-induced increases in vascular resistance have been shown to be mediated solely by ET A receptors. All compounds (except BQ-788) blocked the pressor e ects of endothelin within the kidney; the calculated IC 50 values for BQ-123, BMS 182874, SB 209670, BQ-928 and BQ-238 were 0.4 mM, 2 mM, 0.01 mM, 0.4 mM and 0.09 mM, respectively. 4 In all experiments in the rabbit perfused kidney, endothelin-1 was readministered for a third time, 60 min following cessation of infusion of the above-mentioned antagonists. The response to the third infusion of endothelin-1 following cessation of infusion of BQ-123, BMS 182874 and SB 209670 was not signi®cantly di erent from that to the third infusion of endothelin in control conditions. However, the response to endothelin-1 was signi®cantly higher than control in tissues pre-infused with BQ-788 or BQ-928 (56+9 and 41.6+15%, respectively, n=8 each, P50.05). 5 Our results suggest that in a system where ET A receptor activation is responsible for vasoconstriction and ET B -receptor activation for vasodilatation, ET A receptor selective antagonists or mixed ET A /ET B receptor antagonists which possess high a nity for ET A receptors do not induce hyperresponsiveness to endothelin-1. In contrast, ET B selective antagonists or mixed antagonists possessing a high a nity for ET B receptors (such as BQ-928) interfere with the ET B -receptor-dependent physiological antagonism of endothelin-1-induced pressor responses in these same tissues.
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