The aim of this study was to identify the role of chymase in the conversion of exogenously administered Big endothelin-1 in the mouse in vivo. Real-time polymerase chain reaction analysis detected mRNA of mucosal mast cell chymases 4 and 5, endothelin-converting enzyme 1a, and neutral endopeptidase 24.11 in pulmonary, cardiac, and aorta homogenates derived from C57BL/6J mice, with the latter tissue expressing the highest levels of both chymase isoforms. Furthermore, hydrolysis of a fluorogenic peptide substrate, Suc-Leu-Leu-Val-Tyr-7-amino-4-methylcoumarin, was sensitive to the chymase inhibitors Suc-ValPro-PheS)-Gly-X-Phe-al, where X can be the amino acid Leu, Val, or Ile) (100 M) in supernatants extracted from the same tissue homogenates. In anesthetized mice, Big endothelin-1, endothelin-1 (1-31), and endothelin-1 triggered pressor responses (ED 50 s, 0.67, 0.89, and 0.16 nmol/kg) that were all reduced or potentiated by selective endothelin ET A or ET B receptor antagonists,, each at 1 mg/kg. The pressor responses to big endothelin-1 were significantly reduced by the neutral endopeptidase inhibitor thiorphan (DL-3-mercapto-2-benzylpropanoylglycine) (1 mg/kg) or the endothelin-converting enzyme inhibitorIn contrast, the responses to endothelin-1 (1-31) were abolished by thiorphan but unaffected by CGS 35066. In addition, Suc-Val-Pro-Phe P (OPh) 2 (20 -40 mg/kg) reduced, by more than 60%, the hemodynamic response to big endothelin-1 but not to endothelin-1 (1-31) and endothelin-1. Finally, intravenous administration of big endothelin-1 induced Suc-Val-Pro-Phe P -(OPh) 2 -sensitive increases in plasma-immunoreactive levels of endothelin-1 (1-31) and endothelin-1. The present study suggests that chymase plays a pivotal role in the conversion and cardiovascular properties of big endothelin-1 in vivo. , 2003). It is noteworthy that tissues derived from mice knockdown for both ECE-1 and ECE-2, which are nonviable past late gestational stages, still contain two thirds of mature endothelin peptides found in wild-type congeners, thus suggesting an important role for other pro- The authors of the present manuscript declare that there are no financial links, including consultancies with manufacturers of material or devices described in the article, and no links to the pharmaceutical industry or regulatory agencies or any other potential conflicts of interest.Article, publication date, and citation information can be found at http://jpet.aspetjournals.org. doi:10.1124/jpet.108.142992. -788, N-[N-[N-[(2,6-dimethyl-1-piperidinyl) ABBREVIATIONS: ECE, endothelin-converting enzyme; ET, endothelin; phosphoramidon, N-(␣-rhamno-pyranosyl-oxy-hydroxy-phosphinyl)-Leu-
1 We have developed a model to study the inhibitory properties of endogenous autacoids triggered by systemically-administered vasoactive peptides, on platelet aggregation ex vivo in the mouse. 2 Adenosine diphosphate (ADP) (0.5 ± 10 mM) induces a concentration-dependent aggregation of platelet-rich plasma derived from C57BL/6 mice. Intravenously-administered endothelin-1 (0.01 ± 1 nmol kg 71 ), the selective ET B agonist, IRL-1620 (0.01 ± 1 nmol kg 71 ) or bradykinin (1 ± 100 nmol kg 71 ) signi®cantly reduced in a dose-dependent fashion the ADP-induced platelet aggregation. 3 The non-selective cyclo-oxygenase (COX) inhibitor, indomethacin, a selective COX-2 inhibitor NS-398 or the prostacyclin synthase inhibitor, tranylcypromine (10 mg kg 71 ), markedly reduced the inhibitory properties of endothelin-1, whereas only a combination of both indomethacin, NS-398 or tranylcypromine and L-NAME (10 mg kg 71 ) were required to abolish the response to bradykinin. 4 An ET B -selective antagonist (BQ-788) or knockout of the B 2 receptor gene (in B 2 knockout mice) abolishes the platelet inhibitory properties of endothelin-1 and bradykinin, respectively. 5 Our results suggest that intravenously-administered endothelin-1 and bradykinin, through ET B and B 2 receptor activation, respectively, inhibit platelet aggregation ex vivo in the mouse. The inhibitory properties of endothelin-1 require the activation of COX-2 and the subsequent generation of prostacyclin. In addition to the two previously mentioned factors, nitric oxide is required for the anti-aggregatory e ects of bradykinin. British Journal of Pharmacology (2001) 132, 934 ± 940
In the vascular system, endothelin (ET) type B (ET(B)) receptors for ET-1 are located on endothelial and on venous and arterial smooth muscle cells. In the present study, we investigated the hemodynamic effects of chronic ET(B) receptor blockade at low and high doses in the Syrian Golden hamster. After 16 days of gavage with A-192621 (0.5 or 30 mg.kg(-1).day(-1)), a selective ET(B) receptor antagonist, hamsters were anesthetized with a mixture of ketamine and xylazine (87 and 13 mg/kg im, respectively), and basal mean arterial blood pressure (MAP) and pressor responses to exogenous ET-1 were evaluated. The lower dose of A-192621 (0.5 mg.kg(-1).day(-1)) did not modify basal MAP, whereas the higher dose (30 mg.kg(-1).day(-1)) increased MAP and plasma ET levels. Radio-telemetry recordings confirmed the increase in MAP induced by the higher dose of A-192621 in conscious hamsters. On the other hand, although the lower dose of A-192621 was devoid of intrinsic pressor effects, it markedly reduced the transient hypotensive phase induced by intravenously injected IRL-1620, a selective ET(B) receptor agonist. Finally, A-192621 (0.5 mg.kg(-1).day(-1)) alone or A-192621 (30 mg.kg(-1).day(-1)) + atrasentan (6 mg.kg(-1).day(-1)), a selective ET(A) receptor antagonist, potentiated the pressor response to exogenous ET-1. Our results suggest that, in the hamster, ET(B) receptors on vascular smooth muscle cells are importantly involved in the clearance of endogenous ET-1, whereas the same receptor type on the endothelium is solely involved in the vasodilatory responses to the pressor peptide. Blockade of endothelial and vascular smooth muscle cell ET(B) receptors triggers a marked potentiation of ET(A)-dependent increases in systemic resistance.
Background and purpose: The contribution of endothelin-1 (ET-1) to vascular hyper-reactivity associated with chronic ethanol intake, a major risk factor in several cardiovascular diseases, remains to be investigated. Experimental approach: The biphasic haemodynamic responses to ET-1 (0.01-0.1 nmol kg À1 , i.v.) or to the selective ET B agonist, IRL1620 (0.001-1.0 nmol kg À1 , i.v.), with or without ET A or ET B antagonists (BQ123 (c(DTrp-Dasp-Pro-Dval-Leu)) at 1 and 2.5 mg kg À1 and BQ788 (N-cis-2,6-dimethyl-piperidinocarbonyl-L-g-methylleucyl1-D-1methoxycarbonyltryptophanyl-Dnorleucine) at 0.25 mg kg À1 , respectively) were tested in anaesthetized rats, after 2 weeks' chronic ethanol treatment. Hepatic parameters and ET receptor protein levels were also determined. Key results: The initial hypotensive responses to ET-1 or IRL1620 were unaffected by chronic ethanol intake, whereas the subsequent pressor effects induced by ET-1, but not by IRL1620, were potentiated. BQ123 at 2.5 but not 1 mg kg À1 reduced the pressor responses to ET-1 in ethanol-treated rats. Conversely, BQ788 (0.25 mg kg À1 ) potentiated ET-1-induced increases in mean arterial blood pressure in control as well as in ethanol-treated rats. Interestingly, in the latter group, increases in heart rate, induced by ET-1 at a dose of 0.025 mg kg À1 were enhanced following ET B receptor blockade. Finally, we observed higher levels of ET A receptor in the heart and mesenteric artery and a reduction of ET B receptor protein levels in the aorta and kidney from rats chronically treated with ethanol. Conclusions and implications: Increased vascular reactivity to ET-1 and altered protein levels of ET A and ET B receptors could play a role in the pathogenesis of cardiovascular complications associated with chronic ethanol consumption.
RhEPO exerts a pleotropic effect on the endothelial ET-1/ET(B)R system. The increase in endothelial ET(B)R expression may contribute to maintaining normal BP during rhEPO administration in normal animals. Conversely, conditions with deficient ET(B)R expression, such as in ET(B)R(+/-) mice, may lead to hypertension while receiving the same therapy.
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