{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,21]],"date-time":"2025-10-21T14:55:18Z","timestamp":1761058518696},"reference-count":34,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2009,2,10]],"date-time":"2009-02-10T00:00:00Z","timestamp":1234224000000},"content-version":"vor","delay-in-days":4242,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[1997,7]]},"abstract":"<jats:p>\n<jats:list list-type=\"explicit-label\">\n<jats:list-item><jats:p>Chronic treatment with a combined ET<jats:sub>A<\/jats:sub>\/ET<jats:sub>B<\/jats:sub> endothelin receptor antagonist has been shown to reduce blood pressure in experimental rat models of hypertension in which endothelin\u20101 gene overexpression occurs in the walls of blood vessels, particularly small, resistance\u2010sized arteries, but not in those genetic or experimental models of hypertension in which there is no overexpression of vascular endothelin\u20101. Failure of some experimental models of hypertension to respond to treatment with the combined ET<jats:sub>A<\/jats:sub>\/ET<jats:sub>B<\/jats:sub> endothelin antagonist may be due in part to blockade of vasorelaxant endothelial ET<jats:sub>B<\/jats:sub> receptors which could in theory reduce the efficacy of endothelin antagonism.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>In this study the orally active ET<jats:sub>A<\/jats:sub>\u2010selective endothelin antagonists A\u2010127722.5 and LU\u2003135252 were used in chronic experiments on deoxycorticosterone acetate (DOCA)\u2010salt hypertensive rats (which overexpress vascular endothelin\u20101 and respond with blood pressure lowering to combined ET<jats:sub>A<\/jats:sub>\/ET<jats:sub>B<\/jats:sub> endothelin receptor antagonism), on spontaneously hypertensive rats (SHR) (which do not overexpress vascular endothelin\u20101 and do not respond with blood pressure lowering to the combined ET<jats:sub>A<\/jats:sub>\/ET<jats:sub>B<\/jats:sub> receptor antagonist), and in 1\u2010kidney 1 clip Goldblatt (1\u2010K 1C) hypertensive rats (which present mild overexpression of vascular endothelin\u20101 but do not respond with blood pressure lowering to the combined ET<jats:sub>A<\/jats:sub>\/ET<jats:sub>B<\/jats:sub> receptor antagonist). Additionally, it has been suggested that interruption of the renin\u2010angiotensin system may sensitize responses to endothelin antagonism. Accordingly, SHR were treated with an angiotensin converting enzyme inhibitor, cilazapril, in addition to the ET<jats:sub>A<\/jats:sub> receptor antagonist.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Blood pressure of DOCA\u2010salt hypertensive rats was lowered by a mean of 24 and of 27\u2003mmHg (<jats:italic>P<\/jats:italic>&lt;0.01) by A\u2010127722.5 after 4 weeks of treatment, when given orally at two different doses (10 and 30\u2003mg\u2003kg<jats:sup>\u22121<\/jats:sup>\u2003day<jats:sup>\u22121<\/jats:sup>), and by 18\u2003mmHg by LU\u2003135252 50\u2003mg\u2003kg<jats:sup>\u22121<\/jats:sup>\u2003day<jats:sup>\u22121<\/jats:sup>.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>SHR treated with A\u2010127722.5 for 8 weeks starting at 12 weeks of age exhibited the same progressive rise in blood pressure as untreated SHR. Addition of cilazapril resulted in similar reduction of blood pressure in A\u2010127722.5\u2010treated and untreated SHR.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Treatment of 1\u2010K 1C hypertensive rats with the dose of LU\u2003135252 which lowered blood pressure in DOCA\u2010salt hypertensive rats did not cause any reduction in blood pressure relative to untreated rats.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>These results demonstrate that treatment with either dose of the selective ET<jats:sub>A<\/jats:sub> receptor antagonists A\u2010127722.5 or LU\u2003135252 caused reductions in blood pressure similar to those obtained for a combined ET<jats:sub>A<\/jats:sub>\/ET<jats:sub>B<\/jats:sub> endothelin antagonist. Blood pressure was lowered only in hypertensive rats known to overexpress vascular endothelin\u20101 (DOCA\u2010salt hypertensive rats) but not in those which do not (SHR) or only have mild vascular overexpression of endothelin\u20101 gene (1\u2010K 1C hypertensive rats). Reduction in activity of the renin\u2010angiotensin system in SHR did not sensitize blood pressure to potential hypotensive effects of an ET<jats:sub>A<\/jats:sub>\u2010selective receptor antagonist.<\/jats:p><\/jats:list-item>\n<\/jats:list>\n<\/jats:p>","DOI":"10.1038\/sj.bjp.0701224","type":"journal-article","created":{"date-parts":[[2006,8,25]],"date-time":"2006-08-25T17:11:32Z","timestamp":1156525892000},"page":"935-940","update-policy":"http:\/\/dx.doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":50,"title":["Effect of chronic ET<sub>A<\/sub>\u2010selective endothelin receptor antagonism on blood pressure in experimental and genetic hypertension in rats"],"prefix":"10.1111","volume":"121","author":[{"given":"Ernesto L","family":"Schiffrin","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andr\u00e9","family":"Turgeon","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Li Y","family":"Deng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2009,2,10]]},"reference":[{"key":"e_1_2_5_2_1","doi-asserted-by":"crossref","first-page":"940","DOI":"10.1097\/00005344-199212000-00014","article-title":"Pharmacologic characterization of an endothelinA (ETA) receptor antagonist in conscious rats","volume":"20","author":"Bazil M.K.","year":"1992","journal-title":"J. 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