{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,24]],"date-time":"2026-04-24T15:34:02Z","timestamp":1777044842040,"version":"3.51.4"},"reference-count":34,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"22","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2000,11,28]]},"abstract":"<jats:p><jats:italic>Background<\/jats:italic>\u2014Endothelin (ET)-1 plays an important role in the pathogenesis of deoxycorticosterone acetate (DOCA)-salt\u2013induced hypertension. We evaluated the pathological role of ET<jats:sub>B<\/jats:sub>receptors in DOCA-salt\u2013induced hypertension, cardiovascular hypertrophy, and renal damage by using the spotting-lethal (<jats:italic>sl<\/jats:italic>) rat, which carries a naturally occurring deletion in the ET<jats:sub>B<\/jats:sub>receptor gene.<\/jats:p><jats:p><jats:italic>Methods and Results<\/jats:italic>\u2014Homozygous (<jats:italic>sl<\/jats:italic>\/<jats:italic>sl<\/jats:italic>) rats exhibit abnormal development of neural crest\u2013derived epidermal melanocytes and the enteric nervous system, and they do not live beyond 1 month because of intestinal aganglionosis and intestinal obstruction. The dopamine \u03b2-hydroxylase (D\u03b2H) promoter was used to direct ET<jats:sub>B<\/jats:sub>transgene expression in<jats:italic>sl<\/jats:italic>\/<jats:italic>sl<\/jats:italic>rats to support normal enteric nervous system development. D\u03b2H-ET<jats:sub>B<\/jats:sub><jats:italic>sl\/sl<\/jats:italic>rats live into adulthood and are healthy, expressing ET<jats:sub>B<\/jats:sub>receptors in adrenal glands and other adrenergic neurons. When homozygous (<jats:italic>sl<\/jats:italic>\/<jats:italic>sl<\/jats:italic>) and wild-type (+\/+) rats, all of which were transgenic, were treated with DOCA-salt, homozygous rats exhibited earlier and higher increases in systolic blood pressure than did wild-type rats. Chronic treatment with ABT-627, an ET<jats:sub>A<\/jats:sub>receptor antagonist, completely suppressed DOCA-salt\u2013induced hypertension in both groups. Renal dysfunction and histological damage were more severe in homozygous than in wild-type rats. Marked vascular hypertrophy was observed in homozygous rats than in wild-type rats. Renal and vascular injuries were significantly improved by ABT-627. In DOCA-salt\u2013treated homozygous rats, there were notable increases in renal, urinary, and aortic ET-1, all of which were normalized by ABT-627.<\/jats:p><jats:p><jats:italic>Conclusions<\/jats:italic>\u2014ET<jats:sub>B<\/jats:sub>-mediated actions are protective in the pathogenesis of DOCA-salt\u2013induced hypertension. Enhanced ET-1 production and ET<jats:sub>A<\/jats:sub>-mediated actions are responsible for the increased susceptibility to DOCA-salt hypertension and tissue injuries in ET<jats:sub>B<\/jats:sub>receptor\u2013deficient rats.<\/jats:p>","DOI":"10.1161\/01.cir.102.22.2765","type":"journal-article","created":{"date-parts":[[2012,6,12]],"date-time":"2012-06-12T00:42:29Z","timestamp":1339461749000},"page":"2765-2773","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":54,"title":["Exaggerated Vascular and Renal Pathology in Endothelin-B Receptor\u2013Deficient Rats With Deoxycorticosterone Acetate\u2013Salt Hypertension"],"prefix":"10.1161","volume":"102","author":[{"given":"Yasuo","family":"Matsumura","sequence":"first","affiliation":[{"name":"From the Department of Pharmacology (Y.M., T.K., Y.K., F.K., M.T.), Osaka University of Pharmaceutical Sciences, Nasahara, Takatsuki, Osaka, Japan; the Diabetes and Vascular Research Division (J.L.W., T.J.O.), Abbott Laboratories, Abbott Park, Ill; and the Howard Hughes Medical Institute (C.E.G., M.Y), Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Toshihiko","family":"Kuro","sequence":"additional","affiliation":[{"name":"From the Department of Pharmacology (Y.M., T.K., Y.K., F.K., M.T.), Osaka University of Pharmaceutical Sciences, Nasahara, Takatsuki, Osaka, Japan; the Diabetes and Vascular Research Division (J.L.W., T.J.O.), Abbott Laboratories, Abbott Park, Ill; and the Howard Hughes Medical Institute (C.E.G., M.Y), Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yutaka","family":"Kobayashi","sequence":"additional","affiliation":[{"name":"From the Department of Pharmacology (Y.M., T.K., Y.K., F.K., M.T.), Osaka University of Pharmaceutical Sciences, Nasahara, Takatsuki, Osaka, Japan; the Diabetes and Vascular Research Division (J.L.W., T.J.O.), Abbott Laboratories, Abbott Park, Ill; and the Howard Hughes Medical Institute (C.E.G., M.Y), Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fumiko","family":"Konishi","sequence":"additional","affiliation":[{"name":"From the Department of Pharmacology (Y.M., T.K., Y.K., F.K., M.T.), Osaka University of Pharmaceutical Sciences, Nasahara, Takatsuki, Osaka, Japan; the Diabetes and Vascular Research Division (J.L.W., T.J.O.), Abbott Laboratories, Abbott Park, Ill; and the Howard Hughes Medical Institute (C.E.G., M.Y), Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masanori","family":"Takaoka","sequence":"additional","affiliation":[{"name":"From the Department of Pharmacology (Y.M., T.K., Y.K., F.K., M.T.), Osaka University of Pharmaceutical Sciences, Nasahara, Takatsuki, Osaka, Japan; the Diabetes and Vascular Research Division (J.L.W., T.J.O.), Abbott Laboratories, Abbott Park, Ill; and the Howard Hughes Medical Institute (C.E.G., M.Y), Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jerry L.","family":"Wessale","sequence":"additional","affiliation":[{"name":"From the Department of Pharmacology (Y.M., T.K., Y.K., F.K., M.T.), Osaka University of Pharmaceutical Sciences, Nasahara, Takatsuki, Osaka, Japan; the Diabetes and Vascular Research Division (J.L.W., T.J.O.), Abbott Laboratories, Abbott Park, Ill; and the Howard Hughes Medical Institute (C.E.G., M.Y), Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Terry J.","family":"Opgenorth","sequence":"additional","affiliation":[{"name":"From the Department of Pharmacology (Y.M., T.K., Y.K., F.K., M.T.), Osaka University of Pharmaceutical Sciences, Nasahara, Takatsuki, Osaka, Japan; the Diabetes and Vascular Research Division (J.L.W., T.J.O.), Abbott Laboratories, Abbott Park, Ill; and the Howard Hughes Medical Institute (C.E.G., M.Y), Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cheryl E.","family":"Gariepy","sequence":"additional","affiliation":[{"name":"From the Department of Pharmacology (Y.M., T.K., Y.K., F.K., M.T.), Osaka University of Pharmaceutical Sciences, Nasahara, Takatsuki, Osaka, Japan; the Diabetes and Vascular Research Division (J.L.W., T.J.O.), Abbott Laboratories, Abbott Park, Ill; and the Howard Hughes Medical Institute (C.E.G., M.Y), Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masashi","family":"Yanagisawa","sequence":"additional","affiliation":[{"name":"From the Department of Pharmacology (Y.M., T.K., Y.K., F.K., M.T.), Osaka University of Pharmaceutical Sciences, Nasahara, Takatsuki, Osaka, Japan; the Diabetes and Vascular Research Division (J.L.W., T.J.O.), Abbott Laboratories, Abbott Park, Ill; and the Howard Hughes Medical Institute (C.E.G., M.Y), Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas."}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"276","reference":[{"key":"e_1_3_2_1_2","doi-asserted-by":"publisher","DOI":"10.1161\/hyp.25.6.1135"},{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1161\/hyp.25.6.1191"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.1995.tb16626.x"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.hyp.24.2.183"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.1995.tb13292.x"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1254\/jjp.70.313"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1161\/hyp.33.2.759"},{"key":"e_1_3_2_8_2","unstructured":"Ruschitzka F Noll G Shaw S et al. Endothelin and endothelin receptor antagonists in cardiovascular disease. J Hypertens. 1998;16(suppl 8):S13\u2013S23."},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjp.0701224"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.93.2.867"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1242\/dev.121.11.3787"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI3702"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI8609"},{"key":"e_1_3_2_14_2","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1016\/S0022-3565(25)12297-0","volume":"276","year":"1996","unstructured":"Opgenorth TJ, Adler AL, Calzadilla SV, et al. Pharmacological characterization of A-127722: an orally active and highly potent ETA-selective receptor antagonist. J Pharmacol Exp Ther. 1996;276:473\u2013481.","journal-title":"J Pharmacol Exp Ther"},{"key":"e_1_3_2_15_2","first-page":"H422","volume":"266","year":"1994","unstructured":"Hisaki K, Matsumura Y, Maekawa H, et al. Conversion of big ET-1 in the rat lung: role of phosphoramidon-sensitive endothelin-1-converting enzyme. Am J Physiol. 1994;266:H422\u2013H428.","journal-title":"Am J Physiol"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-2999(99)00865-1"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjp.0703157"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpregu.1998.275.1.R245"},{"key":"e_1_3_2_19_2","doi-asserted-by":"crossref","unstructured":"Kassab S Miller T Novak J et al. Endothelin-A receptor antagonism attenuates the hypertension and renal injury in Dahl salt-sensitive rats. Hypertension. 1998;31(pt 2):397\u2013402.","DOI":"10.1161\/01.HYP.31.1.397"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1161\/hyp.31.4.995"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/0014-5793(96)00212-8"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1248\/bpb.21.800"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.hyp.21.3.294"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.hyp.21.6.916"},{"key":"e_1_3_2_25_2","doi-asserted-by":"crossref","unstructured":"Barton M d\u2019Uscio LV Shaw S et al. ETA receptor blockade prevents increased tissue endothelin-1 vascular hypertrophy and endothelial dysfunction in salt-sensitive hypertension. Hypertension. 1998;31(pt 2):499\u2013504.","DOI":"10.1161\/01.HYP.31.1.499"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0024-3205(96)80001-4"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1096\/fasebj.3.2.2521610"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.hyp.24.2.227"},{"key":"e_1_3_2_29_2","doi-asserted-by":"crossref","first-page":"977","DOI":"10.1016\/S0022-3565(24)37677-3","volume":"286","year":"1998","unstructured":"Shimizu T, Kurodo T, Ikeda M, et al. Potential contribution of endothelin to renal abnormalities in glycerol-induced acute renal failure in rats. J Pharmacol Exp Ther. 1998;286:977\u2013983.","journal-title":"J Pharmacol Exp Ther"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199405193302008"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/0922-4106(92)90109-9"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI114081"},{"key":"e_1_3_2_33_2","doi-asserted-by":"crossref","first-page":"1091","DOI":"10.1016\/S0022-3565(25)38603-9","volume":"268","year":"1994","unstructured":"Brooks DP, DePalma PD, Pullen M, et al. Characterization of canine renal endothelin receptor subtypes and their function. J Pharmacol Exp Ther. 1994;268:1091\u20131097.","journal-title":"J Pharmacol Exp Ther"},{"key":"e_1_3_2_34_2","unstructured":"Kimura G Brenner BM. The renal basis for salt sensitivity in hypertension. In: Laragh JH Brenner BM eds. Hypertension: Pathophysiology Diagnosis and Management. New York NY: Raven Press; 1995:1569\u20131588."}],"container-title":["Circulation"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/01.CIR.102.22.2765","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,30]],"date-time":"2025-03-30T20:19:03Z","timestamp":1743365943000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/01.CIR.102.22.2765"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2000,11,28]]},"references-count":34,"journal-issue":{"issue":"22","published-print":{"date-parts":[[2000,11,28]]}},"alternative-id":["10.1161\/01.CIR.102.22.2765"],"URL":"https:\/\/doi.org\/10.1161\/01.cir.102.22.2765","relation":{},"ISSN":["0009-7322","1524-4539"],"issn-type":[{"value":"0009-7322","type":"print"},{"value":"1524-4539","type":"electronic"}],"subject":[],"published":{"date-parts":[[2000,11,28]]},"assertion":[{"value":"2000-04-26","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2000-06-21","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2000-11-28","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}