{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T05:38:20Z","timestamp":1784266700651,"version":"3.55.0"},"reference-count":28,"publisher":"Portland Press Ltd.","issue":"1","content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2014,7,1]]},"abstract":"<jats:p>The somatic isozyme of ACE (angiotensin I-converting enzyme) comprises two distinct zinc-dependent catalytic domains with different substrate specificities for angiotensin I (cleaved selectively by the C-domain) and bradykinin (cleaved equally efficiently by both the N- and C-domains). Classical ACEIs (ACE inhibitors) target both domains, with side effects such as cough and angio-oedema being attributed, in part, to N-domain inhibition, probably through bradykinin accumulation. We questioned whether a novel C-domain-selective ACEI (lisW-S) has anti-hypertensive effects without influencing bradykinin status. AngII (angiotensin II)-dependent hypertension was studied in mice that express active human renin in the liver (TtRhRen). Compared with wild-type littermates, TtRhRen mice displayed cardiac hypertrophy and had significantly elevated SBP [systolic BP (blood pressure)] as determined by tail cuff sphygmomanometry (150\u00b13 compared with 112\u00b15 mmHg; P&amp;lt;0.05) and telemetry (163\u00b13 compared with 112\u00b12 mmHg; P&amp;lt;0.01). Treatment with the non-selective ACEI lisinopril (1\u00a0mg\/kg of body weight per day via an osmotic mini-pump for 2\u00a0weeks) reduced SBP (127\u00b13 compared with. 154\u00b16; P&amp;lt;0.05). Similarly, treatment with the C-domain selective ACEI lisW-S (lisinopril-tryptophan; 3.6\u00a0mg\/kg of body weight per day via an osmotic mini-pump for 2\u00a0weeks) reduced BP. Treatment with lisinopril or lisW-S significantly reduced levels of AngII in kidneys (~4-fold; P&amp;lt;0.001). Ang-(2\u20138) [angiotensin-2\u20138)] was significantly reduced by lisinopril, but not by lisW-S. Plasma bradykinin levels were significantly increased only in the lisinopril group. These data suggest that C-domain-selective ACEIs reduce BP and AngII levels similarly to classical ACEIs. C-domain-selective ACEIs have the potential to avoid undesirable effects on the bradykinin system common to classic ACEIs and may represent a novel approach to the treatment of hypertension.<\/jats:p>","DOI":"10.1042\/cs20130808","type":"journal-article","created":{"date-parts":[[2014,2,11]],"date-time":"2014-02-11T09:14:17Z","timestamp":1392110057000},"page":"57-63","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["Effects of a domain-selective ACE inhibitor in a mouse model of chronic angiotensin II-dependent hypertension"],"prefix":"10.1042","volume":"127","author":[{"given":"Dylan","family":"Burger","sequence":"first","affiliation":[{"name":"Kidney Research Centre, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy\u00a0L.","family":"Reudelhuber","sequence":"additional","affiliation":[{"name":"Clinical Research Institute of Montreal, Montreal, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aman","family":"Mahajan","sequence":"additional","affiliation":[{"name":"Department of Chemistry and South African Medical Research Council Drug Discovery and Development Research Unit, University of Cape Town, Rondebosch, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelly","family":"Chibale","sequence":"additional","affiliation":[{"name":"Department of Chemistry and South African Medical Research Council Drug Discovery and Development Research Unit, University of Cape Town, Rondebosch, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward\u00a0D.","family":"Sturrock","sequence":"additional","affiliation":[{"name":"Institute of Infectious Diseases and Molecular Medicine and Division of Medical Biochemistry, University of Cape Town, Cape Town, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rhian\u00a0M.","family":"Touyz","sequence":"additional","affiliation":[{"name":"Kidney Research Centre, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Canada"},{"name":"BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2014,3,10]]},"reference":[{"key":"2021113011082817000_B1","doi-asserted-by":"crossref","first-page":"1110","DOI":"10.1089\/ars.2012.4641","article-title":"Angiotensin II, NADPH oxidase, and redox signaling in the vasculature","volume":"19","author":"Nguyen Dinh Cat","year":"2013","journal-title":"Antioxid. Redox Signal."},{"key":"2021113011082817000_B2","doi-asserted-by":"crossref","first-page":"e11","DOI":"10.1017\/S1462399411001815","article-title":"Angiotensin II and the vascular phenotype in hypertension","volume":"13","author":"Savoia","year":"2011","journal-title":"Expert Rev. Mol. Med."},{"key":"2021113011082817000_B3","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1124\/pr.112.006809","article-title":"A modern understanding of the traditional and nontraditional biological functions of angiotensin-converting enzyme","volume":"65","author":"Bernstein","year":"2013","journal-title":"Pharmacol. Rev."},{"key":"2021113011082817000_B4","doi-asserted-by":"crossref","first-page":"11945","DOI":"10.1016\/S0021-9258(18)80158-2","article-title":"Mouse angiotensin-converting enzyme is a protein composed of two homologous domains","volume":"264","author":"Bernstein","year":"1989","journal-title":"J. Biol. Chem."},{"key":"2021113011082817000_B5","doi-asserted-by":"crossref","first-page":"9386","DOI":"10.1073\/pnas.85.24.9386","article-title":"Two putative active centers in human angiotensin I-converting enzyme revealed by molecular cloning","volume":"85","author":"Soubrier","year":"1988","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2021113011082817000_B6","doi-asserted-by":"crossref","first-page":"9002","DOI":"10.1016\/S0021-9258(18)31543-6","article-title":"The two homologous domains of human angiotensin I-converting enzyme are both catalytically active","volume":"266","author":"Wei","year":"1991","journal-title":"J. Biol. Chem."},{"key":"2021113011082817000_B7","doi-asserted-by":"crossref","first-page":"13398","DOI":"10.1016\/S0021-9258(18)42224-7","article-title":"The two homologous domains of human angiotensin I-converting enzyme interact differently with competitive inhibitors","volume":"267","author":"Wei","year":"1992","journal-title":"J. Biol. Chem."},{"key":"2021113011082817000_B8","doi-asserted-by":"crossref","first-page":"1143","DOI":"10.1007\/s00109-013-1051-z","article-title":"Rediscovering ACE: novel insights into the many roles of the angiotensin-converting enzyme","volume":"91","author":"Gonzalez-Villalobos","year":"2013","journal-title":"J. Mol. Med."},{"key":"2021113011082817000_B9","doi-asserted-by":"crossref","first-page":"9496","DOI":"10.1016\/S0021-9258(18)98378-X","article-title":"Differences in the properties and enzymatic specificities of the two active sites of angiotensin I-converting enzyme (kininase II). Studies with bradykinin and other natural peptides","volume":"268","author":"Jaspard","year":"1993","journal-title":"J. Biol. Chem."},{"key":"2021113011082817000_B10","doi-asserted-by":"crossref","first-page":"S17","DOI":"10.1097\/00004872-199509003-00004","article-title":"Putative mechanisms of cough after treatment with angiotensin converting enzyme inhibitors","volume":"13","author":"Semple","year":"1995","journal-title":"J. Hypertens. Suppl."},{"key":"2021113011082817000_B11","doi-asserted-by":"crossref","first-page":"169S","DOI":"10.1378\/chest.129.1_suppl.169S","article-title":"Angiotensin-converting enzyme inhibitor-induced cough: ACCP evidence-based clinical practice guidelines","volume":"129","author":"Dicpinigaitis","year":"2006","journal-title":"Chest"},{"key":"2021113011082817000_B12","doi-asserted-by":"crossref","first-page":"606","DOI":"10.1016\/S0022-3565(24)29576-8","article-title":"RXP 407, a selective inhibitor of the N-domain of angiotensin I-converting enzyme, blocks in\u00a0vivo the degradation of hemoregulatory peptide acetyl-Ser-Asp-Lys-Pro with no effect on angiotensin I hydrolysis","volume":"297","author":"Junot","year":"2001","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"2021113011082817000_B13","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1042\/BJ20100056","article-title":"Characterization of domain-selective inhibitor binding in angiotensin-converting enzyme using a novel derivative of lisinopril","volume":"428","author":"Watermeyer","year":"2010","journal-title":"Biochem. J."},{"key":"2021113011082817000_B14","doi-asserted-by":"crossref","first-page":"4616","DOI":"10.1016\/j.bmcl.2006.06.004","article-title":"Synthesis and molecular modeling of a lisinopril-tryptophan analogue inhibitor of angiotensin I-converting enzyme","volume":"16","author":"Nchinda","year":"2006","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"2021113011082817000_B15","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1152\/physiolgenomics.2000.4.1.67","article-title":"Contribution of circulating renin to local synthesis of angiotensin peptides in the heart","volume":"4","author":"Prescott","year":"2000","journal-title":"Physiol. 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Hum. Hypertens."},{"key":"2021113011082817000_B19","doi-asserted-by":"crossref","first-page":"854","DOI":"10.1161\/01.HYP.0000119190.06968.f1","article-title":"Effect of reduced angiotensin-converting enzyme gene expression and angiotensin-converting enzyme inhibition on angiotensin and bradykinin peptide levels in mice","volume":"43","author":"Campbell","year":"2004","journal-title":"Hypertension"},{"key":"2021113011082817000_B20","doi-asserted-by":"crossref","first-page":"1898","DOI":"10.1161\/ATVBAHA.110.222703","article-title":"Endothelial microparticle formation by angiotensin II is mediated via Ang II receptor type\u00a0I\/NADPH oxidase\/Rho kinase pathways targeted to lipid rafts","volume":"31","author":"Burger","year":"2011","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"2021113011082817000_B21","doi-asserted-by":"crossref","first-page":"E1","DOI":"10.1161\/01.HYP.35.2.e1","article-title":"Long-term telemetric recording of arterial pressure and heart rate in mice fed basal and high NaCl diets","volume":"35","author":"Carlson","year":"2000","journal-title":"Hypertension"},{"key":"2021113011082817000_B22","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1161\/01.HYP.0000085331.22169.3F","article-title":"Attenuated responses to angiotensin II in follitropin receptor knockout mice, a model of menopause-associated hypertension","volume":"42","author":"Javeshghani","year":"2003","journal-title":"Hypertension"},{"key":"2021113011082817000_B23","doi-asserted-by":"crossref","first-page":"1007","DOI":"10.1111\/j.1440-1681.2006.04479.x","article-title":"Phenotyping the level of blood pressure by telemetry in mice","volume":"33","author":"Van Vliet","year":"2006","journal-title":"Clin. Exp. Pharmacol. Physiol."},{"key":"2021113011082817000_B24","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1161\/HYPERTENSIONAHA.107.097865","article-title":"Angiotensin-converting enzyme C-terminal catalytic domain is the main site of angiotensin I cleavage in\u00a0vivo","volume":"51","author":"Fuchs","year":"2008","journal-title":"Hypertension"},{"key":"2021113011082817000_B25","doi-asserted-by":"crossref","first-page":"15946","DOI":"10.1074\/jbc.M400149200","article-title":"Role of the N-terminal catalytic domain of angiotensin-converting enzyme investigated by targeted inactivation in mice","volume":"279","author":"Fuchs","year":"2004","journal-title":"J. Biol. 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