{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T00:21:08Z","timestamp":1793319668586,"version":"4.5.0"},"reference-count":35,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"15","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2022,8,2]]},"abstract":"<jats:sec sec-type=\"background\" xml:lang=\"en\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p xml:lang=\"en\">A single dose of small interfering RNA (siRNA) targeting liver angiotensinogen eliminates hepatic angiotensinogen and lowers blood pressure. Angiotensinogen elimination raises concerns for clinical application because an angiotensin rise is needed to maintain perfusion pressure during hypovolemia. Here, we investigated whether conventional vasopressors can raise arterial pressure after angiotensinogen depletion.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Methods and Results<\/jats:title>\n                    <jats:p xml:lang=\"en\">Spontaneously hypertensive rats on a low\u2010salt diet were treated with siRNA (10\u2009mg\/kg fortnightly) for 4\u2009weeks, supplemented during the final 2\u2009weeks with fludrocortisone (6\u2009mg\/kg per day), the \u03b1\u2010adrenergic agonist midodrine (4\u2009mg\/kg per day), or a high\u2010salt diet (all groups n=6\u20137). Pressor responsiveness to angiotensin II and norepinephrine was assessed before and after siRNA administration. Blood pressure was measured via radiotelemetry. Depletion of liver angiotensinogen by siRNA lowered plasma angiotensinogen concentrations by 99.2\u00b10.1% and mean arterial pressure by 19\u2009mm\u2009Hg. siRNA\u2010mediated blood pressure lowering was rapidly reversed by intravenous angiotensin II or norepinephrine, or gradually reversed by fludrocortisone or high salt intake. Midodrine had no effect. Unexpectedly, fludrocortisone partially restored plasma angiotensinogen concentrations in siRNA\u2010treated rats, and nearly abolished plasma renin concentrations. To investigate whether this angiotensinogen originated from nonhepatic sources, fludrocortisone was administered to mice lacking hepatic angiotensinogen. Fludrocortisone did not increase angiotensinogen in these mice, implying that the rise in angiotensinogen in the siRNA\u2010treated rats must have depended on the liver, most likely reflecting diminished cleavage by renin.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p xml:lang=\"en\">Intact pressor responsiveness to conventional vasopressors provides pharmacological means to regulate the blood pressure\u2013lowering effect of angiotensinogen siRNA and may support future therapeutic implementation of siRNA.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/jaha.122.026426","type":"journal-article","created":{"date-parts":[[2022,7,25]],"date-time":"2022-07-25T08:09:42Z","timestamp":1658736582000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":39,"title":["Conventional Vasopressor and Vasopressor\u2010Sparing Strategies to Counteract the Blood Pressure\u2013Lowering Effect of Small Interfering RNA Targeting Angiotensinogen"],"prefix":"10.1161","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9138-6639","authenticated-orcid":false,"given":"Estrellita","family":"Uijl","sequence":"first","affiliation":[{"name":"Division of Vascular Medicine and Pharmacology, Department of Internal Medicine Erasmus MC, University Medical Center Rotterdam Rotterdam the Netherlands"},{"name":"Division of Nephrology and Transplantation, Department of Internal Medicine Erasmus MC, University Medical Center Rotterdam Rotterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dien","family":"Ye","sequence":"additional","affiliation":[{"name":"Division of Vascular Medicine and Pharmacology, Department of Internal Medicine Erasmus MC, University Medical Center Rotterdam Rotterdam the Netherlands"},{"name":"Saha Cardiovascular Research Center and Department of Physiology University of Kentucky Lexington KY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3243-460X","authenticated-orcid":false,"given":"Liwei","family":"Ren","sequence":"additional","affiliation":[{"name":"Division of Vascular Medicine and Pharmacology, Department of Internal Medicine Erasmus MC, University Medical Center Rotterdam Rotterdam the Netherlands"},{"name":"Department of Pharmacy Shenzhen People\u2019s Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital Southern University of Science and Technology) Shenzhen China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katrina M.","family":"Mirabito Colafella","sequence":"additional","affiliation":[{"name":"Cardiovascular Program, Biomedicine Discovery Institute and Department of Physiology Monash University Melbourne Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"van Veghel","sequence":"additional","affiliation":[{"name":"Division of Vascular Medicine and Pharmacology, Department of Internal Medicine Erasmus MC, University Medical Center Rotterdam Rotterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2061-6737","authenticated-orcid":false,"given":"Ingrid M.","family":"Garrelds","sequence":"additional","affiliation":[{"name":"Division of Vascular Medicine and Pharmacology, Department of Internal Medicine Erasmus MC, University Medical Center Rotterdam Rotterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0577-2558","authenticated-orcid":false,"given":"Hong S.","family":"Lu","sequence":"additional","affiliation":[{"name":"Saha Cardiovascular Research Center and Department of Physiology University of Kentucky Lexington KY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2093-3775","authenticated-orcid":false,"given":"Alan","family":"Daugherty","sequence":"additional","affiliation":[{"name":"Saha Cardiovascular Research Center and Department of Physiology University of Kentucky Lexington KY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8738-3571","authenticated-orcid":false,"given":"Ewout J.","family":"Hoorn","sequence":"additional","affiliation":[{"name":"Division of Nephrology and Transplantation, Department of Internal Medicine Erasmus MC, University Medical Center Rotterdam Rotterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Nioi","sequence":"additional","affiliation":[{"name":"Alnylam Pharmaceuticals Cambridge MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Don","family":"Foster","sequence":"additional","affiliation":[{"name":"Alnylam Pharmaceuticals Cambridge MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5052-3585","authenticated-orcid":false,"given":"A. 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