{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T15:52:32Z","timestamp":1784735552824,"version":"3.55.0"},"reference-count":46,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ: Heart Failure"],"published-print":{"date-parts":[[2026,6]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>Symptomatic hypotension can limit sacubitril\/valsartan therapy. Neprilysin inhibition may augment vasodilators, such as bradykinin. We hypothesized that bradykinin contributes to blood pressure (BP) lowering with sacubitril\/valsartan in stable ambulatory patients with heart failure and reduced ejection fraction &lt;50%.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>In a randomized, double-blind crossover trial, participants received intravenous infusion of the bradykinin B2 receptor inhibitor icatibant and a matching placebo for 6 hours following sacubitril\/valsartan dosing at acute initiation (n=36) and after 8 weeks of chronic therapy (n=30). The primary end point was maximal change in mean arterial pressure (MAP). Plasma natriuretic peptides, urine cyclic GMP, urine volume, sodium excretion, renal plasma flow, and renovascular resistance were measured.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      The first dose of sacubitril\/valsartan (50 mg) significantly lowered MAP by a mean maximum of \u224810 mm\u2009Hg, which was similar during icatibant and placebo. Within 6 hours after the first sacubitril\/valsartan dose, plasma ANP (atrial natriuretic peptide [1\u201328]) and urine cGMP\/creatinine increased significantly, whereas B-type NP (1\u201332) and NT-proBNP (N-terminal pro B-type natriuretic peptide) did not. Icatibant partially blunted the rise in urine cGMP\/creatinine, but did not affect other parameters. After 8 weeks of sacubitril\/valsartan titrated to maximally tolerated doses, baseline ANP (1\u201328) remained increased, and baseline MAP and NT-proBNP were decreased compared with before sacubitril\/valsartan initiation. MAP decreased further after dose administration of sacubitril\/valsartan, and the mean maximal reduction in MAP was significantly attenuated during icatibant compared with placebo (9 versus 12 mm\u2009Hg;\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      =0.013). Icatibant also decreased renal plasma flow and increased renal vascular resistance after chronic dosing, without affecting heart rate, urine volume, urine sodium, cGMP\/creatinine, or natriuretic peptides.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>BP lowering with sacubitril\/valsartan occurs with both acute and chronic dosing. ANP (1\u201328) appears to mediate the initial BP reduction, whereas bradykinin contributes to BP lowering after dosing during chronic therapy. Clarifying these mechanisms may inform clinical management to optimize the benefit of this important heart failure and reduced ejection fraction therapy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>REGISTRATION:<\/jats:title>\n                    <jats:p>\n                      URL:\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/www.clinicaltrials.gov\">https:\/\/www.clinicaltrials.gov<\/jats:ext-link>\n                      ; Unique identifier: NCT04113109.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circheartfailure.125.014117","type":"journal-article","created":{"date-parts":[[2026,4,24]],"date-time":"2026-04-24T09:00:20Z","timestamp":1777021220000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":1,"title":["Modest Contribution of Bradykinin to Blood Pressure Reduction by Sacubitril\/Valsartan in Chronic Heart Failure"],"prefix":"10.1161","volume":"19","clinical-trial-number":[{"clinical-trial-number":"nct04113109","registry":"10.18810\/clinical-trials-gov"}],"author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2191-3485","authenticated-orcid":true,"given":"Deepak K.","family":"Gupta","sequence":"first","affiliation":[{"name":"Vanderbilt Translational and Clinical Cardiovascular Research Center and Division of Cardiovascular Medicine (D.K.G., L.W.S.), Vanderbilt University Medical Center, Nashville, TN."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8626-5258","authenticated-orcid":true,"given":"Lynne W.","family":"Stevenson","sequence":"additional","affiliation":[{"name":"Vanderbilt Translational and Clinical Cardiovascular Research Center and Division of Cardiovascular Medicine (D.K.G., L.W.S.), Vanderbilt University Medical Center, Nashville, TN."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8703-2678","authenticated-orcid":true,"given":"Erica M.","family":"Garner","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetes, and Metabolism (E.M.G.), Vanderbilt University Medical Center, Nashville, TN."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2510-4266","authenticated-orcid":true,"given":"Christopher","family":"Maulion","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Yale University School of Medicine, New Haven, CT (C.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0047-8330","authenticated-orcid":true,"given":"Hui","family":"Nian","sequence":"additional","affiliation":[{"name":"Department of Biostatistics (H.N.), Vanderbilt University Medical Center, Nashville, TN."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia R.","family":"Wright","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacology (P.R.W., S.W.), Vanderbilt University Medical Center, Nashville, TN."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9831-6190","authenticated-orcid":true,"given":"Adina F.","family":"Turcu","sequence":"additional","affiliation":[{"name":"Division of Metabolism, Endocrinology, and Diabetes, University of Michigan School of Medicine, Ann Arbor (A.F.T.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shouzou","family":"Wei","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacology (P.R.W., S.W.), Vanderbilt University Medical Center, Nashville, TN."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7109-3142","authenticated-orcid":true,"given":"Nancy J.","family":"Brown","sequence":"additional","affiliation":[{"name":"Yale University School of Medicine, New Haven, CT (N.J.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1409077"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.119.044586"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijcard.2021.01.061"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIR.0000000000001063"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1002\/ejhf.548"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1002\/ejhf.799"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jchf.2020.06.020"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1002\/ejhf.1342"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jchf.2020.09.013"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCHEARTFAILURE.122.010111"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.3389\/fmed.2018.00257"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi00282a035"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/0196-9781(84)90020-2"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.hyp.35.6.1314"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10741-024-10393-y"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/hr.2010.82"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.clpt.2004.06.004"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/0014-2999(92)90661-m"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.cir.0000046268.59922.a4"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2125.1994.tb04360.x"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.cir.102.18.2190"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI111176"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.3109\/00365517209084290"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cardfail.2021.05.026"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jsbmb.2025.106717"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199810293391804"},{"key":"e_1_3_3_28_2","volume-title":"Design and analysis of cross-over trials","author":"Jones B","unstructured":"Jones B, Kenward MG. Design and analysis of cross-over trials. Chapman and Hall\/CRC; 2003."},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCHEARTFAILURE.115.002735"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jchf.2020.05.005"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0104001"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/s0014-2999(99)00115-6"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.hyp.29.3.757"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2104508"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2022.10.033"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.1042\/cs0950547"},{"key":"e_1_3_3_37_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2016.09.931"},{"key":"e_1_3_3_38_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2024.02.035"},{"key":"e_1_3_3_39_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jchf.2022.09.009"},{"key":"e_1_3_3_40_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tetlet.2011.11.029"},{"key":"e_1_3_3_41_2","doi-asserted-by":"publisher","DOI":"10.1056\/nejmoa1812851"},{"key":"e_1_3_3_42_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000105765.54573.60"},{"key":"e_1_3_3_43_2","doi-asserted-by":"publisher","DOI":"10.1007\/s40262-017-0558-9"},{"key":"e_1_3_3_44_2","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.12331"},{"key":"e_1_3_3_45_2","doi-asserted-by":"publisher","DOI":"10.1159\/000489898"},{"key":"e_1_3_3_46_2","doi-asserted-by":"publisher","DOI":"10.1177\/0091270009343932"},{"key":"e_1_3_3_47_2","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.116.08484"}],"container-title":["Circulation: Heart Failure"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/CIRCHEARTFAILURE.125.014117","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,21]],"date-time":"2026-06-21T18:00:33Z","timestamp":1782064833000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/CIRCHEARTFAILURE.125.014117"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6]]},"references-count":46,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2026,6]]}},"alternative-id":["10.1161\/CIRCHEARTFAILURE.125.014117"],"URL":"https:\/\/doi.org\/10.1161\/circheartfailure.125.014117","relation":{},"ISSN":["1941-3289","1941-3297"],"issn-type":[{"value":"1941-3289","type":"print"},{"value":"1941-3297","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6]]},"assertion":[{"value":"2025-12-29","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-04-03","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-04-24","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}