{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,21]],"date-time":"2026-02-21T10:31:31Z","timestamp":1771669891529,"version":"3.50.1"},"reference-count":52,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2021,3,16]]},"abstract":"<jats:sec xml:lang=\"en\">\n            <jats:title>Background<\/jats:title>\n            <jats:p xml:lang=\"en\">The long\u2010term effects of dipeptidyl peptidase 4 (DPP4) inhibitors on blood pressure and cardiovascular and renal health remain controversial. Herein, we investigated the extended (&gt;182\u00a0days) effects of DPP4 inhibition in a model of spontaneous hypertension, heart failure, diabetes mellitus, obesity and hyperlipidemia.<\/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\">\n              Adult obese spontaneously hypertensive heart failure rats (SHHF) were implanted with radio transmitters for measurement of arterial blood pressures. Two weeks later, SHHF were randomized to receive either a DPP4 inhibitor (sitagliptin, 80\u00a0mg\/kg per day in drinking water) or placebo. At the end of the radiotelemetry measurements, renal and cardiac function and histology, as well as other relevant biochemical parameters, were assessed. For the first 25\u00a0days, mean arterial blood pressures were similar in sitagliptin\u2010treated versus control SHHF; afterwards, mean arterial blood pressures increased more in sitagliptin\u2010treated SHHF (\n              <jats:italic>P<\/jats:italic>\n              &lt;0.000001). The time\u2010averaged mean arterial blood pressures from day 26 through 182 were 7.2\u00a0mm\u00a0Hg higher in sitagliptin\u2010treated SHHF. Similar changes were observed for systolic (8.6\u00a0mm\u00a0Hg) and diastolic (6.1\u00a0mm\u00a0Hg) blood pressures, and sitagliptin augmented hypertension throughout the light\u2010dark cycle. Long\u2010term sitagliptin treatment also increased kidney weights, renal vascular resistances, the excretion of kidney injury molecule\u20101 (indicates injury to proximal tubules), renal interstitial fibrosis, glomerulosclerosis, renal vascular hypertrophy, left ventricular dysfunction, right ventricular degeneration, and the ratios of collagen IV\/collagen III and collagen IV\/laminin in the right ventricle.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p xml:lang=\"en\">These findings indicate that, in some genetic backgrounds, long\u2010term DPP4 inhibitor treatment is harmful and identify an animal model to study mechanisms of, and test ways to prevent, DPP4 inhibitor\u2013induced pathological conditions.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/jaha.120.020088","type":"journal-article","created":{"date-parts":[[2021,3,8]],"date-time":"2021-03-08T10:16:35Z","timestamp":1615198595000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":2,"title":["Long\u2010Term Dipeptidyl Peptidase 4 Inhibition Worsens Hypertension and Renal and Cardiac Abnormalities in Obese Spontaneously Hypertensive Heart Failure Rats"],"prefix":"10.1161","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8101-6009","authenticated-orcid":false,"given":"Edwin K.","family":"Jackson","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Chemical Biology University of Pittsburgh School of Medicine Pittsburgh PA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zaichuan","family":"Mi","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Chemical Biology University of Pittsburgh School of Medicine Pittsburgh PA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Delbert G.","family":"Gillespie","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Chemical Biology University of Pittsburgh School of Medicine Pittsburgh PA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dongmei","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Chemical Biology University of Pittsburgh School of Medicine Pittsburgh PA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stevan P.","family":"Tofovic","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Chemical Biology University of Pittsburgh School of Medicine Pittsburgh PA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"276","reference":[{"key":"e_1_3_1_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.regpep.2004.06.001"},{"key":"e_1_3_1_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.metabol.2020.154242"},{"key":"e_1_3_1_4_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1307684"},{"key":"e_1_3_1_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(14)62225-X"},{"key":"e_1_3_1_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijcard.2014.09.038"},{"key":"e_1_3_1_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijcard.2014.12.017"},{"key":"e_1_3_1_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijcard.2016.02.146"},{"key":"e_1_3_1_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijcard.2014.12.029"},{"key":"e_1_3_1_10_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pmed.1002051"},{"key":"e_1_3_1_11_2","doi-asserted-by":"publisher","DOI":"10.1210\/en.2017-00416"},{"key":"e_1_3_1_12_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.00316.2016"},{"key":"e_1_3_1_13_2","doi-asserted-by":"publisher","DOI":"10.1159\/000348756"},{"key":"e_1_3_1_14_2","doi-asserted-by":"publisher","DOI":"10.1210\/en.2013-1096"},{"key":"e_1_3_1_15_2","doi-asserted-by":"publisher","DOI":"10.1002\/oby.20833"},{"key":"e_1_3_1_16_2","doi-asserted-by":"publisher","DOI":"10.1210\/en.2013-1920"},{"key":"e_1_3_1_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2019.104391"},{"key":"e_1_3_1_18_2","doi-asserted-by":"publisher","DOI":"10.1042\/CS20180031"},{"key":"e_1_3_1_19_2","doi-asserted-by":"publisher","DOI":"10.1097\/MNH.0000000000000291"},{"key":"e_1_3_1_20_2","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.119.13778"},{"key":"e_1_3_1_21_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00395-019-0743-0"},{"key":"e_1_3_1_22_2","doi-asserted-by":"publisher","DOI":"10.1093\/ndt\/gfy397"},{"key":"e_1_3_1_23_2","doi-asserted-by":"publisher","DOI":"10.4093\/dmj.2018.0181"},{"key":"e_1_3_1_24_2","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.114.04631"},{"key":"e_1_3_1_25_2","first-page":"83","article-title":"Context\u2010dependent effects of dipeptidyl peptidase 4 inhibitors","volume":"26","author":"Jackson EK.","year":"2017","unstructured":"Jackson EK. 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