{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T16:17:25Z","timestamp":1753892245776,"version":"3.41.2"},"reference-count":52,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,6,14]],"date-time":"2023-06-14T00:00:00Z","timestamp":1686700800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009647","name":"Ministry of Health","doi-asserted-by":"publisher","award":["NV18-02-00014"],"award-info":[{"award-number":["NV18-02-00014"]}],"id":[{"id":"10.13039\/100009647","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Physiol."],"abstract":"<jats:p>The aim of the study was to clarify the role of the interplay between hypertension and the renin-angiotensin system (RAS) in the pathophysiology of myocardial ischemia\/reperfusion (I\/R) injury. We hypothesized that in the late phase of hypertension with already developed signs of end-organ damage, inappropriate RAS activation could impair cardiac tolerance to I\/R injury. Experiments were performed in male <jats:italic>Cyp1a1-Ren-2<\/jats:italic> transgenic rats with inducible hypertension. The early phase of ANG II-dependent hypertension was induced by 5\u00a0days and the late phase by the 13\u00a0days dietary indole-3-carbinol (I3C) administration. Noninduced rats served as controls. Echocardiography and pressure-volume analysis were performed, angiotensins\u2019 levels were measured and cardiac tolerance to ischemia\/reperfusion injury was studied. The infarct size was significantly reduced (by 50%) in 13\u00a0days I3C-induced hypertensive rats with marked cardiac hypertrophy, this reduction was abolished by losartan treatment. In the late phase of hypertension there are indications of a failing heart, mainly in reduced preload recruitable stroke work (PRSW), but only nonsignificant trends in worsening of some other parameters, showing that the myocardium is in a compensated phase. The influence of the RAS depends on the balance between the vasoconstrictive and the opposed vasodilatory axis. In the initial stage of hypertension, the vasodilatory axis of the RAS prevails, and with the development of hypertension the vasoconstrictive axis of the RAS becomes stronger. We observed a clear effect of AT1 receptor blockade on maximum pressure in left ventricle, cardiac hypertrophy and ANG II levels. In conclusion, we confirmed improved cardiac tolerance to I\/R injury in hypertensive hypertrophied rats and showed that, in the late phase of hypertension, the myocardium is in a compensated phase.<\/jats:p>","DOI":"10.3389\/fphys.2023.1151308","type":"journal-article","created":{"date-parts":[[2023,6,14]],"date-time":"2023-06-14T05:23:46Z","timestamp":1686720226000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Inappropriate activation of the renin-angiotensin system improves cardiac tolerance to ischemia\/reperfusion injury in rats with late angiotensin II-dependent hypertension"],"prefix":"10.3389","volume":"14","author":[{"given":"Zuzana","family":"Huskov\u00e1","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"So\u0148a","family":"Kikerlov\u00e1","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mat\u00fa\u0161","family":"Miklovi\u010d","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Petr","family":"Kala","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Franti\u0161ek","family":"Papou\u0161ek","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jan","family":"Neck\u00e1\u0159","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2023,6,14]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1016\/j.vph.2015.08.013","article-title":"Orally active epoxyeicosatrienoic acid analog does not exhibit antihypertensive and reno- or cardioprotective actions in two-kidney, one-clip Goldblatt hypertensive rats","volume":"73","author":"Al\u00e1nov\u00e1","year":"2015","journal-title":"Vasc. Pharmacol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"285","DOI":"10.1161\/HYPERTENSIONAHA.119.12786","article-title":"Angs (angiotensins) of the alternative renin-angiotensin system predict outcome in patients with heart failure and preserved ejection fraction","volume":"74","author":"Binder","year":"2019","journal-title":"Hypertension"},{"key":"B3","doi-asserted-by":"publisher","first-page":"607","DOI":"10.1152\/PHYSREV.00011.2009","article-title":"Physiology of kidney renin","volume":"90","author":"Castrop","year":"2010","journal-title":"Physiol. Rev."},{"key":"B4","doi-asserted-by":"publisher","first-page":"1326","DOI":"10.1097\/HJH.0000000000001708","article-title":"Two pharmacological epoxyeicosatrienoic acid-enhancing therapies are effectively antihypertensive and reduce the severity of ischemic arrhythmias in rats with angiotensin II-dependent hypertension","volume":"36","author":"\u010cervenka","year":"2018","journal-title":"J. Hypertens."},{"key":"B5","doi-asserted-by":"publisher","first-page":"1242","DOI":"10.1093\/ajh\/hpt096","article-title":"Renal nitric oxide synthase and antioxidant preservation in Cyp1a1-Ren-2 transgenic rats with inducible malignant hypertension","volume":"26","author":"Cunningham","year":"2013","journal-title":"Am. J. Hypertens."},{"key":"B6","doi-asserted-by":"publisher","first-page":"1520","DOI":"10.1161\/CIRCRESAHA.118.313568","article-title":"Medical therapy for heart failure caused by ischemic heart disease","volume":"124","author":"Elgendy","year":"2019","journal-title":"Circ. Res."},{"key":"B7","doi-asserted-by":"publisher","first-page":"575","DOI":"10.1097\/HJH.0b013e32831cbd5a","article-title":"Impairment of the autoregulation of renal hemodynamics and of the pressure-natriuresis relationship precedes the development of hypertension in Cyp1a1-Ren-2 transgenic rats","volume":"27","author":"Erbanov\u00e1","year":"2009","journal-title":"J. Hypertens."},{"key":"B8","doi-asserted-by":"publisher","first-page":"17136","DOI":"10.1038\/S41598-021-96618-8","article-title":"Right versus left ventricular remodeling in heart failure due to chronic volume overload","volume":"11","author":"Havlenova","year":"2021","journal-title":"Sci. Rep."},{"key":"B9","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1113\/jphysiol.2010.199505","article-title":"Renal mechanisms contributing to the antihypertensive action of soluble epoxide hydrolase inhibition in Ren-2 transgenic rats with inducible hypertension","volume":"589","author":"Honetschl\u00e4gerov\u00e1","year":"","journal-title":"J. Physiol. J. Physiol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1113\/jphysiol.2010.199505","article-title":"Renal mechanisms contributing to the antihypertensive action of soluble epoxide hydrolase inhibition in Ren-2 transgenic rats with inducible hypertension","volume":"589","author":"Honetschl\u00e4gerov\u00e1","year":"","journal-title":"J. Physiol. J. Physiol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"159","DOI":"10.3389\/fphar.2019.00159","article-title":"Epoxyeicosatrienoic acid-based therapy attenuates the progression of postischemic heart failure in normotensive sprague-dawley but not in hypertensive ren-2 transgenic rats","volume":"10","author":"Hrdli\u010dka","year":"2019","journal-title":"Front. Pharmacol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"679060","DOI":"10.3389\/fphar.2021.679060","article-title":"Increased endogenous activity of the renin-angiotensin system reduces infarct size in the rats with early angiotensin II-dependent hypertension which survive the acute ischemia\/reperfusion injury","volume":"12","author":"Huskov\u00e1","year":"2021","journal-title":"Front. Pharmacol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"438","DOI":"10.1111\/1440-1681.12553","article-title":"Intrarenal alterations of the angiotensin-converting enzyme type 2\/angiotensin 1-7 complex of the renin-angiotensin system do not alter the course of malignant hypertension in Cyp1a1-Ren-2 transgenic rats","volume":"43","author":"Huskov\u00e1","year":"2016","journal-title":"Clin. Exp. Pharmacol. Physiol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1159\/000092981","article-title":"Effects of anesthesia on plasma and kidney ANG II levels in normotensive and ANG II-dependent hypertensive rats","volume":"29","author":"Huskov\u00e1","year":"2006","journal-title":"Kidney Blood Press. Res."},{"key":"B15","doi-asserted-by":"publisher","first-page":"495","DOI":"10.1097\/HJH.0b013e3283345d69","article-title":"Inappropriately high circulating and intrarenal angiotensin II levels during dietary salt loading exacerbate hypertension in Cyp1a1-Ren-2 transgenic rats","volume":"28","author":"Huskov\u00e1","year":"2010","journal-title":"J. Hypertens."},{"key":"B16","doi-asserted-by":"publisher","first-page":"2008","DOI":"10.1097\/HJH.0000000000001029","article-title":"Epoxyeicosatrienoic acid analog attenuates the development of malignant hypertension, but does not reverse it once established: A study in cyp1a1-ren-2 transgenic rats","volume":"34","author":"J\u00edchov\u00e1","year":"2016","journal-title":"J. Hypertens."},{"key":"B17","doi-asserted-by":"publisher","first-page":"9337","DOI":"10.3390\/IJMS21249337","article-title":"Deleterious effects of hyperactivity of the renin-angiotensin system and hypertension on the course of chemotherapy-induced heart failure after doxorubicin administration: A study in ren-2 transgenic rat","volume":"21","author":"Kala","year":"2020","journal-title":"Int. J. Mol. Sci."},{"key":"B18","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1097\/HJH.0000000000003307","article-title":"Endothelin type A receptor blockade attenuates aorto-caval fistula-induced heart failure in rats with angiotensin II-dependent hypertension","volume":"41","author":"Kala","year":"2023","journal-title":"J. Hypertens."},{"key":"B19","doi-asserted-by":"publisher","first-page":"1053","DOI":"10.3390\/biomedicines9081053","article-title":"Effects of epoxyeicosatrienoic acid-enhancing therapy on the course of congestive heart failure in angiotensin ii-dependent rat hypertension: From mrna analysis towards functional in vivo evaluation","volume":"9","author":"Kala","year":"2021","journal-title":"Biomedicines"},{"key":"B20","doi-asserted-by":"publisher","first-page":"36727","DOI":"10.1074\/jbc.M103296200","article-title":"Controlled hypertension, a transgenic toggle switch reveals differential mechanisms underlying vascular disease","volume":"276","author":"Kantachuvesiri","year":"2001","journal-title":"J. Biol. Chem."},{"key":"B21","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1016\/J.PHRS.2017.05.008","article-title":"AT1 receptor signaling pathways in the cardiovascular system","volume":"125","author":"Kawai","year":"2017","journal-title":"Pharmacol. Res."},{"key":"B22","doi-asserted-by":"publisher","first-page":"1102","DOI":"10.1161\/CIRCRESAHA.118.312784","article-title":"Reflection of cardioprotection by remote ischemic perconditioning in attenuated ST-segment elevation during ongoing coronary occlusion in pigs: Evidence for cardioprotection from ischemic injury","volume":"122","author":"Kleinbongard","year":"2018","journal-title":"Circulation Res."},{"key":"B23","doi-asserted-by":"publisher","first-page":"839","DOI":"10.1038\/AJH.2011.246","article-title":"Control of renin synthesis and secretion","volume":"25","author":"Kurtz","year":"2012","journal-title":"Am. J. Hypertens."},{"key":"B24","doi-asserted-by":"publisher","first-page":"257","DOI":"10.1186\/S13054-018-2171-1","article-title":"The meaning of blood pressure","volume":"22","author":"Magder","year":"2018","journal-title":"Crit. Care"},{"key":"B25","doi-asserted-by":"publisher","first-page":"198","DOI":"10.1177\/1535370217743919","article-title":"Pyruvate enhancement of cardiac performance: Cellular mechanisms and clinical application","volume":"243","author":"Mallet","year":"2018","journal-title":"Exp. Biol. Med."},{"key":"B26","doi-asserted-by":"publisher","first-page":"e012250","DOI":"10.1161\/JAHA.119.012250","article-title":"Prevalence of unexplained left ventricular hypertrophy by cardiac magnetic resonance imaging in MESA","volume":"8","author":"Massera","year":"2019","journal-title":"J. Am. Heart Assoc."},{"key":"B27","doi-asserted-by":"publisher","first-page":"1319","DOI":"10.1161\/CIRCRESAHA.108.184911","article-title":"Angiotensin(1-7) blunts hypertensive cardiac remodeling by a direct effect on the heart","volume":"103","author":"Mercure","year":"2008","journal-title":"Circ. Res."},{"key":"B28","doi-asserted-by":"publisher","first-page":"1153","DOI":"10.1681\/ASN.V541153","article-title":"Tubular fluid concentrations and kidney contents of angiotensins I and II in anesthetized rats","volume":"5","author":"Navar","year":"1994","journal-title":"J. Am. Soc. Nephrol. JASN"},{"key":"B29","doi-asserted-by":"publisher","first-page":"2143","DOI":"10.1042\/CS20210648","article-title":"Excess ischemic tachyarrhythmias trigger protection against myocardial infarction in hypertensive rats","volume":"135","author":"Neck\u00e1\u0159","year":"2021","journal-title":"Clin. Sci."},{"key":"B30","doi-asserted-by":"publisher","first-page":"513","DOI":"10.1042\/CS20110622","article-title":"Inhibition of soluble epoxide hydrolase by cis-4-[4-(3-adamantan-1-ylureido)cyclohexyl-oxy]benzoic acid exhibits antihypertensive and cardioprotective actions in transgenic rats with angiotensin II-dependent hypertension","volume":"122","author":"Neck\u00e1r","year":"2012","journal-title":"Clin. Sci."},{"key":"B31","doi-asserted-by":"publisher","first-page":"e006939","DOI":"10.1161\/CIRCHEARTFAILURE.120.006939","article-title":"Circulation: Heart failure elevated angiotensin 1-7\/angiotensin II ratio predicts favorable outcomes in patients with heart failure","volume":"13","author":"Oudit","year":"2020","journal-title":"Circ. Heart Fail"},{"key":"B32","doi-asserted-by":"publisher","first-page":"1313","DOI":"10.1161\/CIRCRESAHA.116.307708","article-title":"Role of the ACE2\/angiotensin 1-7 axis of the renin-angiotensin system in heart failure","volume":"118","author":"Patel","year":"2016","journal-title":"Circ. Res."},{"key":"B33","doi-asserted-by":"publisher","first-page":"102","DOI":"10.1097\/HJH.0b013e3282f0ab66","article-title":"Dose-dependent titration of prorenin and blood pressure in Cyp1a1ren-2 transgenic rats: Absence of prorenin-induced glomerulosclerosis","volume":"26","author":"Peters","year":"2008","journal-title":"J. Hypertens."},{"key":"B34","doi-asserted-by":"publisher","first-page":"373","DOI":"10.1002\/jmri.23661","article-title":"Regression of cardiac hypertrophy in cyp1a1ren-2 transgenic rats","volume":"36","author":"Peters","year":"2012","journal-title":"J. Magn. Reson. Imaging"},{"key":"B35","doi-asserted-by":"publisher","first-page":"H1845","DOI":"10.1152\/ajpheart.01135.2008","article-title":"Lack of cardiac fibrosis in a new model of high prorenin hyperaldosteronism","volume":"297","author":"Peters","year":"2009","journal-title":"Am. J. Physiol. - Hear. Circ. Physiol."},{"key":"B36","doi-asserted-by":"publisher","first-page":"811","DOI":"10.1161\/01.HYP.0000209020.69734.73","article-title":"A place in our hearts for the lowly angiotensin 1-7 peptide?","volume":"47","author":"Reudelhuber","year":"2006","journal-title":"Hypertension"},{"key":"B37","doi-asserted-by":"publisher","first-page":"1723","DOI":"10.1152\/ajpheart.00553.2011","article-title":"Pathophysiology of myocardial reperfusion injury: Preconditioning, postconditioning, and translational aspects of protective measures","volume":"301","author":"Sanada","year":"2011","journal-title":"Am. J. Physiol. Hear. Circ. Physiol."},{"key":"B38","doi-asserted-by":"publisher","first-page":"H1883","DOI":"10.1152\/AJPHEART.00617.2006","article-title":"Intermittent peripheral tissue ischemia during coronary ischemia reduces myocardial infarction through a KATP-dependent mechanism: First demonstration of remote ischemic perconditioning","volume":"292","author":"Schmidt","year":"2007","journal-title":"Am. J. Physiology. Heart Circulatory Physiology"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1042\/BSR20171496","article-title":"20-Hydroxyeicosatetraenoic acid antagonist attenuates the development of malignant hypertension and reverses it once established: A study in cyp1a1-ren-2 transgenic rats","volume":"38","author":"Sedl\u00e1kov\u00e1","year":"2018","journal-title":"Biosci. Rep."},{"key":"B40","doi-asserted-by":"publisher","first-page":"567","DOI":"10.33549\/PHYSIOLRES.932338","article-title":"Short-term fasting reduces the extent of myocardial infarction and incidence of reperfusion arrhythmias in rats","volume":"61","author":"\u0160norek","year":"2012","journal-title":"Physiological Res."},{"key":"B41","doi-asserted-by":"publisher","first-page":"449","DOI":"10.1042\/CS20120519","article-title":"Angiotensin II type 1 receptor blockade restores angiotensin-(1-7)-induced coronary vasodilation in hypertrophic rat hearts","volume":"125","author":"Souza","year":"2013","journal-title":"Clin. Sci. (Lond)."},{"key":"B42","doi-asserted-by":"publisher","first-page":"1003","DOI":"10.1111\/1440-1681.12310","article-title":"Different mechanisms of acute versus long-term antihypertensive effects of soluble epoxide hydrolase inhibition: Studies in Cyp1a1-Ren-2 transgenic rats","volume":"41","author":"Sporkov\u00e1","year":"2014","journal-title":"Clin. Exp. Pharmacol. Physiol."},{"key":"B43","doi-asserted-by":"publisher","first-page":"1197","DOI":"10.1161\/CIRCRESAHA.108.189068","article-title":"The angiotensin converting enzyme 2\/ang-(1-7) axis in the heart: A role for MAS communication?","volume":"103","author":"Stewart","year":"2008","journal-title":"Circ. Res."},{"key":"B44","doi-asserted-by":"publisher","first-page":"335","DOI":"10.2217\/14796678.2.3.335","article-title":"Cardioprotective role for angiotensin-(1-7) and angiotensin converting enzyme 2 in the heart","volume":"2","author":"Tallant","year":"2006","journal-title":"Future Cardiol."},{"key":"B45","doi-asserted-by":"publisher","first-page":"1243","DOI":"10.1016\/S0891-5849(02)01020-1","article-title":"Urate produced during hypoxia protects heart proteins from peroxynitrite-mediated protein nitration","volume":"33","author":"Teng","year":"2002","journal-title":"Free Radic. Biol. Med."},{"key":"B46","doi-asserted-by":"publisher","first-page":"e153","DOI":"10.1161\/CIR.0000000000001052","article-title":"Heart disease and stroke statistics-2022 update: A report from the American heart association","volume":"145","author":"Tsao","year":"2022","journal-title":"Circulation"},{"key":"B47","doi-asserted-by":"publisher","first-page":"447","DOI":"10.1093\/cvr\/22.7.447","article-title":"The lambeth conventions: Guidelines for the study of arrhythmias in ischaemia, infarction, and reperfusion","volume":"22","author":"Walker","year":"1988","journal-title":"Cardiovasc. Res."},{"key":"B48","doi-asserted-by":"publisher","first-page":"1973","DOI":"10.3892\/MMR.2017.6848","article-title":"The ACE2-Ang (1-7)-Mas receptor axis attenuates cardiac remodeling and fibrosis in post-myocardial infarction","volume":"16","author":"Wang","year":"2017","journal-title":"Mol. Med. Rep."},{"key":"B49","doi-asserted-by":"publisher","first-page":"e006939","DOI":"10.1161\/CIRCHEARTFAILURE.120.006939","article-title":"Elevated angiotensin 1-7\/angiotensin II ratio predicts favorable outcomes in patients with heart failure","volume":"13","author":"Wang","year":"2020","journal-title":"Circ. Heart Fail."},{"key":"B50","doi-asserted-by":"publisher","first-page":"738","DOI":"10.11817\/J.ISSN.1672-7347.2018.07.007","article-title":"Role of ACE2-Ang (1-7)-Mas receptor axis in heart failure with preserved ejection fraction with hypertension","volume":"43","author":"Yu","year":"2018","journal-title":"Zhong Nan Da Xue Xue Bao. Yi Xue Ban."},{"key":"B51","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1016\/J.EJPHAR.2018.04.019","article-title":"Treatment with D-\u03b2-hydroxybutyrate protects heart from ischemia\/reperfusion injury in mice","volume":"829","author":"Yu","year":"2018","journal-title":"Eur. J. Pharmacol."},{"key":"B52","doi-asserted-by":"publisher","first-page":"2617","DOI":"10.1016\/J.CELREP.2018.04.104","article-title":"Accumulation of succinate in cardiac ischemia primarily occurs via canonical krebs cycle activity","volume":"23","author":"Zhang","year":"2018","journal-title":"Cell. Rep."}],"container-title":["Frontiers in Physiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphys.2023.1151308\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,6,14]],"date-time":"2023-06-14T05:23:51Z","timestamp":1686720231000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphys.2023.1151308\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,6,14]]},"references-count":52,"alternative-id":["10.3389\/fphys.2023.1151308"],"URL":"https:\/\/doi.org\/10.3389\/fphys.2023.1151308","relation":{},"ISSN":["1664-042X"],"issn-type":[{"type":"electronic","value":"1664-042X"}],"subject":[],"published":{"date-parts":[[2023,6,14]]},"article-number":"1151308"}}