title: Levosimendan improves cardiac function and survival in rats with angiotensin II-induced hypertensive heart failure.
abstract: Calcium-sensitizing agents improve cardiac function in acute heart failure; however, their long-term effects on cardiovascular mortality are unknown. We tested the hypothesis that levosimendan, an inodilator that acts through calcium sensitization, opening of ATP-dependent potassium channels and phosphodiesterase III inhibition, improves cardiac function and survival in double transgenic rats harboring human renin and angiotensinogen genes (dTGRs), a model of angiotensin II (Ang II)-induced hypertensive heart failure. Levosimendan (1 mg kg(-1)) was administered orally to 4-week-old dTGRs and normotensive Sprague-Dawley rats for 4 weeks. Untreated dTGRs developed severe hypertension, cardiac hypertrophy, heart failure with impaired diastolic relaxation, and exhibited a high mortality rate at the age of 8 weeks. Levosimendan did not decrease blood pressure and did not prevent cardiac hypertrophy. However, levosimendan improved systolic function, decreased cardiac atrial natriuretic peptide mRNA expression, ameliorated Ang II-induced cardiac damage and decreased mortality. Levosimendan did not correct Ang II-induced diastolic dysfunction and did not influence heart rate. In a separate survival study, levosimendan increased dTGR survival by 58% and median survival time by 27% (P=0.004). Our findings suggest that levosimendan ameliorates Ang II-induced hypertensive heart failure and reduces mortality. The results also support the notion that the effects of levosimendan in dTGRs are mediated by blood pressure-independent mechanisms and include improved systolic function and amelioration of Ang II-induced coronary and cardiomyocyte damage.
authors.affiliation: Institute of Biomedioine, University of Helsinki, Helsinki, Finland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Biala
authors.forename: Essi
authors.initials: E
authors.lastname: Martonen
authors.forename: Petri
authors.initials: P
authors.lastname: Kaheinen
authors.forename: Jouko
authors.initials: J
authors.lastname: Levijoki
authors.forename: Piet
authors.initials: P
authors.lastname: Finckenberg
authors.forename: Saara
authors.initials: S
authors.lastname: Merasto
authors.forename: Marjut
authors.initials: M
authors.lastname: Louhelainen
authors.forename: Dominik N
authors.initials: DN
authors.lastname: Muller
authors.forename: Friedrich C
authors.initials: FC
authors.lastname: Luft
authors.forename: Eero
authors.initials: E
authors.lastname: Mervaala
mesh_terms: D000804:Angiotensin II / Q000009:adverse effects* / Q000378:metabolism; D000808:Angiotensinogen / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D002316:Cardiotonic Agents / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D006321:Heart / Q000187:drug effects / Q000502:physiology*; D006333:Heart Failure / Q000188:drug therapy* / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D006801:Humans; D006835:Hydrazones / Q000494:pharmacology / Q000627:therapeutic use*; D006973:Hypertension / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D008285:Major Histocompatibility Complex / Q000502:physiology; D008297:Male; D011724:Pyridazines / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D012083:Renin / Q000235:genetics / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000502:physiology; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D000077464:Simendan; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: C506948:Atp2a2 protein, rat; D002316:Cardiotonic Agents; D006835:Hydrazones; D011724:Pyridazines; D051028:bcl-2-Associated X Protein; D000808:Angiotensinogen; D000804:Angiotensin II; D000077464:Simendan; D012083:Renin; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases