Effects of levosimendan on cardiac remodeling and cardiomyocyte apoptosis in hypertensive Dahl/Rapp rats

Abstract

Background and purpose: Progression of heart failure in hypertensive Dahl rats is associated with cardiac remodeling and increased cardiomyocyte apoptosis. This study was conducted to study whether treatment with a novel inotropic vasodilator compound, levosimendan, could prevent hypertension-induced cardiac remodeling and cardiomyocyte apoptosis. Experimental approach: 6-week-old salt-sensitive Dahl/Rapp rats received levosimendan (0.3 mg kg -1 and 3 mg kg -1 via drinking fluid) and high salt diet (NaCl 7%) for 7 weeks, Dahl/Rapp rats on low-salt diet served as controls. Blood pressure, cardiac functions by echocardiography, cardiomyocyte apoptosis by TUNEL technique, tissue morphology, myocardial expression of calcium cycling proteins, and markers of neurohumoral activation were determined. Key Results: Untreated Dahl/Rapp rats on high salt diet developed severe hypertension, cardiac hypertrophy and moderate systolic dysfunction. 38% of Dahl/Rapp rats (9/24) survived the 7-week-follow-up period. Cardiomyocyte apoptosis was increased by 6-fold during high salt diet. Levosimendan improved survival (survival rates in low-and high-dose levosimendan groups 12/12 and 9/12, po0.001 and p ¼ 0.05, respectively), increased cardiac function, and ameliorated cardiac hypertrophy. Levosimendan dose-dependently prevented cardiomyocyte apoptosis. Levosimendan normalized salt-induced increased expression of natriuretic peptide, and decreased urinary noradrenaline excretion. Levosimendan also corrected saltinduced decreases in myocardial SERCA2a protein expression and myocardial SERCA2a/NCX-ratio. Conclusions and Implications: Improved survival by the novel inotropic vasodilator levosimendan in hypertensive Dahl/Rapp rats is mediated, at least in part, by amelioration of hypertension-induced cardiac remodeling and cardiomyocyte apoptosis.

Levosimendan improves cardiac function and survival in rats with angiotensin II-induced hypertensive heart failure

“…[34][35][36] We showed recently that oral levosimendan ameliorated inflammatory responses, exerted antiapoptotic effects and prevented cardiomyocyte senescence in Dahl/Rapp salt-sensitive rats and in spontaneously diabetic GotoKakizaki rats with postinfarction heart failure. 17,18 Sareila et al 37 recently reported that levosimendan downregulated nuclear factor-kBdependent transcription, decreased inducible nitric oxide synthase promoter activity, inducible nitric oxide synthase expression and nitric oxide production using macrophages and fibroblasts exposed to inflammatory stimuli. Therefore, we examined cardiac MCP-1 mRNA expression in our animal model.…”

“…Levosimendan (a kind gift from Orion Pharma, Espoo, Finland) was administered orally through drinking fluid to produce an approximate daily dosage of 1 mg kg À1 as in our previous rat experiments. 17,18 Fresh levosimendan solutions were prepared daily. Owing to the dipsogenic effect of Ang II, 24,25 the water intake in dTGRs is approximately three-fold higher compared with SD rats.…”

“…The cross-sectional area was evaluated in a blinded manner and analyzed using the ISIimaging software (Image Solutions, Whippany, NJ, USA). 17,18 Cardiac mRNA expression analysis by quantitative real-time reverse transcriptase-PCR Quantitative real-time reverse transcriptase-PCR was performed using the LightCycler instrument (Roche Diagnostics, Neuilly sur Seine, France) for detection of atrial natriuretic peptide (ANP), SERCA2, NCX-1, a-MHC, b-MHC, MCP-1, Bax, PGC-1a and ribosomal 18S mRNA as described elsewhere. 18,27 Briefly, total RNA from the rat hearts were collected using Trizol (Gibco, Invitrogen, Carlsbad, CA, USA), treated with DNAse 1 (deoxyribonuclease 1, Sigma Chemicals, St Louis, MO, USA) and reverse transcribed to cDNA by reverse transcription enzyme (Im-Prom-II reverse transcription system, Promega, Madison, WI, USA).…”

“…We showed earlier that levosimendan improved survival and ameliorated hypertension-induced cardiac remodeling in Dahl salt-sensitive rats 17 and prevented postinfarct heart failure in spontaneously diabetic Goto-Kakizaki rats. 18 Furthermore, Nieminen et al 19 showed that patients with severe chronic heart failure showed improved quality of life and reduced plasma brain natriuretic peptide levels, although their cardiovascular mortality did not decrease.…”

Value of IGF-I levels in the evaluation of response to treatment with levosimendan in patients with severe heart failure

“…It has been shown to prevent or limit myocyte apoptosis via the activation of mitoKATP channels, a potentially protective mechanism that could be exploited for the management of acute HF (6,7).…”