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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, p<0.001 and p=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 salt-induced 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.

SUBMITTER: Louhelainen M

PROVIDER: S-EPMC2013885 | biostudies-other | 2007 Apr

REPOSITORIES: biostudies-other

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Project description:The role of autophagy in high-salt (HS) intake associated hypertensive left ventricular (LV) remodeling remains unclear. The present study investigated the LV autophagic change and its association with the hypertensive LV remodeling induced by chronic HS intake in spontaneously hypertensive rats (SHR). Wistar Kyoto (WKY) rats and SHR were fed low-salt (LS; 0.5% NaCl) and HS (8.0% NaCl) diets and were subjected to invasive LV hemodynamic analysis after 8, 12 and 16 weeks of dietary intervention. Reverse transcription-quantitative PCR and western blot analysis were performed to investigate the expression of autophagy-associated key components. The LV morphologic staining was performed at the end of the study. The rat H9c2 ventricular myoblast cell-associated experiments were performed to explore the mechanism of HS induced autophagic change. A global autophagy-associated key component, as well as increased cardiomyocyte autophagic vacuolization, was observed after 12 weeks of HS intake. During this period, the heart from HS-diet-fed SHR exhibited a transition from compensated LV hypertrophy to decompensation, as shown by progressive impairment of LV function and interstitial fibrosis. Myocardial extracellular [Na+] and the expression of tonicity-responsive enhancer binding protein (TonEBP) was significantly increased in HS-fed rats, indicating myocardial interstitial hypertonicity by chronic HS intake. The global autophagic change and overt deterioration of LV function were not observed in LS-fed SHR and HS-fed WKY rats. The study of rat H9c2 cardiomyocytes demonstrated a cytosolic [Na+] elevation-mediated, reactive oxygen species-dependent the autophagic change occurred when exposed to an increased extracellular [Na+]. The present findings demonstrated that a myocardial autophagic change participates in the maladaptive LV remodeling induced by chronic HS intake in SHR, which provides a possible target for future intervention studies on HS-induced hypertensive LV remodeling.

Project description:Hypertensive cerebropathy is a pathological condition associated with cerebral edema and disruption of the blood-brain barrier. However, the molecular pathways leading to this condition remains obscure. We hypothesize that MMP-9 inhibition can help reducing blood pressure and endothelial disruption associated with hypertensive cerebropathy. Dahl salt-sensitive (Dahl/SS) and Lewis rats were fed with high-salt diet for 6 weeks and then treated without and with GM6001 (MMP inhibitor). Treatment of GM6001 (1.2 mg/kg body weight) was administered through intraperitoneal injections on alternate days for 4 weeks. GM6001 non-administered groups were given vehicle (0.9% NaCl in water) treatment as control. Blood pressure was measured by tail-cuff method. The brain tissues were analyzed for oxidative/nitrosative stress, vascular MMP-9 expression, and tight junction proteins (TJPs). GM6001 treatment significantly reduced mean blood pressure in Dahl/SS rats which was significantly higher in vehicle-treated Dahl/SS rats. MMP-9 expression and activity was also considerably reduced in GM6001-treated Dahl/SS rats, which was otherwise notably increased in vehicle-treated Dahl/SS rats. Similarly MMP-9 expression in cerebral vessels of GM6001-treated Dahl/SS rats was also alleviated, as devised by immunohistochemistry analysis. Oxidative/nitrosative stress was significantly higher in vehicle-treated Dahl/SS rats as determined by biochemical estimations of malondialdehyde, nitrite, reactive oxygen species, and glutathione levels. RT-PCR and immunohistochemistry analysis further confirmed considerable alterations of TJPs in hypertensive rats. Interestingly, GM6001 treatment significantly ameliorated oxidative/nitrosative stress and TJPs, which suggest restoration of vascular integrity in Dahl/SS rats. These findings determined that pharmacological inhibition of MMP-9 in hypertensive Dahl-SS rats attenuate high blood pressure and hypertension-associated cerebrovascular pathology.

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

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