Cardiac sympathetic hyperinnervation in deoxycorticosterone acetate-salt hypertensive rats

Sympathetic activities are elevated in the central SNSs (sympathetic nervous systems) of hypertensive animals, but it is not known whether sympathetic innervation is also elevated in the heart. Sympathetic hyper-responsiveness in hypertension may result from oxidative stress. The aim of the present study was to investigate sympathetic hyperinnervation in DOCA (deoxycorticosterone acetate)-salt hypertensive rats with established hypertension. At 4 weeks after the start of DOCA-salt treatment and uninephrectomization, male Wistar rats were randomized into three groups for 8 weeks: vehicle, NAC (N-acetylcysteine) and triple therapy (hydralazine, hydrochlorothiazide and reserpine). DOCA-salt was associated with increased oxidant release. DOCA-salt produced concentric left ventricular hypertrophy and cardiomyocyte hypertrophy. Sympathetic hyperinnervation was observed in DOCA-salt rats, as assessed by myocardial noradrenaline levels, immunofluorescent analysis of tyrosine hydroxylase, growth-associated factor 43 and neurofilament and Western blotting and real-time quantitative RT–PCR (reverse transcription–PCR) of NGF (nerve growth factor). Arrhythmic scores during programmed stimulation in DOCA-salt rats were significantly higher than those in the control rats. Triple therapy, despite being effective on BP (blood pressure), offered neither attenuated cardiomyocyte hypertrophy nor anti-arrhythmia. The effects of DOCA-salt treatment on NGF expression, sympathetic hyperinnervation and arrhythmias were attenuated by NAC. Furthermore, the effects of NAC on NGF were abolished by administering BSO (L-buthionine sulfoximine), an inhibitor of glutamate–cysteine ligase. In conclusion, DOCA-salt treatment contributes to up-regulation of NGF proteins probably through a free radical-dependent pathway in a BP-independent manner. DOCA-salt rats treated with NAC attenuate sympathetic hyperinnervation and thus show a beneficial effect on arrhythmogenic response to programmed electrical stimulation.

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(−)-Epicatechin Reduces Blood Pressure and Improves Left Ventricular Function and Compliance in Deoxycorticosterone Acetate-Salt Hypertensive Rats

Molecules ◽

10.3390/molecules23071511 ◽

2018 ◽

Vol 23 (7) ◽

pp. 1511 ◽

Cited By ~ 9

Author(s):

Douglas Jackson ◽

Kylie Connolly ◽

Romeo Batacan ◽

Kimberly Ryan ◽

Rebecca Vella ◽

...

Keyword(s):

Blood Pressure ◽

Left Ventricular Function ◽

Ventricular Function ◽

Left Ventricular ◽

Hypertensive Rats ◽

Deoxycorticosterone Acetate ◽

Acetate Salt

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Abstract P352: An Antiplatelet Agent Sarpogrelate Suppresses Pressure Overload-induced Development Of Heart Failure In A 5-ht 2a Receptor-independent Manner

Circulation Research ◽

10.1161/res.129.suppl_1.p352 ◽

2021 ◽

Vol 129 (Suppl_1) ◽

Author(s):

Kana Shimizu ◽

Masafumi Funamoto ◽

Yoichi Sunagawa ◽

Yasufumi Katanasaka ◽

Yusuke Miyazaki ◽

...

Keyword(s):

Heart Failure ◽

Western Blotting ◽

Drug Repositioning ◽

Antiplatelet Agent ◽

Left Ventricular ◽

Antiplatelet Drug ◽

Cardiomyocyte Hypertrophy ◽

Sham Operation ◽

Mrna Levels ◽

Independent Manner

Purpose: The cost of new drug development is increasing year by year, and drug repositioning is being used as a strategy to develop new treatments at low-cost. We used a library of approved drugs to screen for compounds that suppress cardiomyocyte hypertrophy, and identified as a candidate the antiplatelet drug sarpogrelate, a selective serotonin-2A (5-HT 2A ) receptor antagonist. In this study, we examined the effect of sarpogrelate on cultured cardiomyocyte hypertrophy and development of heart failure. Methods & Results: First, primary cultured cardiomyocytes were treated with 1 μM sarpogrelate and then stimulated with various hypertrophic stimuli (30 μM phenylephrine (PE), 0.1 μM angiotensin II and 0.1 μM endothelin 1). The results of immunofluorescence staining with anti-MHC antibody showed that sarpogrelate significantly suppressed cardiomyocyte hypertrophy induced by each stimulus. Western blotting and qPCR analysis showed that the mRNA and protein levels of 5-HT 2A receptor did not change by PE, and sarpogrelate significantly suppressed PE-induced phosphorylation of ERK1/2 and GATA4. Next, C57BL/6j male mice were subjected to a transverse aortic constriction (TAC) and sham operation. One day after the operation, the mice were randomly divided into 3 groups: sarpogrelate at 1 mg/kg or 5 mg/kg, and vehicle as a control. Daily oral administration was repeated for 8 weeks. Echocardiographic analysis showed that 5 mg/kg sarpogrelate significantly prevented a TAC-induced increase in posterior left ventricular wall thickness and a decrease in fractional shortening at 8 weeks after the operation. Five mg/kg sarpogrelate also suppressed TAC-induced increase in HW/BW ratio, cross-sectional areas, perivascular fibrosis, and mRNA levels of ANF and BNP. Moreover, the western blotting analysis showed that 5 mg/kg sarpogrelate significantly suppressed TAC-induced phosphorylation of ERK1/2. Conclusions: These results indicate that sarpogrelate significantly suppresses cardiomyocyte hypertrophy and the development of heart failure via at least, in part, by inhibition of ERK1/2-GATA4 pathway. These findings suggest that sarpogrelate may be an effective agent for heart failure therapy.

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