Abstract
The physiological mechanisms involved in isoproterenol (ISO)-induced chronic heart failure (CHF) are not fully understood. In this study, we investigated local changes in cardiac aldosterone and its synthase in rats with ISO-induced CHF, and evaluated the effects of treatment with recombinant human brain natriuretic peptide (rhBNP). Sprague-Dawley rats were divided into 4 different groups. Fifty rats received subcutaneous ISO injections to induce CHF and the control group (n=10) received equal volumes of saline. After establishing the rat model, 9 CHF rats received no further treatment, rats in the low-dose group (n=8) received 22.5 μg/kg rhBNP and those in the high-dose group (n=8) received 45 μg/kg rhBNP daily for 1 month. Cardiac function was assessed by echocardiographic and hemodynamic analysis. Collagen volume fraction (CVF) was determined. Plasma and myocardial aldosterone concentrations were determined using radioimmunoassay. Myocardial aldosterone synthase (CYP11B2) was detected by quantitative real-time PCR. Cardiac function was significantly lower in the CHF group than in the control group (P<0.01), whereas CVF, plasma and myocardial aldosterone, and CYP11B2 transcription were significantly higher than in the control group (P<0.05). Low and high doses of rhBNP significantly improved hemodynamics (P<0.01) and cardiac function (P<0.05) and reduced CVF, plasma and myocardial aldosterone, and CYP11B2 transcription (P<0.05). There were no significant differences between the rhBNP dose groups (P>0.05). Elevated cardiac aldosterone and upregulation of aldosterone synthase expression were detected in rats with ISO-induced CHF. Administration of rhBNP improved hemodynamics and ventricular remodeling and reduced myocardial fibrosis, possibly by downregulating CYP11B2 transcription and reducing myocardial aldosterone synthesis.
Highlights
Chronic heart failure (CHF) represents the most serious stage of many cardiovascular diseases, and it carries a poor prognosis
Aldosterone concentrations in plasma and myocardial tissues were significantly higher in the CHF group than in the control group (P,0.01)
There were no significant differences in the aldosterone concentrations in the plasma and myocardial tissues between low- and high-dose recombinant human brain natriuretic peptide (rhBNP) groups
Summary
Chronic heart failure (CHF) represents the most serious stage of many cardiovascular diseases, and it carries a poor prognosis. Ventricular remodeling plays a role in both the occurrence and development of heart failure. Heart failure is accompanied by significantly increased aldosterone levels in the circulation and locally within the myocardium. This results, directly or indirectly, in the formation of fibrosis and progression of heart failure [1]. Aldosterone inhibitors have been shown to improve left ventricular remodeling in heart failure [2]. A significant elevation in CYPB112 expression has been observed in myocardial tissue in patients with heart failure [3]. It has been demonstrated that the aldosterone synthase inhibitor FAD286 improves left ventricular hemodynamics, remodeling, and cardiac function after myocardial infarction (MI) induced by coronary artery ligation in a rat model of CHF. FAD286 has been shown to normalize the left ventricular redox status more effectively than spironolactone [4]
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