Effect of Long-term Administration of a Prostacyclin Analogue (Beraprost Sodium) on Myocardial Fibrosis in Dahl Rats

Abstract

ABSTRACT. Beraprost sodium (BPS) is an orally active prostacyclin analogue. The effects of BPS on the heart, including coronary circulation improvement, myocardial and vascular protection and anti-fibrosis effect on myocardium interstitium, have previously been demonstrated. However, the effects of BPS on hemodynamics, cardiac function and myocardial contractility in patients in the hypertrophic phase have not been clarified. Therefore, in the present study, the effects of BPS under long-term administration were investigated using the hypertension model of salt-sensitive Dahl rats. Six-week-old Dahl rats were divided into three groups, an 8% high salt diet group treated with BPS (BPS group), an untreated 8% high salt diet group (HHF group) and an untreated 0.3% low salt diet group (Control group), and observations were conducted until 17 weeks of age. In the BPS and HHF groups, the survival rates after 11 weeks of high salt diet intake were 87.5% and 47.1%, respectively (p<0.05). At 17 weeks of age, the atrial systolic peak velocity/early diastolic peak velocity and heart weight index of the BPS group decreased significantly compared with the HHF group (p<0.05). The HHF group exhibited significantly more severe myocardial fibrosis mainly in the endocardial layer of the left and right ventricles compared with the BPS and Control groups (p<0.05). In the present study, long-term BPS administration preserved diastolic function and prevented myocardial interstitial fibrosis in the non-compensatory phase. The results of the present study suggest that BPS is effective for treatment of hypertensive cardiac hypertrophy. KEY WORDS: beraprost sodium, Dahl rat, echocardiography, hypertension, myocardial fibrosis.J. Vet. Med. Sci. 69(12): 1271-1276, 2007 Prostacyclin is found in all body tissues and body fluids and is the major metabolite of arachidonic acid in the vasculature [6,16]. It is a potent vasodilator that affects both systemic and pulmonary circulations. Prostacyclin also prevents vascular smooth muscle proliferation and inhibits platelet adhesion and aggregation [6]. These features make it a very attractive substance for treatment of various cardiovascular diseases [6,15,16,20]. Beraprost sodium (BPS) is an orally active prostacyclin analogue that was discovered and developed by Toray Industries in Japan [1,16]. In human medicine, long-term administration of BPS has been approved as a treatment for chronic arterial occlusion [16] and primary pulmonary hypertension [2,8,16]. In addition, oral administration of BPS can be used as a therapeutic treatment for secondary precapillary pulmonary hypertension [17], cerebral infarction [9,13], glomerulonephritis [12,28], diabetic nephropathy [29] and atherosclerotic vascular damage in coronary artery disease [23]. In heart failure with pressure overload, compensated concentric hypertrophy in the left ventricular progresses due to the increase in pressure after overload. As a result, then the interstitial fibrosis changes the myocardial structure [21,26,27]. In addition, th...

Histological Study of Right Ventricle-Pulmonary Artery Valved Conduit Implantation (RPVC) in Dogs with Pulmonic Stenosis

“…The present histological findings indicated that RPVC inhibits RV myocardial fibrosis, perhaps through a decrease in RV pressure overload [17]. On the other hand, myocardial fibrosis was also inhibited in the LV free wall.…”

“…To measure the area of fibrosis in the stained sections, 5 fields per section under 100  magnification were histologically imaged from the RV (endocardial, median and epicardial layer), IVS (RV, median and LV layer) and LV (endocardial, median and epicardial layer), respectively and loaded into a personal computer. Areas of blue-stained collagenous fiber in sections were calculated using image processing software (Mac SCOPE, Mitani Corporation, Japan) [17,21]. Interstitial collagenous fiber is expressed as a ratio (%) of the microscopic field.…”

Prostacyclin Analogue Beraprost Inhibits Cardiac Fibroblast Proliferation Depending on Prostacyclin Receptor Activation through a TGF β-Smad Signal Pathway

“…Beraprost decreased growth rate and DNA synthesis of fibroblasts and inhibited collagen expression in WKY cells, which is less responsive in SHR cells [14]. Long-term prostacyclin administration preserved diastolic function and prevented myocardial interstitial fibrosis in the hypertension model of salt-sensitive Dahl rats [44]. However, whether beraprost could attenuate Ang II-induced cardiac fibroblasts proliferation was unknown.…”

L-Carnitine prevents the development of ventricular fibrosis and heart failure with preserved ejection fraction in hypertensive heart disease

“…Previous studies showed that prostacyclin has antifibrotic effects [39,40] and that L-carnitine increased its production [52,53]. Thus, the antifibrotic effects of L-carnitine may be partly explained by the enhanced production of prostacyclin.…”

“…In vivo, the administration of L-carnitine significantly increased left-ventricular tissue levels of 6-keto-PGF1a, a L-Carnitine prevents hypertensive HFpEF stable hydrolysis product of prostacyclin which is known to have antifibrotic effect [39,40], at age 20 weeks (Fig. 5a).…”