Benidipine Inhibits Expression of ET-1 and TGF-.BETA.1 in Dahl Salt-Sensitive Hypertensive Rats.

Abstract

Endothelin and growth factors such as transforming growth factor (TGF)-beta1 are important regulators of the cardiovascular system. Although increased production of endothelin-1 (ET-1) and TGF-beta1 have been reported in left ventricular hypertrophy, the detailed roles of these substances in hypertrophy remain to be determined. To elucidate the cardioprotective effects of calcium antagonists in left ventricular hypertrophy, we evaluated the effects of long-term treatment with benidipine, a long-acting calcium antagonist, on preproET-1, ET(A) receptor (ETAR) and TGF-beta1 expression in the left ventricle and evaluated the relations between these effects and myocardial remodeling in Dahl salt-sensitive hypertensive (DS) rats fed a high-salt diet. After 5 weeks of feeding an 8% NaCl diet to 6-week-old DS rats (i.e., at 11 weeks of age), a distinct stage of concentric left ventricular hypertrophy (DSLVH) was noted. Benidipine (DSLVH-B group, n= 8; 1 mg/kg/day, subdepressor dose) or vehicle (DSLVH-V group, n=8) was administered to 6-week-old DS rats for 5 weeks, or until the onset of DSLVH stage, and age-matched (11-week-old) Dahl salt-resistant rats fed the same diet served as a control group (DR-C, n=8). Blood pressure was similar between the DSLVH-B and DSLVH-V groups, but was significantly lower in DR-C rats. The preproET-1, ETAR and TGF-beta1 expressions in the left ventricle were significantly higher in DSLVH-V than in DR-C rats, and significantly lower in DSLVH-B than in DSLVH-V. Benidipine administration resulted in significant improvements in the wall-to-lumen ratio and perivascular fibrosis in the coronary arterioles, and in myocardial fibrosis. We therefore concluded that myocardial remodeling and left ventricular hypertrophy in DS hypertensive rats fed a high-salt diet were significantly ameliorated by a subdepressor dose of benidipine, and that this amelioration was partly due to decreases in the expression of ET-1 and TGF-beta1 in the left ventricle.

Transforming Growth Factor-.BETA. Expression in Cardiovascular Organs in Stroke-Prone Spontaneously Hypertensive Rats with the Development of Hypertension.

“…SHR-derived VSMC in culture also show exaggerated growth (1). We have found that VSMC from SHR increasingly produce angiotensin II and growth factors including TGF-β1 owing to changes to the synthetic VSMC phenotype and abnormal regulation of TGF-β by angiotensin II, suggesting that these abnormalities are associated with the exaggerated growth of VSMC in SHR (7,(26)(27)(28). It is therefore possible that the glomerulosclerosis observed in SHR-SP is partially due to increased production of TGF-β in mesangial cells.…”

Eicosapentaenoic Acid Suppresses Basal and Insulin-Stimulated Endothelin-1 Production in Human Endothelial Cells

“…Various substances, such as insulin (24), lipopolysaccharides (25), tumor necrosis factor (26), interleukin 1-γ, and transforming growth factor-β (TGF-β) (27), are known to stimulate ET-1 production in endothelial cells. On the other hand, benidipine inhibits the expression of ET-1 and TGF-β1 in Dahl saltsensitive hypertensive rats (28). In cultured bovine mesangial cells (29), EPA has been reported to inhibit mitogen-induced ET-1 production, but the effects of EPA on human endothelial cells and its underlying mechanism remain to be clarified.…”

Enhancement of Glomerular Platelet-Derived Growth Factor β-Receptor Tyrosine Phosphorylation in Hypertensive Rats and Its Inhibition by Calcium Channel Blocker

“…SHRSP and DS-rats are two commonly used rat hypertensive models that exhibit severe glomerular injury (12)(13)(14)(15). Spontaneously hypertensive rats (SHR), on the other hand, show no significant glomerular injury despite their hypertension.…”