Calorie restriction (CR) can modulate the features of obesity-related metabolic and cardiovascular diseases. We have recently characterized DahlS.Z-Lepr(fa)/Lepr(fa) (DS/obese) rats, derived from a cross between Dahl salt-sensitive and Zucker rats, as a new animal model of metabolic syndrome. DS/obese rats develop hypertension and manifest left ventricular remodeling and diastolic dysfunction, as well as increased cardiac oxidative stress and inflammation. We have now investigated the effects of CR on cardiac pathophysiology in DS/obese rats. DS/obese rats were fed either normal laboratory chow ad libitum or a calorie-restricted diet (65% of the average food intake for ad libitum) from 9 to 13 weeks. Age-matched homozygous lean (DahlS.Z-Lepr(+)/Lepr(+) or DS/lean) littermates served as controls. CR reduced body weight in both DS/obese and DS/lean rats, as well as attenuated the development of hypertension in DS/obese rats without affecting blood pressure in DS/lean rats. CR also reduced body fat content, ameliorated left ventricular hypertrophy, fibrosis, and diastolic dysfunction, and attenuated cardiac oxidative stress and inflammation in DS/obese rats. In addition, it increased serum adiponectin concentration, as well as downregulated the expression of angiotensin-converting enzyme and angiotensin II type 1A receptor genes in the heart of DS/obese rats. Our results thus show that CR attenuated obesity and hypertension, as well as left ventricular remodeling and diastolic dysfunction in DS/obese rats, with these latter effects being associated with reduced cardiac oxidative stress and inflammation.

Cilnidipine attenuated LV fibrosis and diastolic dysfunction as well as LV concentricity to a greater extent than did amlodipine in Dahl salt-sensitive rats. The superior cardioprotective action of cilnidipine is likely attributable, at least in part, to the greater antioxidant and anti-inflammatory effects associated with inhibition of cardiac RAS gene expression observed with this drug.

Abstract-Although recent clinical trials have found an increased incidence of cardiovascular disease in women on estrogen replacement therapy, the underlying mechanism remains unclear. We have recently characterized DahlS.Z-Lepr fa /Lepr fa (DS/obese) rats, derived from a cross between Dahl salt-sensitive and Zucker rats, as a new animal model of metabolic syndrome. We have now examined the effects of estrogen replacement on cardiac pathophysiology in ovariectomized female DS/obese (Ovx-DS/obese) rats. Animals subjected to ovariectomy at 7 weeks of age were implanted subcutaneously with a 60-day release pellet containing 0.5 mg of 17␤-estradiol (E 2 ) or placebo at 8 weeks. Age-matched female homozygous lean littermates (DahlS.Z-Lepr ϩ /Lepr ϩ or DS/lean rats) of DS/obese rats served as controls. Animals were maintained on a normal diet and were subjected to echocardiography followed by various pathological analyses at 13 weeks of age. Ovx-DS/obese rats manifested hypertension at 7 weeks of age and thereafter and showed left ventricular (LV) fibrosis and diastolic dysfunction at 13 weeks. Treatment with E 2 attenuated hypertension in Ovx-DS/obese rats but had no effect on blood pressure in ovariectomized female DS/lean (Ovx-DS/lean) rats. E 2 treatment exacerbated LV fibrosis and diastolic dysfunction, as well as further increased cardiac oxidative stress and inflammation in Ovx-DS/obese rats, and it elicited similar effects in Ovx-DS/lean rats. E 2 reduced food intake, body weight, and visceral fat content in both Ovx-DS/obese and Ovx-DS/lean rats. E 2 treatment attenuated hypertension and obesity but exacerbated LV fibrosis and diastolic dysfunction in Ovx-DS/obese rats, with these latter effects being associated with increased cardiac oxidative stress and inflammation. (Hypertension. 2012;59:694-704.) • Online Data Supplement Key Words: metabolic syndrome Ⅲ estrogen Ⅲ hypertension Ⅲ myocardial fibrosis Ⅲ diastolic dysfunction Ⅲ oxidative stress Ⅲ inflammation M etabolic syndrome (MetS), a complex of highly debilitating disorders including hypertension, diabetes mellitus, and dyslipidemia, is associated with the development of visceral obesity. 1 MetS afflicts both men and women and increases the risk of heart disease in both sexes, although it appears to inflict a greater burden in women. The incidence of cardiovascular disease among women is low before menopause but steadily increases thereafter. 2 This increase is thought to result in part from the loss of endogenous estrogen and its associated cardioprotective effects. 3 A key issue faced by most postmenopausal women is the potential impact of estrogen replacement therapy on the prevalence of cardiovascular disease. Estrogen replacement in postmenopausal women has been associated with a reduced risk of cardiovascular disease. 4 However, the Heart and Estrogen/Progestin Replacement Study 5 and the Women's Health Initiative Study 6 do not support the notion that hormone replacement therapy protects the cardiovascular system but rather suggest the opposite vi...