Although angiotensin converting enzyme inhibitors and a,-blockers have been reported to improve insulin sensitivity, their mechanisms of action have not been elucidated. To investigate the role of kinins in insulin sensitivity, we treated 4-week-old spontaneously hypertensive rats with either an angiotensin converting enzyme inhibitor (enalapril), an a,-blocker (doxazosin), or an angiotensin II antagonist (losartan) for 3 weeks. A control group received no drugs. In addition, 18 rats treated with enalapril or doxazosin received a simultaneous administration of a kinin antagonist (Hoe 140). Glucose clamp testing was performed in each group. Enalapril (128±1 mmHg) and doxazosin (132±2 mm Hg) decreased mean blood pressure compared with control levels (148±1 mm Hg) (P<.01). The glucose requirement for the clamp test during the administration of enalapril (25.8±0.5 mg/kg per A lthough recent antihypertensive medications con-/ \ trol blood pressure (BP) as expected, it has not J. \ -been entirely determined that they prevent cardiovascular events.1 The management of concomitant conditions such as obesity, diabetes mellitus, and hyperlipidemia is advocated as one of the keys to improving the prevention of cardiovascular events. Insulin resistance is common in the above-mentioned conditions, and hypertension itself is believed to be an insulin-resistant state.2 It has been proposed that the management of insulin resistance may contribute to the prevention of cardiovascular events.1 Thus, in the management of hypertension, consideration should be given to the influence of antihypertensive medication on insulin sensitivity. It has been demonstrated that angiotensin converting enzyme (ACE) inhibitors and a,-blockers have a beneficial effect on insulin sensitivity. 3With regard to the effect of ACE inhibitors, the reninangiotensin system, kallikrein-kinin system, or both have been suggested to participate, but the precise mechanisms of action of ACE inhibitors have not been determined. ACE is also known as kininase II and acts to degradate several kinins. Thus, ACE inhibitors de-

High salt intake is a known cardiovascular risk factor and is associated with cardiac alterations. To better understand this effect, male Wistar rats were fed a normal (NSD: 1.3% NaCl), high 4 (HSD4: 4%), or high 8 (HSD8: 8%) salt diet from weaning until 18 wk of age. The HSD8 group was subdivided into HSD8, HSD8+HZ (15 mg . kg(-1) . d(-1) hydralazine in the drinking water), and HSD8+LOS (20 mg . kg(-1) . d(-1) losartan in the drinking water) groups. The cardiomyocyte diameter was greater in the HSD4 and HSD8 groups than in the HSD8+LOS and NSD groups. Interstitial fibrosis was greater in the HSD4 and HSD8 groups than in the HSD8+HZ and NSD groups. Hydralazine prevented high blood pressure (BP) and fibrosis, but not cardiomyocyte hypertrophy. Losartan prevented high BP and cardiomyocyte hypertrophy, but not fibrosis. Angiotensin II type 1 receptor (AT(1)) protein expression in both ventricles was greater in the HSD8 group than in the NSD group. Losartan, but not hydralazine, prevented this effect. Compared with the NSD group, the binding of an AT(1) conformation-specific antibody that recognizes the activated form of the receptor was lower in both ventricles in all other groups. Losartan further lowered the binding of the anti-AT(1) antibody in both ventricles compared with all other experimental groups. Angiotensin II was greater in both ventricles in all groups compared with the NSD group. Myocardial structural alterations in response to HSD are independent of the effect on BP. Salt-induced cardiomyocyte hypertrophy and interstitial fibrosis possibly are due to different mechanisms. Evidence from the present study suggests that salt-induced AT(1) receptor internalization is probably due to angiotensin II binding.

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Several studies support the hypothesis that chronic diseases in adulthood might be triggered by events that occur during fetal development. This study examined the consequences of perinatal salt intake on blood pressure (BP) and carbohydrate and lipid metabolism in adult offspring of dams on high-salt [HSD; 8% (HSD2) or 4% (HSD1)], normal-salt (NSD; 1.3%), or low-salt (LSD; 0.15% NaCl) diet during pregnancy and lactation. At 12 wk of age, female Wistar rats were matched with adult male rats that were fed NSD. Weekly tail-cuff BP measurements were performed before, during, and after pregnancy. After weaning, the offspring received only NSD and were housed in metabolic cages for 24-h urine collection for sodium and potassium and nitrate and nitrite excretion measurements. At 12 wk of age, intra-arterial mean BP was measured, a euglycemic-hyperinsulinemic clamp was performed, and plasma lipids and nitrate and nitrite concentrations were determined. Tail-cuff BP was higher during pregnancy in HSD2 and HSD1 than in NSD and LSD dams. Mean BP (mm Hg) was also higher in the offspring of HSD2 (110 Ϯ 5) and HSD1 (107 Ϯ 5) compared with NSD (100 Ϯ 2) and LSD (92 Ϯ 2). Lower glucose uptake and higher plasma cholesterol and triacylglycerols were observed in male offspring from LSD dams (glucose uptake: HSD2 17 Ϯ 4, HSD1 15 Ϯ 3, NSD 11 Ϯ 3, LSD 4 Ϯ 1 mg · kg Ϫ1 · min Ϫ1 ; cholesterol: HSD2 62 Ϯ 6, HSD1 82 Ϯ 11, NSD 68 Ϯ 10, LSD 98 Ϯ 17 mg/dL; triacylglycerols: HSD2 47 Ϯ 15, HSD1 49 Ϯ 12, NSD 56 Ϯ 19, LSD 83 Ϯ 11 mg/dL). In conclusion, maternal salt intake during pregnancy and lactation has long-term influences on arterial pressure, insulin sensitivity, and plasma lipids of the adult offspring. (Pediatr Res 56: 842-848, 2004) Abbreviations BP, blood pressure HSD, high-salt diet HR, heart rate LSD, low-salt diet MBP, mean blood pressure NSD, normal-salt diet NOx, nitrate plus nitrite RAS, renin-angiotensin system tcBP, tail-cuff blood pressure Almost two decades ago, Barker and Osmond (1) proposed that ischemic heart disease could be triggered by events that occur during fetal life and early childhood (1). They showed an association between poor living standard during the perinatal period and ischemic heart disease in adulthood. This lifestyle possibly goes along with intrauterine growth retardation. Despite criticisms about the validity of their observations (2), the association between low birth weight and adult diseases is now further supported by several studies with similar findings (3-6). Moreover, the understanding of the mechanisms of this association represents a challenge for investigators in this area.Intrauterine growth is controlled by a complex interplay of maternal and fetal factors, including circulatory, endocrine, and metabolic systems (7). An increasing number of studies have shown that small modifications in fetal growth may have profound consequences in later life (8 -10).

A severe restriction of sodium chloride intake has been associated with insulin resistance and obesity. The molecular mechanisms by which the low salt diet (LS) can induce insulin resistance have not yet been established. The c-jun N-terminal kinase (JNK) activity has been involved in the pathophysiology of obesity and induces insulin resistance by increasing inhibitory IRS-1 ser307 phosphorylation. In this study we have evaluated the regulation of insulin signaling, JNK activation and IRS-1 ser307 phophorylation in liver, muscle and adipose tissue by immunoprecipitation and immunoblotting in rats fed with LS or normal salt diet (NS) during 9 weeks. LS increased body weight, visceral adiposity, blood glucose and plasma insulin levels, induced insulin resistance and did not change blood pressure. In LS rats a decrease in PI3-K/Akt was observed in liver and muscle and an increase in this pathway was seen in adipose tissue. JNK activity and IRS-1 ser307 phosphorylation were higher in insulin-resistant tissues. In summary, the insulin resistance, induced by LS, is tissue-specific and is accompanied by activation of JNK and IRS-1 ser307 phosphorylation. The impairment of the insulin signaling in these tissues, but not in adipose tissue, may lead to increased adiposity and insulin resistance in LS rats.

This study aimed at measuring the influence of a low salt diet on the development of experimental atherosclerosis in moderately hyperlipidemic mice. Experiments were carried out on LDL receptor (LDLR) knockout (KO) mice, or apolipoprotein E (apoE) KO mice on a low sodium chloride diet (LSD) as compared with a normal salt diet (NSD). On LSD, the rise of the plasma concentrations of TG and nonesterified fatty acid (NEFA) was, respectively, 19% and 34% in LDLR KO mice, and 21% and 35% in apoE KO mice, and that of plasma cholesterol was limited to the LDLR KO group alone (15%). Probably due to the apoE KO severe hypercholesterolemia, the arterial inner-wall fat storage was not influenced by the diet salt content and was far more abundant in the apoE KO than in the LDLR KO mice. However, in the less severe hypercholesterolemia of the LDLR KO mice, lipid deposits on the LSD were greater than on the NSD. Arterial fat storage correlated with NEFA concentrations in the LDLR KO mice alone (n ‫؍‬ 14, P ‫؍‬ 0.0065).Thus, dietary sodium chloride restriction enhances aortic wall lipid storage in moderately hyperlipidemic mice.

Abstract-Because of conflicting results in the literature, further studies are needed to confirm an association between the degree of salt consumption and insulin sensitivity. The aim of this study was to measure insulin sensitivity in rats fed from weaning to adulthood with a low (LSD), normal (NSD), or high (HSD) salt diet. Body weight, carcass lipid content, blood glucose, nonesterified fatty acids, plasma insulin, plasma renin activity, and a glucose transporter (GLUT4) were measured. A euglycemic hyperinsulinemic clamp was used in 52 anesthetized rats. Body weight was higher in rats on LSD than in those on NSD (PϽ0.05) or HSD (PϽ0.001). Percentage fat carcass content was higher (PϽ0.05) in rats on LSD than in those on NSD. Basal plasma insulin and glucose levels were not altered (PϾ0.05) by salt consumption. Nonesterified fatty acids were lower in rats on HSD than in those on LSD (PϽ0.05) or NSD (PϽ0.01). Glucose uptake was lower in rats on LSD than in those on NSD (PϽ0.05) or HSD (PϽ0.001). When a euglycemic hyperinsulinemic clamp was used on pair-weight rats, similar results were obtained, which suggests that the effect of LSD on insulin sensitivity was not due to higher body weight. GLUT4 in insulin-sensitive tissues was increased in rats on HSD except in the cardiac muscle. Captopril treatment partially reversed low insulin sensitivity in LSD rats, whereas losartan did not change it, which indicates that the effect of LSD on insulin sensitivity is angiotensin independent. In conclusion, the present results demonstrate that chronic dietary salt restriction induces a decrease in insulin sensitivity not associated with renin-angiotensin system activity or body weight changes. Key Words: insulin resistance Ⅲ sodium, dietary Ⅲ insulin Ⅲ captopril Ⅲ angiotensin I nsulin resistance has been shown to occur in hypertensive subjects and has been proposed as a metabolic link between hypertension, non-insulin-dependent diabetes mellitus, obesity, dyslipidemia, and atherosclerotic cardiovascular disease. 1,2 Therefore, in hypertension treatment, consideration should be given to the effect of antihypertensive agents on insulin sensitivity (IS).Salt restriction is recommended for antihypertensive treatment, 3-5 and its effect on IS has been studied by several groups. Most of the studies 6,7 showed that salt restriction lowers IS, although some of them concluded the opposite. 8 Almost all studies from the literature analyzed the effects of short-term changes in salt consumption. However, to better understand the antihypertensive effects of salt restriction on IS, a long-term study was advisable. Recently, we have shown in rats that chronic salt restriction compared with overload is associated with lower blood pressure (BP) and decreased insulin-independent and dependent glucose uptake (GU) in epididymal isolated adipocytes. However, on the basis of the unchanged EC 50 of GU, no alteration on IS was observed. 9 Therefore, the present study was planned to evaluate, by use of the euglycemic hyperinsulinemic clamp (EHC), I...