Modulation of age-related hyperparathyroidism and senile bone loss in Fischer rats by soy protein and food restriction

Studies were carried out to explore the influence of soy protein and food restriction on age-related changes in serum PTH and bone. Three groups of male Fischer 344 rats were studied from 6 weeks of age. Group A rats were fed ad libitum diet A, which has casein as the protein source. Group B rats were fed diet B (with casein as protein source) at 60% of the mean ad libitum food intake. Group C rats were fed ad libitum diet C, which has soy protein as the protein source. The animals were killed at periodic intervals beginning at 6 months of age after an overnight fast. Serum PTH, measured with an intact N-terminal-specific RIA, and immunoreactive calcitonin increased progressively with aging. The increase was markedly suppressed by food restriction, and in the case of PTH by the soy protein diet as well. Serum creatinine started to increase after 18 months of age, and both dietary regimens of groups 2 and 3 retarded the increase. Aging was associated with a fall in serum 25-hydroxyvitamin D, and loss of bone occurred during the terminal part of life in the ad libitum-fed animals. These were prevented by food restriction, while the soy protein diet delayed the onset of bone loss. We conclude from these findings and other data from this study that in the male F344 rats 1) an age-related increase in serum PTH precedes an age-related increase in serum creatinine concentration; 2) an age-related decline in renal function probably contributes to age-related hyperparathyroidism, which, in turn, contributes to senile bone loss; 3) food restriction inhibits age-related hyperparathyroidism and senile bone loss; 4) on the basis of the data from rats fed a soy protein-containing diet, a decline in renal function and progressive hyperparathyroidism are not inevitable consequences of aging in the ad libitum fed rats.     

Diets containing salmon fillet delay development of high blood pressure and hyperfusion damage in kidneys in obese Zucker fa/fa rats

Hypertension is the leading risk factor for cardiovascular and chronic renal diseases, affecting more than 1 billion people. Fish intake is inversely correlated with the prevalence of hypertension in several, but not all, studies, and intake of fish oil and fish proteins has shown promising potential to delay development of high blood pressure in rats. The effects of baked and raw salmon fillet intake on blood pressure and renal function were investigated in obese Zucker fa/fa rats, which spontaneously develop hypertension with proteinuria and renal failure. Rats were fed diets containing baked or raw salmon fillet in an amount corresponding to 25% of total protein from salmon and 75% of protein from casein, or casein as the sole protein source (control group) for 4 weeks. Results show lower blood pressure and lower urine concentrations of albumin and cystatin C (relative to creatinine) in salmon diet groups when compared to control group. Morphological examinations revealed less prominent hyperfusion damage in podocytes from rats fed diets containing baked or raw salmon when compared to control rats. In conclusion, diets containing baked or raw salmon fillet delayed the development of hypertension and protected against podocyte damage in obese Zucker fa/fa rats.     

Differential effects of captopril and enalapril on tissue renin-angiotensin systems in experimental heart failure.

BACKGROUND. Angiotensin converting enzyme (ACE) inhibitor therapy elicits beneficial responses from patients with heart failure. We hypothesized that a major site of action of these drugs is tissue ACE and that ACE inhibitors might differ in their ability to inhibit tissue ACE. To test this hypothesis, we assessed the effects of captopril and enalapril on blood pressure and renal function and on serum and tissue ACE activities in sham-operated rats and rats with heart failure induced by coronary artery ligation. METHODS AND RESULTS. During short-term (1-week) treatment, captopril (200 mg.kg-1.day-1) and enalapril (25 mg.kg-1.day-1) elicited equipotent effects on blood pressure and inhibition of serum ACE activity (85%). The effects of long-term treatment (47 days) were then studied beginning 45 +/- 5 days after coronary ligation in four treatment groups: sham-operated, vehicle (n = 14); heart failure, vehicle (n = 10); heart failure, captopril (n = 8); and heart failure, enalapril rats (n = 7). During long-term treatment, captopril and enalapril caused comparable falls of 12-18 mm Hg in blood pressure (p < 0.01 compared with vehicle treatment). There was no change in urine volume or sodium or potassium excretion in vehicle- or captopril-treated heart failure rats; in contrast, enalapril-treated heart failure rats demonstrated 83% and 10% increases in urine volume and daily sodium excretion, respectively, compared with vehicle-treated rats (both p < or = 0.01). No significant changes in blood urea nitrogen or creatinine were observed with either treatment. Enalapril but not captopril elicited a significant decrease in serum and lung ACE activities. Captopril but not enalapril inhibited aortic ACE activity. Both agents caused a comparable inhibition of renal ACE activity. The magnitude of inhibition of renal ACE activity but not serum and vascular (aortic) ACE activities correlated with the long-term blood pressure response. Enalapril but not captopril normalized renal angiotensinogen expression; the magnitude of this effect correlated with the increase in daily urinary sodium excretion (r = -0.43; p < or = 0.005). CONCLUSIONS. These data suggest that chronic treatment with these two agents elicits differential effects on tissue ACE activities and renal angiotensinogen regulation. The differential renal effects of these agents may be important in the treatment of heart failure.     

Protective effects of dietary potassium chloride on hemodynamics of Dahl salt-sensitive rats in response to chronic administration of sodium chloride

BACKGROUND: Dietary potassium supplementation decreases blood pressure and prevents strokes in humans, and prevents strokes and renal damage in Dahl salt-sensitive (DSS) rats. OBJECTIVE: To study the effects of various concentrations of dietary potassium chloride (KCl) on the hemodynamics of Dahl salt-resistant (DSR) and DSS rats receiving a 1% sodium chloride (NaCl) diet for 8 months, to determine whether there is an optimal dietary concentration of KCl that minimizes increases in blood pressure and causes least impairment of blood flow in the brain and kidneys. METHODS AND RESULTS: We found a biphasic effect on hemodynamic parameters as a function of dietary KCl in DSS rats of the Rapp strain fed 1% NaCl with increasing dietary KCl (0.7, 2.6, 4 and 8%). After 8 months receiving a diet containing 1% NaCl and 0.7% KCl, DSS rats had mean arterial pressures (MAP), plasma volumes, cardiac outputs and renal and cerebral vascular resistances that were significantly increased compared with those of DSR rats receiving the same diet. With a 2.6% KCl diet, all these parameters were significantly reduced compared with those in DSS rats fed the 0.7% KCl diet and were similar to those in DSR rats fed 2.6% KCl. Total peripheral resistance in DSR and DSS rats was similar on all diets. When KCl was increased to 4 and 8%, MAP, plasma volume, cardiac output and renal vascular resistance progressively increased in DSR and DSS rats, without changing total peripheral resistance. These changes paralleled increases in plasma aldosterone, which resulted from adrenocortical stimulation by the increasing dietary KCl; however, cerebral vascular resistance of DSR and DSS rats decreased significantly with a 4% KCl diet, despite increased aldosterone and sodium retention. Only DSS rats fed a 2.6% KCl diet had hemodynamics similar to those of DSR control rats fed the same diet, and hyperaldosteronism, sodium retention and increased plasma volume did not occur. CONCLUSION: 'Optimal' dietary KCl (2.6%) prevents hypertension and preserves cerebral and renal hemodynamics in DSS rats fed a diet containing 1% NaCl for 8 months, which causes hypertension when dietary KCl is limited or excessive.     

Sodium intake influences hemodynamic and neural responses to angiotensin receptor blockade in rostral ventrolateral medulla

To determine the effects of physiological alterations in endogenous angiotensin II activity on basal renal sympathetic nerve activity (RSNA) and its arterial baroreflex regulation, angiotensin II type 1 receptor antagonists were microinjected into the rostral ventrolateral medulla of anesthetized rats consuming a low, normal, or high sodium diet that were instrumented for simultaneous measurement of arterial pressure and RSNA. Plasma renin activity was increased in rats fed a low sodium diet and decreased in those fed a high sodium diet. Losartan (50, 100, and 200 pmol) decreased heart rate and RSNA (but not mean arterial pressure) dose-dependently; the responses were significantly greater in rats fed a low sodium diet than in those fed a high sodium diet. Candesartan (1, 2, and 10 pmol) decreased mean arterial pressure, heart rate, and RSNA dose-dependently; the responses were significantly greater in rats fed a low sodium diet than in those fed a normal or high sodium diet. [D-Ala(7)]Angiotensin-(1-7) (100, 200, and 1000 pmol) did not affect mean arterial pressure, heart rate, or RSNA in rats fed either a low or a high sodium diet. In rats fed a low sodium diet, candesartan reset the arterial baroreflex control of RSNA to a lower level of arterial pressure, and in rats with congestive heart failure, candesartan increased the arterial baroreflex gain of RSNA. Physiological alterations in the endogenous activity of the renin-angiotensin system influence the bradycardic, vasodepressor, and renal sympathoinhibitory responses to rostral ventrolateral medulla injection of antagonists to angiotensin II type 1 receptors but not to angiotensin-(1-7) receptors.     

肾上腺髓质素缓慢注入对盐敏感大鼠的肾脏保护作用

目的:探讨缓慢注入肾上腺髓质素(AM)对高血压引起的肾衰竭大鼠的肾脏保护作用及其机制。方法:Dahl盐敏感(DS)大鼠18只和盐抵抗(DR组)大鼠9只从6周龄开始喂以高盐饮食形成肾衰竭模型。11周龄时将DS大鼠分为2组:DS-AM组(9只)注入重组人AM,DS组(9只)注入0.9%氯化钠溶液,均7周。结果:7周后,DS组及DS-AM组大鼠表现为肾功能减退、形态异常、激素水平升高。但与DS组比较,DS-AM组大鼠的肾功能以及组织学表现可显著改善,并抑制血浆肾素浓度及醛固酮水平的增加(P<0.01),而平均动脉压没有改变,DR组、DS组、DS-AM组大鼠的肾小球损伤分数分别为13.13、95.65、47.82,两两比较均差异有统计学意义(P<0.01或P<0.05)。结论:增加内源性AM对慢性高血压性肾衰竭起代偿作用,长期注入AM在该高血压模型中可部分通过抑制循环及肾素-血管紧张素系统而发挥肾脏保护作用。     

Haemodynamic effects of dual blockade of the renin-angiotensin system in spontaneously hypertensive rats: influence of salt

OBJECTIVE: To elucidate the mechanisms responsible for the adverse renal effects induced by dual blockade of the renin-angiotensin system (RAS) and the role of salt therein. METHODS: The effects of enalapril, losartan and their combination on blood pressure, renal haemodynamics, renal function and RAS were investigated over a wide range of doses in spontaneously hypertensive rats fed either a low-sodium or a high-sodium diet. RESULTS: In rats fed the low-sodium diet, the losartan-enalapril combination induced the same dose-dependent haemodynamic and hormonal changes as did three- to 10-fold greater doses of enalapril or losartan alone. When a strong decrease (> 50%) in blood pressure was achieved (with 10 mg/kg enalapril plus 10 mg/kg losartan, 100 mg/kg enalapril or 100 mg/kg losartan), a massive renal vasoplegia occurred and renal insufficiency developed. In addition, because of the huge release of renin, angiotensinogen concentrations were reduced, leading to a decrease in intrarenal angiotensins. In rats fed the high-sodium diet, those treated with the enalapril 30 mg/kg plus losartan 30 mg/kg combination, despite complete functional RAS blockade, exhibited smaller decreases in blood pressure and renal resistance, lesser release of renin and angiotensinogen consumption, and a normal renal function. These effects were similar to those produced by 100 mg/kg of enalapril or losartan in rats fed the high-salt diet, or by 10 mg/kg of enalapril or of losartan in rats fed the low-salt diet. CONCLUSIONS: Dual RAS blockade could be either beneficial, when sodium intake is unrestricted, or dangerous, when sodium intake is restricted.     

Renal effects of omapatrilat and captopril in salt-loaded, nitric oxide-deficient rats

Inhibition of nitric oxide synthases causes systemic hypertension and renal injury in rats. Our objective was to examine whether omapatrilat, a vasopeptidase inhibitor that inhibits both angiotensin-converting enzyme (ACE) and neutral endopeptidase, could induce better regression of renal injury than ACE inhibitor alone. Ten groups of rats were studied. They were fed either a normal (0.8% NaCl) or a high (4% NaCl) sodium diet. Eight of these groups received NG-nitro-L-arginine methyl ester (L-NAME, 20 mg x kg(-1) x d(-1)) in their drinking water. After 4 weeks, 1 group on each diet was killed and considered the L-NAME group, whereas the others received L-NAME alone, captopril (200 mg x kg(-1) x d(-1)) plus L-NAME, or omapatrilat (80 mg x kg(-1) x d(-1)) plus L-NAME for 4 additional weeks. In rats receiving L-NAME alone for 8 weeks, the mortality rate was approximately 90%, irrespective of the diet. In contrast, all rats survived in the captopril and the omapatrilat groups. In rats fed a normal-sodium diet, captopril and omapatrilat normalized systolic blood pressure and induced a complete regression of renal injury. Creatinine clearance and proteinuria were also normalized. In the high-sodium-diet groups, both treatments were less efficient: blood pressure remained elevated, and the regression of renal fibrosis was only partial. Although proteinuria decreased significantly with captopril or omapatrilat, creatinine clearance remained lower than in the controls. These results demonstrate that, in nitric oxide-deficient rats fed a normal-sodium diet, ACE and vasopeptidase inhibitors exhibit a marked renoprotective effect, whereas these treatments are less efficient in rats fed a high-sodium diet.     

Decreased ornithine decarboxylase activity in the kidneys of Dahl salt-sensitive rats.

To assess the roles of polyamines (putrescine, spermidine, and spermine) and ornithine decarboxylase (ODC), the rate-limiting enzyme of polyamine synthesis, in the development of salt-sensitive hypertension, we evaluated activity and expression of ODC, urinary polyamine excretion, and antizyme (endogenous ODC inhibitor protein) expression in Dahl salt-sensitive (SS) and salt-resistant (SR) rats after they were fed on a low (0.3%) or high (4%) salt diet for 4 weeks. We also examined the effects of spermidine and difluoromethylornithine (DFMO: a specific inhibitor of ODC) on the systolic blood pressure and ODC protein expression in SS rats fed a high salt diet. Renal ODC activity and urinary polyamine excretion in SS rats were lower than those in SR rats after 4 weeks treatment with a low or high salt diet. The renal ODC protein expression of SS rats was paradoxically increased as compared to the SR group. A high salt diet did not alter ODC activity but increased ODC protein only in SS rats. ODC mRNA and antizyme protein expressions were not significantly different among the four groups. Spermidine supplementation attenuated and DFMO exaggerated hypertension in SS rats fed a high salt diet. Spermidine down-regulated and DFMO up-regulated renal ODC protein in SS rats on a high salt diet. ODC activity was decreased but protein was paradoxically increased in kidneys of SS rats. ODC protein was suggested to increase in compensation for the inhibition of its activity. Impaired ODC activity and polyamine production in the kidney may exaggerate salt-sensitive hypertension in SS rats.     

Fish protein stimulated the fibrinolysis in rats

OBJECTIVE: We hypothesized that fish protein affects blood coagulation and/or fibrinolysis, and compared the activity and amounts of factors involved in blood coagulation and fibrinolysis in rats fed the fish protein, which was treated to remove water-soluble and ethanol-soluble elements, from sardine (sardine protein). METHODS: In the first experiment, rats were fed for 21 days an AIN-93G-based control diet, and diets in which the casein of the control diet was exchanged for sardine protein at 5, 10 and 20% levels. In the second experiment, rats were fed an AIN-93G control diet and diets containing 5% fish oil, 10% sardine protein or both (5% fish oil + 10% sardine protein) for 21 days. At the end of the experiments, blood coagulation time, hemostatic parameters and fibrinolysis parameters were measured. RESULTS: The activated partial thromboplastin time (APTT), which is an assay for blood coagulation time in the intrinsic blood coagulation pathway, of rats fed the 20% sardine protein diet was significantly prolonged compared to that of rats fed the control diet. The prolonged APTT by dietary sardine protein was due to a significant decrease of the activities of plasma blood coagulation factors VIII, IX, XI and XII. On the other hand, dietary sardine protein significantly increased the activity of tissue-type plasminogen activator, and the amount of plasma plasmin-alpha(2)-plasmin inhibitor complex, which are markers of activated plasmin. Moreover, we observed that the 20% sardine protein diet increased the amount of plasma D-dimer, which is a degraded product of the fibrin polymer by plasmin. In the second experiment, the APTT and PT of rats fed the F diet were prolonged compared to those of rats fed the control diet, however the concentration and amount of fibrinolytic parameters in the plasma were almost the same as those of rats fed the control diet. In contrast, the F+S diet not only prolonged APTT and PT, but also increased the concentration and amount of fibrinolytic parameters in plasma. CONCLUSIONS: We consider that the beneficial effects to health and amelioration of cardiovascular and cerebrovascular diseases by fish consumption are caused by a combination of the suppressing effect on blood coagulation of n-3 polyunsaturated fatty acids and the promoting effect on fibrinolysis of fish protein.     

Angiotensin-converting enzyme II in the heart and the kidney

The renin-angiotensin system (RAS) has been recognized for many years as critical pathway for blood pressure control and kidney functions. Although most of the well-known cardiovascular and renal effects of RAS are attributed to angiotensin-converting enzyme (ACE), much less is known about the function of ACE2. Experiments using genetically modified mice and inhibitor studies have shown that ACE2 counterbalances the functions of ACE and that the balance between these two proteases determines local and systemic levels of RAS peptides such as angiotensin II and angiotensin1-7. Ace2 mutant mice exhibit progressive impairment of heart contractility at advanced ages, a phenotype that can be reverted by loss of ACE, suggesting that these enzymes directly control heart function. Moreover, ACE2 is also found to be upregulated in failing hearts. In the kidney, ACE2 protein levels are significantly decreased in hypertensive rats, suggesting a negative regulatory role of ACE2 in blood pressure control. Moreover, ACE2 expression is downregulated in the kidneys of diabetic and pregnant rats and ACE2 mutant mice develop late onset glomerulonephritis resembling diabetic nephropathy. Importantly, ACE2 not only controls angiotensin II levels but functions as a protease on additional molecular targets that could contribute to the observed in vivo phenotypes of ACE2 mutant mice. Thus, ACE2 seems to be a molecule that has protective roles in heart and kidney. The development of drugs that could activate ACE2 function would allow extending our treatment options in diabetic nephropathy, heart failure, or hypertension.     

Dual ECE/NEP inhibition on cardiac and neurohumoral function during the transition from hypertrophy to heart failure in rats

CGS 26303 is a vasopeptidase inhibitor that simultaneously inhibits endothelin-converting enzyme (ECE) and neutral endopeptidase (NEP). We compared the effects of chronic treatment with CGS 26303 to the selective inhibition of angiotensin-converting enzyme (ACE) and NEP during the transition from left ventricular hypertrophy (LVH) to congestive heart failure (CHF) in hypertensive rats. LV geometry and function were assessed in Dahl salt-sensitive rats placed on a high-salt diet from age 6 weeks (hypertensive rats) and in control rats fed a low-salt diet. The hypertensive rats were randomized into groups that received no treatment or were treated with an ACE inhibitor (temocapril), an ECE/NEP inhibitor (CGS 26303), or a NEP inhibitor (CGS 24592) from the LVH stage (11 weeks) to the CHF stage (17 weeks). All treatments decreased the systolic blood pressure equally and significantly improved LV fractional shortening. Both temocapril and CGS 26303 ameliorated LV perivascular fibrosis, reduced mRNA levels of types I and III collagen, and decreased the heart weight/body weight ratio. CHF rats had increased plasma ET-1 levels compared with control rats. Only CGS 26303 reduced ET-1 to normal levels. ET-1 levels were found to correlate with heart/body weight, right ventricle/body weight and perivascular fibrosis ratios. During the transition to CHF, CGS 26303 produces effects that are comparable to temocapril and superior to CGS 24592. The beneficial effects of CGS 26303 are likely caused in part by the greater reduction of plasma ET-1. Dual ECE/NEP inhibitor may provide a new strategy for the treatment of human heart failure.     

Moderate calorie restriction improves cardiac remodeling and diastolic dysfunction in the Dahl-SS rat

Caloric restriction extends longevity and reduces the onset of chronic disease in many animal models. Recently, caloric restriction was shown in humans to be associated with lower blood pressure, decreased systemic inflammation, and improved cardiac diastolic parameters. However, the causation and mechanisms of caloric restriction were obscured by the varied diet composition of the participants. The Dahl salt-sensitive rat which develops gradual, hypertension-associated diastolic dysfunction was used in this study to assess the impact of caloric restriction upon decompensated pressure-overload hypertrophy. Male Dahl salt-sensitive rats were provided either a low-salt diet or a high-salt diet to initiate heart failure progression. A further subset of high-salt rats underwent 15% calorie restriction, with salt load held constant. Parameters measured included serial systolic blood pressure, body weight, and changes of left ventricular systolic and diastolic parameters and ventricular geometry by echocardiography. After 18 weeks, fasting glucose, blood lipids, heart weight, kidney weight, lung weight, plasma interleukin-6 and TNF-alpha, and cardiac lipid peroxidation were measured. Low-salt rats did not develop heart failure. While high-salt rats displayed features of decompensated pressure-overload hypertrophy, moderate calorie restriction remarkably reduced morbidity. Compared to the high-salt fed group, the high-salt, calorie-restricted group showed reduced blood pressure, delayed onset of cachexia, lower fasting hyperlipidemia, lower cardiac, renal and lung weight, less plasma IL-6 and TNF-alpha, less cardiac oxidative damage, and improved diastolic chamber function and cardiac index. Modest calorie restriction, independent of salt intake, reduced pathogenesis in this well described model of decompensated pressure-overload hypertrophy.     

Renal effects of angiotensin-converting enzyme inhibition in congestive heart failure

Some studies report that inhibition of angiotensin-converting enzyme (ACE) improves renal function in patients with congestive heart failure, whereas others report that renal deterioration is a frequent complication of treatment with ACE inhibitors. This article explores the mechanisms by which antagonism of the renin-angiotensin system improves kidney function in some patients while causing harm in others. ACE inhibition may alter renal blood flow, glomerular perfusion pressure, basement membrane activity and renal tubular function both directly and indirectly. In most patients, renal function is maintained as other neurohormonal mechanisms compensate for the negative effects and permit the positive effects (such as improved renal flow) to predominate. However, when physiologic characteristics or iatrogenic interventions (such as volume reduction or prostaglandin inhibition) limit the effectiveness of neurohormonal compensation to maintain renal autoregulation, clinically important deterioration in renal function may occur. An understanding of the renal effects of ACE inhibitors permits their safe and effective use in most patients with congestive heart failure.     

Metabolic effects of low dose angiotensin converting enzyme inhibitor in dietary obesity in the rat

Background and aimsGiven the recent observation of a local renin-angiotensin system (RAS) in adipose tissue, and its association with obesity-related hypertension, the metabolic effects of treatment with a low dose angiotensin converting enzyme inhibitor (ACEI) were investigated in a rodent model of diet-induced obesity.Methods and resultsMale Sprague Dawley rats were exposed to either standard laboratory chow (12% calories as fat) or palatable high fat (30% calories as fat) diet for 12 weeks. A subset from both dietary groups was given low dose ACEI in drinking water (perindopril, 0.3 mg/kg/day) throughout the study. The high fat diet increased body weight, adiposity, circulating leptin and insulin and in the liver we observed fat accumulation and increased tissue ACE activity. Treatment with perindopril decreased food intake and circulating insulin in both diet groups, and hepatic ACE activity in high fat fed animals only. Decreased plasma leptin concentration with ACE inhibition was only evident in chow fed animals. These effects were independent of any blood pressure lowering effect of ACE inhibition.ConclusionChronic low dose ACEI treatment reduced circulating insulin and leptin levels with some reduction in food intake in chow fed rats. Fewer beneficial effects were observed in obesity, and further work is required to investigate higher ACEI doses. Our data suggest a reduction in hepatic ACE activity may affect lipid accumulation and other inflammatory responses, as well as improving insulin resistance. Our findings may have implications for maximizing the clinical benefit of ACEI in patients without overt cardiovascular complications.     

Impact of exercise and angiotensin converting enzyme inhibition on tumor necrosis factor-alpha and leptin in fructose-fed hypertensive rats.

The aim of this study was to evaluate the effects of moderate-intensity regular exercise and/or an angiotensin converting enzyme (ACE) inhibition on tumor necrosis factor-alpha (TNF-alpha) and glucose and lipid metabolism parameters. Spontaneously hypertensive rats (SHRs) were fed a fructose-rich diet during 16 weeks of either exercise training (Ex group: 20 m/min, 0% grade, 60 min/day, 5 days/week), administration of an ACE inhibitor (TM group: temocapril, 10 mg/kg/day), or a combination of both (TM+Ex group). The systolic blood pressure was reduced exclusively in the TM and TM+Ex group. Epididymal fat pads (EPI) weighed less in the TM+Ex group than in the single-treatment (TM) group. The serum leptin level was significantly and directly correlated with the EPI weight (p < 0.001). The TNF-alpha content per gram of EPI was the highest in the TM+Ex group. In addition, the EPI TNF-alpha level was negatively correlated with both the EPI weight and the serum leptin level (p < 0.001, respectively). In contrast, the TNF-alpha level of skeletal muscles was identical among the groups. The extensor digitorum longus had a significantly higher abundance of TNF-alpha protein than the soleus muscle. These data indicate that the local TNF-alpha expression is tissue-specific, and that upregulation of TNF-alpha in EPI by exercise training and/or ACE inhibition may have contributed to the reduction in fat cell volume via the induction of apoptosis and/or the regulation of metabolic homeostasis.     

Effects of soy components on blood and liver lipids in rats fed high-cholesterol diets

AIM: To assess the effects of soy protein, isoflavone, and saponin on liver and blood lipid in rats that consumed high-cholesterol diets. METHODS: High-cholesterol diets (1%) with or without soy material were fed to 6-wk-old male Sprague-Dawley rats for 8 wk. Blood lipids, liver lipids, glutamic oxaloacetic transaminase (GOT), and glutamic pyruvic transaminase (GPT) levels were measured. The in vitro bile acid-binding ability of soy materials was analyzed. RESULTS: The results of in vitro studies showed that soy protein isolate had a significantly higher bile acid-binding ability (8.4±0.8%) than soy saponin (3.1±0.7%) and isoflavone (1.3±0.4%, P<0.05). On the other hand, at the end of the experimental period, rats that consumed soy protein diets had lower GOT and GPT levels than rats that consumed casein under high-cholesterol diets. Rats that consumed soy protein also had lower total cholesterol (TC) levels in the liver than those that consumed casein under high-cholesterol diets. Rats that consumed the soy protein diet containing both saponin and isoflavone had lower hepatic TC level than those that consumed the soy protein diet without isoflavone alone. The effect of different types of proteins on triglyceride was not significant. CONCLUSION: Consumption of soy provided benefits to control lipid levels under high-cholesterol dieting conditions in this rat model of hypercholesterolemia. The major component that reduced hepatic TC was not saponin, but possibly isoflavone.     

Contribution of Renal Angiotensin Converting Enzyme(ACE) to Blood Pressure Regulation: Possible Role of Brush Border Ace

The role of renal angiotensin converting enzyme(ACE) in blood pressure regulation is not well understood. In our studies, both acute and chronic treatment of hypertensive rats SHR and SHRSP with ACE inhibitors Enalapril and SA446 had a blood pressure lowering effect that coincided with an inhibition of renal cortical and aortic ACE, but not plasma ACE. Further, ACE activities in the renal cortex and aorta were found to increase with aging of the SHRSP, therefore concomitantly with hypertension development. In the kidney, brush border membranes(BBM) contained abundant ACE. We found that the activities of ACE in the renal cortex closely correlated to the activities in isolated BBM, in Wistar Kyoto rats and in the SHRSP. Thus, renal cortical ACE activity and blood pressure correlated in cases of ACE inhibition and hypertension development. Since the ACE activity in the renal cortex appeared to reflect the enzyme activity in BBM, the brush border ACE may have to be taken into account, in view of the relationship between renal ACE, and blood pressure.     

Additive beneficial effects of the combination of a calcium channel blocker and an angiotensin blocker on a hypertensive rat-heart failure model.

The present study was undertaken to examine the effects of a calcium channel blocker, azelnidipine (1 mg/kg/day), an angiotensin converting enzyme (ACE) inhibitor, temocapril (10 mg/kg/day), an angiotensin II type 1 (AT1) receptor blocker (ARB), olmesartan (5 mg/kg/day), and their combination on Dahl salt-sensitive rats (DS rats) developing heart failure with preserved systolic function. DS rats were fed a high-salt diet (8% NaCl) from 7 weeks of age and progressively developed hypertension. Although monotherapy with azelnidipine lowered the blood pressure of DS rats to a greater extent than monotherapy with temocapril or olmesartan, the three drugs had similar effects on cardiac hypertrophy, cardiac fibrosis, the expressions of brain natriuretic peptide, transforming growth factor-beta1, collagen I, collagen III and monocyte chemoattractant protein-1 mRNA (as estimated by Northern blot analysis), and cardiac diastolic dysfunction (as estimated by echocardiography). These results show that ACE and AT1 receptor, as well as hypertension, are involved in the development of heart failure with preserved systolic function in DS rats. The combination of azelnidipine with olmesartan or temocapril produced no additive hypotensive effect in DS rats and no additive effect on cardiac hypertrophy or gene expressions. However, the combination therapy prolonged the survival rate of DS rats more than azelnidipine (p <0.01) or temocapril alone (p <0.05), and this additive beneficial effect by the combination therapy was associated with a greater reduction of cardiac fibrosis, urinary albumin excretion and serum creatinine. Our results thus showed that the combination of a calcium channel blocker with an ARB or an ACE inhibitor had additive preventive effects on a rat model of hypertensive heart failure with preserved systolic function. Thus, combination therapy with these agents seems to be a useful therapeutic strategy for the prevention of hypertensive heart failure.     

Thromboxane synthesis and blood pressure in spontaneously hypertensive rats

The present study examines effects of administration of OKY 046, an inhibitor of thromboxane synthesis, for 100 days on systemic blood pressure and renal function in spontaneously hypertensive rats and in normotensive control rats. Untreated spontaneously hypertensive rats had higher values for thromboxane excretion in the urine and higher values for blood pressure than did normotensive control rats. Administration of OKY 046 decreased systolic and mean arterial blood pressure and urinary excretion of thromboxane and protein in spontaneously hypertensive rats. Administration of OKY 046 decreased thromboxane excretion in the urine of normotensive control rats but had no effect on blood pressure or protein excretion. Renal function, as assessed by the clearances of inulin and p-aminohippuric acid, was greater in spontaneously hypertensive rats treated with OKY 046 than in those receiving vehicle alone. In normotensive control rats, OKY 046 administration did not affect renal function. These results suggest that increased renal synthesis of thromboxane may play a role in the pathogenesis of the elevated blood pressure of spontaneously hypertensive rats.