Normal Chow Group Research Articles

Hypercholesterolemia and Myocardial function evaluated via Tissue Doppler Imaging

ObjectiveTo establish a link between hypercholesterolemia and myocardial dysfunction.BackgroundHeart failure is a complex disease involving changes in systolic and diastolic function. Newer echocardiographic imaging modalities may be able to detect discreet changes in myocardial function associated with hypercholesterolemia. Therefore we sought to establish a link between hypercholesterolemia and myocardial dysfunction with tissue Doppler imaging (TDI).MethodsTwenty-seven rabbits were studied: 7 were fed normal chow (group 1) and 20 a high cholesterol diet (10 with ezetimibe, 1 mg/kg/day; group 2 and 10 without, group 3). Echocardiographic images were obtained under general anesthesia. Serum cholesterol levels were obtained at baseline, 3 and 6 months and myocardial cholesterol levels measured following euthanasia.ResultsDoppler measurements, including E/A, E'/A' and S' were significantly lower in group 3 compared to both groups 1 and 2 but no significant differences were noted in chamber sizes or ejection fraction among the groups. Average serum cholesterol was higher in group 3 compared to groups 1 and 2 respectively (495 ± 305 mg/dl vs. 114 ± 95 mg/dl and 87 ± 37 mg/dl; p < 0.01). Myocardial cholesterol content was also higher in group 3 compared to group 2 (0.10 ± 0.04 vs. 0.06 mg/dl ± 0.02; p = 0.05). There was significant correlation between S', E'/A', E/E' and serum cholesterol (r2 = 0.17 p = 0.04, r2 = 0.37 p = 0.001 and r2 = 0.24 p = 0.01).ConclusionCholesterol load in the serum and myocardium was significantly associated with decreased systolic and diastolic function by TDI. Moreover, lipid lowering was protective.

Hot Fat

We have previously demonstrated that modification with diet and exercise improved inflammation in adipose tissue in sedentary adult mice after being placed on a high fat diet. Given that adolescent obesity is on the rise, there is little to no data available on inflammation in adipose and the effect exercise would have in such a population. PURPOSE: To determine the effects of a 6 wk intervention of exercise or no exercise with either a high fat (HF) diet or normal chow (NC) diet in juvenile mice. METHODS: At 5 wks of age, C57BL/6 mice were divided into 4 groups (n=10/grp): NC/sedentary (NC/SED), NC/exercise (NC/EX), HF/sedentary (HF/SED), and HF/exercise (HF/EX). The HF diet was 45 % fat, 35 % carbohydrate and 20 % protein. Treadmill exercise was performed 5 d/wk at 13 m/min, 10% grade for 40 min/d. Mice were placed on the 6 wk diet and exercise intervention concomitantly. Body weights were measured weekly and the liver, epidydmal and peri-renal fat pads were weighed at sacrifice. Liver triglycerides were measured and quantitative RT-PCR was performed using F480 to assess inflammation. RESULTS: After 1 wk of intervention, the NC groups had lower body weights than the HF groups (19.8 ± 0.3 vs. 21.4 ± 0.3 g) (p<.01). This pattern remained at 6 wks (22.8 ± 0.2 vs. 25.7 ± 0.4 g) (p<0.0001). Fat pad weights were highest among the HF diet groups (p<0.0001), with the HF/SED having the greatest epidydmal and peri-renal fat pads and the HF/EX having the next largest fat pad weights. No differences were observed between the two NC groups. F480 gene expression, an indicator of macrophage infiltration and inflammation, and liver triglycerides were greatest amongst the HF/SED group, with no differences between the remaining 3 groups. CONCLUSIONS: Exposure to a HF diet in sedentary juvenile mice increased visceral adipose depots and liver triglycerides versus a NC diet. Interestingly, exercise training while on the HF diet appeared to "protect" the liver and inflammation within adipose. These data suggest that promoting physical activity in adolescents is paramount for reducing obesity-related health complications.Table

Candesartan improves insulin resistance induced by high-fat diet in rats

To investigate the effects of candesartan, an angiotension II type I receptor antagonist, in improvement of insulin resistance (IR) induced by high-fat diet and the possible mechanism thereof. 45 male Wistar rats were randomly divided into 3 groups: normal chow group (NC, n = 15) fed with normal diet, high fat diet group (HF, n = 15) fed with high fat diet, and high-fat diet with daily candesartan treatment group (HF + C, n = 15) fed with high fat diet and given orally with candesartan 8 mg/kg per day. Body weight was measured regularly. Four weeks later, oral glucose tolerance test (OGTT) and euglycemic-hyperinsulinemic clamp technique were performed to estimate the insulin sensitivity. After 12 h fasting blood samples were collected from the abdominal aorta to test the contents of blood glucose, and serum triglyceride (TG), total cholesterol (TC), LDL, HDL, and free fatty acid (FFA). Radioimmunoassay was used to detect the serum insulin. Viscera were taken out. Immunohistochemistry was used to examine the expression of peroxisome proliferation activated receptor (PPAR)-gamma in hepatic and adipose tissues. The body weight 16 weeks later of the HF group was significantly higher than that of the HF + C group (P < 0.01). The liver weight and epididymal and peri-renal fat weights of the HF group were all significantly higher than those of the HF + C group and NC group (all P < 0.01). There was no significant difference in fasting blood sugar among these 3 groups (P > 0.05). The glucose levels 2 h after OGTT in the HF + C group was (6.3 +/- 0.5) mmol/L, significantly lower than that of the HF group [(7.3 +/- 1.2) mmol/L, P < 0.01]. The glucose infusion rate (GIR) of the HF + C group was (22 +/- 5) mmol/L, significantly higher than that of the HF group [(14 +/- 4) mmol/L, P < 0.01]. The PPARgamma expression levels in liver and adipose tissue of the HF + C group were up-regulated significantly compared with those of the HF group. Candesartan may improve insulin resistance through promoting the expression of PPARgamma in liver and adipose tissue.

Sleeve Gastrectomy Relieves Steatohepatitis in High-Fat-Diet-Induced Obese Rats

Sleeve gastrectomy is thought to decrease the appetite and body weight of morbid obesity patients in the clinic. The purpose is to investigate the effect of sleeve gastrectomy on preventing steatohepatitis in morbid obesity rats. Thirty rats were randomized into normal chow group (NC), high-fat-diet group (HD), and sleeve group (SG). Rats in the SG group received sleeve gastrectomy operation. After operation, rats in SG and HD group received a high-fat diet, while rats in the NC group received normal chow. Body weight was measured every 10 days. Thirty days later, animals were sacrificed and blood samples were collected to check total cholesterol, HDL, and triglyceride. Fresh liver sections were made and stained with Nile red and observed under a fluorescence microscope. Rats in the SG group received a moderate body weight decrease (191 +/- 16.2 g) in the first 10 days, while this did not happen in the other two groups (213 +/- 13.7 g and 243 +/- 11.9 g). At the sacrifice date, weight of rats in the SG group was still much lower than those in the HD group. Plasma triglycerol (102.3 +/- 18.6 mg/dL) and cholesterol (84.3 +/- 6.1 mg/dL) of rats in the SG group were much lower than those in the HD group (198.5 +/- 18.5 mg/dL, 133.9 +/- 22.0 mg/dL). Under the fluorescence microscope, adipose infiltration was very obvious in the liver of the HD animals, while adipose infiltration was not serious in the SG group. High-fat diet can result in obvious body weight increase and hepatic adipose infiltration compared with normal chow. Sleeve gastrectomy can decrease body weight even in high-fat-diet models. Body weight control caused by sleeve gastrectomy can relieve high-fat-diet-induced steatohepatitis in rats.

The effect of calorie restriction on the expression of liver's gluconeogenesis genes of rats fed a high fat diet

To observe the effect of calorie restriction on the high fat diet rats mRNA expressions of liver forkhead box O1(FoxO1), phosphoenolpyruvate carboxykinase (PEPCK), glucose-6-phosphatase (G-6-P) and to explore the possible mechanisms. 24 normal 6-week-old male Wistar rats were randomly divided into three groups: normal chow group (NC, n = 7), high fat diet group (HF, n = 9) and calorie restriction group (CR, n = 8). They were fed for 12 weeks. At the end of the experiment, the rats were sacrificed and their fasting blood glucose (FBG), insulin (INS), triglycerides (TG), total cholesterol (TC) were measured. Their visceral fat (VF) and body weight (BW) were also measured and VF/BW was calculated. Gene expression was investigated by using semi-quantitative RT-PCR methods. Liver histology was studied with HE stained slides. Compared with the NC group, HF group rats developed visceral obesity which was accompanied by higher FBG, plasma INS, TG, and TC. The levels of FoxO1, PEPCK, and G-6-P increased by 18.9%, 33.8%, and 24.6%, respectively (P less than 0.01). Liver steatosis was observed with microscopy. The BW, VF FBG, INS, TG and TC of the CR group rats were lower in comparison to those of the HF group. The levels of FoxO1, PEPCK and G-6-P were lower by 26.6%, 35.0%, 34.3% (P less than 0.01). Meanwhile, liver steatosis was also milder. Calorie restriction can inhibit the expressions of FoxO1, PEPCK and G-6-P, strengthen insulin signal conduction, suppress gluconeogenesis and thus regulate glycometabolism.

HIGH‐FAT DIET PREVENTS CARDIAC HYPERTROPHY AND IMPROVES CONTRACTILE FUNCTION IN THE HYPERTENSIVE DAHL SALT‐SENSITIVE RAT

1. The role that dietary lipid and plasma fatty acid concentration play in the development of cardiac hypertrophy in response to hypertension is not clear. 2. In the present study, we treated Dahl salt-sensitive rats with either normal chow (NC), normal chow with salt added (NC + salt) or a diet high in long-chain saturated fatty acids with added salt (HFD + salt). Cardiac function was assessed by echocardiography and left ventricular (LV) catheterization. 3. The HFD + salt group had significantly higher plasma free fatty acid concentrations and myocardial triglyceride content compared with the NC + salt group, but did not upregulate the activity of the fatty acid oxidation enzyme medium chain acyl-coenzyme A dehydrogenase. Systolic blood pressure was elevated to a similar extent in the NC + salt and HFD + salt groups compared with the NC group. Although LV mass was increased in the NC + salt group compared with the NC group, LV mass in the HFD + salt group did not differ from that of the NC group and was significantly lower than that in the NC + salt group. 4. There was no evidence of cardiac dysfunction in the NC + salt group compared with the NC group; however, high fat feeding significantly increased LV contractile performance (e.g. increased cardiac output and peak dP/dt). 5. In conclusion, the HFD + salt diet prevented the hypertrophic response to hypertension and improved the contractile performance of the heart. It remains to be determined whether preventing cardiac hypertrophic adaptations would be deleterious to the heart if the hypertensive stress is maintained long term.

W05.155 The role of T-cadherin in cell adhesion and migration, interaction with LDL and signalling

The purpose of this study was to test the hypothesis that plasma renin activity (PRA) is a risk factor for cardiovascular disease. Four groups of New Zealand rabbits were used to study the effects of PRA and hypertension on atherogenesis. Control groups were fed normal rabbit chow (Group I), or normal chow supplemented with 0.25% cholesterol (Group III) Group II animals were fed normal chow, had a clip placed around the left renal artery and were contralaterally nephrectomized (one-kidney-one-clip, 1K-1C). The renal arteries and kidneys of Group IV animals, which were fed a cholesterol diet, were manipulated similarly. Blood pressure and blood chemistry measurements were performed periodically over a 7-month period. The blood pressure was unaffected by either diet; however, PRA and aldosterone levels were greatly reduced in the 1 K-1 C groups (Groups II and IV). No atheroma were observed in any of the animals consuming the normal diet (Groups I and II) despite sharply elevated blood pressure in the Group II animals. Medial hypertrophy of small muscular arteries was observed in several Group II animals. All of the animals fed the atherogenic diet showed extensive aortic atheromata. There was, however, a significantly smaller lesion index for the normotensive cholesterol-fed animals (Group III) than those with increased blood pressure (Group IV). Likewise, microscopic evaluation of the aorta, coronary arteries, renal arteries, and kidneys mirrored this difference in the vascular involvement between the animals of Groups III and IV. We conclude that neither relatively high nor low PRA levels affect the development of atherosclerosis or other cardiovascular lesions. However, hypertension with a concomitantly high cholesterol diet acts synergistically in exacerbating atherogenesis.

Comparison of Early Postoperative Enteral Nutrients versus Chow on Colonic Anastomotic Healing in Normal Animals

We aimed to clarify the effects of different enteral nutrients (normal chow, complete balanced nutrition, elemental nutrition enriched with glutamine, immune-enhancing diet and fiber) on colonic anastomotic healing in the stress-free metabolic state. The study was carried out with 50 male Balb-C mice in five groups of 10 animals each. After transverse colon anastomosis, animals were fed with early enteral nutrients using normal chow (group 1), Ensure^® (group 2), Alitraq^® (group 3), Impact^® (group 4), and Benefiber Resource^® orange juice drink (group 5) for 7 days. There were no significant differences among the groups in bursting pressure (p > 0.05). There was no statistical difference in terms of hydroxyproline level among groups 1–3. The hydroxyproline levels of groups 4 and 5 were statistically higher than that of the control group (p < 0.05 for both comparisons). Under normal conditions without stress, we could not demonstrate the superior effects of early enteral feeding with specialized enteral preparations over normal diets on colonic anastomoses when the bursting pressures were compared.

The selective peroxisomal proliferator-activated receptor-gamma agonist has an additive effect on plaque regression in combination with simvastatin in experimental atherosclerosis: in vivo study by high-resolution magnetic resonance imaging

ObjectivesWe sought to investigate the anti-atherogenic effects of a selective peroxisomal proliferator-activated receptor-gamma (PPAR-gamma) agonist and simvastatin, as well as their combination, over time, in a rabbit model of experimental atherosclerosis. BackgroundThe PPARs are nuclear transcription factors that control a variety of cellular functions, with the potential effects required to induce plaque regression and stabilization. MethodsAtherosclerosis was induced in rabbits (n = 37) by the combination of double-balloon injury and a nine-month high-cholesterol (HC) diet. The rabbits were randomized into a continued HC diet, a normal chow (NC) diet, NC plus simvastatin, NC plus PPAR-gamma agonist, and NC plus simvastatin plus PPAR-gamma agonist. All rabbits underwent magnetic resonance imaging (MRI) at randomization and after six months of treatment and were then sacrificed for histopathologic study. ResultsAll groups had a similar vessel wall area by MRI (8.45 ± 0.65 mm2, p = NS between groups) at randomization. Significant progression was seen in the HC diet group (15 ± 4%, p < 0.01). In the NC and NC plus PPAR-gamma agonist groups, progression was abolished (−2.5 ± 3% and −4.5 ± 5%, respectively; p = NS). The NC plus simvastatin and NC plus simvastatin plus PPAR-gamma agonist groups had significant plaque regression (−12 ± 4% [p < 0.05] and −22 ± 4% [p < 0.01], respectively). Regression was independent of plasma lipid levels. All NC groups had similar lipid profiles at the end of treatment. Histopathologic analysis of the NC groups showed a decreased macrophage content and matrix metalloproteinase activity and an increased smooth muscle cell/collagen content of lesions. ConclusionsOur data indicate that normalization of plasma lipid levels abolishes progression of atherosclerosis. Simvastatin elicits regression of atherosclerotic lesions, and the combination simvastatin plus PPAR-gamma agonist has additive regression effects on plaque. This is paralleled by structural alterations in plaque composition, which may increase plaque stability. These observations support the beneficial effects of statins on atherosclerosis and show additional anti-atherogenic benefits of combining a PPAR-gamma agonist with simvastatin.

Effects of VasoCare™ therapy on the initiation and progression of atherosclerosis

VasoCare™ therapy, which involves the administration of autologous blood following the ex vivo exposure to physico-chemical stressors, has been shown to modulate immune responses. Since immune mechanisms have been recognized to be pivotal in the pathogenesis of atherosclerosis, we hypothesized that VasoCare™ treatment would inhibit atherosclerosis in LDL-R (−/−) mice. Three groups of LDL-R (−/−) mice were studied: a control group that was fed normal chow (Group I) and no other treatment; a control group that received a high cholesterol (HC) diet for 8 weeks (group II) with sham saline injections; and a third group (III) that received HC diet for 8 weeks and VasoCare™ treatment initiated after four weeks of HC feeding. Atherosclerotic area (AA), relative to total aortic area (TA), was assessed after 8 weeks of HC feeding by oil red O staining, and cross sectional plaque area at the level of the aortic valve leaflets was determined by quantitative morphometry. HC mice exhibited substantial aortic lipid deposition which was profoundly reduced in the VasoCare™ treated animals (AA/TA ratios in group II: 0.32±0.15 vs. group III: 0.17±0.06; P<0.05). This was associated with a significant decrease in cross sectional area of plaque in the aortic sinuses. VasoCare™ therapy also reduced the xanthoma formation and limb swelling characteristic of this animal model. However, cholesterol levels, measured by an enzymatic assay, showed similar marked increases in total serum cholesterol (CHO) in the animals receiving HC diet alone and those receiving the HC diet and VasoCare™ treatment [group I: 5.4±0.8 mM, group II: 46.7±3.6 mM, and group III: 44.7±2.8 mM ( P<0.01 vs. group I)]. We conclude that VasoCare™ treatment inhibits progression of atherosclerotic lesions in a murine model of human familial hypercholesterolemia by a mechanism independent of cholesterol lowering.

Blockade of endothelin receptors markedly reduces atherosclerosis in LDL receptor deficient mice: role of endothelin in macrophage foam cell formation.

We evaluated the direct effects of long-term blockade of ET(A) and ET(B) receptors using a mixed endothelin (ET) receptor antagonist, LU224332, in the low density lipoprotein receptor (LDL-R) knockout mouse model of atherosclerosis. Four groups of LDL-R deficient mice were studied: control mice fed normal chow (group I); mice fed a high cholesterol (HC, 1.25%) diet alone (group II), HC fed animals treated with LU224332 (group III); and mice fed normal chow treated with the LU compound (group IV). All treatments were continued for 8 weeks at which time the animals were sacrificed and the aortae were removed and stained with oil red O. Atherosclerotic area (AA) was determined by quantitative morphometry and normalized relative to total aortic area (TA). Cholesterol feeding resulted in a marked increased in total plasma cholesterol ( approximately 15 fold) and widespread aortic atherosclerosis (AA/TA: group I: 0.013+/-0.007; group II: 0.33+/-0. 11; P<0.001). Atherosclerotic lesions were characterized by immunohistochemistry as consisting mainly of macrophages which also showed high levels of ET-1 expression. Treatment with ET antagonist significantly reduced the development of atherosclerosis (AA/TA: group III: 0.19+/-0.07, P<0.01 vs. group II), without altering plasma cholesterol levels and blood pressure. The direct effect of LU224332 on macrophage activation and foam-cell formation was determined in vitro using a human macrophage cell line, THP-1. Treatment of the THP-1 cells with LU224332 significantly reduced cholesterol ester and triacylglycerol accumulation and foam-cell formation on exposure to oxidized LDL (P<0.01 and P<0.05, respectively). We conclude that a nonselective ET receptor antagonist substantially inhibited the development of atherosclerosis in a genetic model of hyperlipidemia, possibly by inhibiting macrophage foam-cell formation, suggesting a role for these agents in the treatment and prevention of atherosclerotic vascular disease.

Iron Overload Augments the Development of Atherosclerotic Lesions in Rabbits

Iron, a major oxidant in vivo, could be involved in atherosclerosis through the induction of the formation of oxidized LDL, a major atherogenic factor. This study was designed to test this hypothesis experimentally. Four groups of New Zealand White rabbits were included: iron-overloaded/hypercholesterolemic (group A, n = 8), iron-overloaded (group B, n = 6), hypercholesterolemic (group C, n = 6), and untreated (group D, n = 6). Iron overload was achieved by the intramuscular administration of 1.5 g of iron dextran divided in 30 doses. Hypercholesterolemia was produced by feeding rabbit chow enriched with 0.5% (wt/wt) cholesterol. Serum iron, ferritin, cholesterol, triglycerides, and lipoperoxides in serum were measured throughout the study. Lipoperoxides were measured at the end of the study in liver, aorta, and spleen homogenates. Aortas of groups A and C had multiple lesions; however, group A had greater lesional involvement than group C (P < .05). Lesions were not observed in rabbits fed normal chow (group D). As expected, serum iron and ferritin were above normal levels in groups A and B. Serum cholesterol increased in groups A and C. Lipoperoxides in liver and spleen homogenates of iron-overloaded rabbits were increased. Interestingly, iron deposits were seen by ultrastructural studies in the arterial walls of rabbits in groups A and B. Our study suggests that iron overload augments the formation of atherosclerotic lesions in hypercholesterolemic rabbits.

Evening primrose oil reduces urinary calcium excretion in both normal and hypercalciuric rats.

Hypercalciuria is an important risk factor in the aetiology of idiopathic urolithiasis and many treatment modalities in clinical practice are directed towards reducing urinary calcium excretion. There are no natural animal models of hypercalciuria, such as the spontaneous hypertensive rat; however, the streptozotocin-diabetic rat is accepted as a good model for studies of disordered renal function associated with diabetes mellitus. Hypercalciuria is a prominent feature of the streptozotocin-diabetic rat and the model was, therefore, used to study the influence of evening primrose oil on urinary calcium excretion. Twenty rats divided into two groups of ten rats each were maintained on either normal rat chow (group 1) or primrose oil enriched diet (group 2) for 10 weeks. At 4 weeks both groups of rats were made diabetic with streptozotocin. Urine calcium measurements were serially performed before commencement of the diet, during the pre-streptozotocin (pre-diabetic) phase and during the post streptozotocin (diabetic) phase. The urine calcium excretion was significantly less in the primrose oil fed animals during both the pre-diabetic phase and the diabetic phase compared with the rats on the normal rat chow. These results indicate that evening primrose oil, a rich source of gamma-linolenic acid, helps to reduce urine calcium excretion in normal animals as well as in the hypercalciuric streptozotocin-diabetic rat. Dietary modifications with long-chain omega-6 and omega-3 fatty acids might be a useful adjunct in the treatment of idiopathic hypercalciuric urolithiasis.

Exacerbation of chronic aminonucleoside nephrosis by dietary cholesterol supplementation

Abnormalities in lipid metabolism resulting from nephrotic syndrome may play a role in the progression of initial glomerular injury to focal and segmental glomerulosclerosis (FSGS). In order to more specifically assess this, we fed male Sprague-Dawley rats, made nephrotic with a single intravenous injection of puromycin aminonucleoside (PA), either normal rodent chow (Group 1) or the same formulation supplemented with 4% cholesterol/1% cholic acid (Group 2). This 4% cholesterol/1% cholic acid-added diet was utilized because, in normal, non-nephrotic rats, this alimentary supplement produces, for the most part, only a significant rise in fasting serum cholesterol and not fasting serum triglycerides. FSGS developed 18 weeks after PA delivery, and both groups of rats were studied functionally and morphologically. Group 2 rats had significantly higher daily urine protein excretion, lower inulin clearance, and greater blood urea nitrogen concentrations than Group 1 animals. Histologically, Group 2 animals demonstrated a significantly greater percentage of glomeruli examined with segmental areas of glomerulosclerosis/hyalinosis, mesangial cell proliferation, and mesangial "foam" cells. At 2, 4, 12, and 18 weeks after PA delivery, the fasting serum cholesterol was always significantly greater in Group 2 rats, whereas in regards to fasting serum triglycerides it was only significantly elevated in Group 2 rats at 4 and 12 weeks after PA administration.

Renin as a risk factor for atherogenesis: Part 3. Effects of hypercholesterolemia, hyporeninemia and one-kidney-one-clip hypertension in the rabbit

The purpose of this study was to test the hypothesis that plasma renin activity (PRA) is a risk factor for cardiovascular disease. Four groups of New Zealand rabbits were used to study the effects of PRA and hypertension on atherogenesis. Control groups were fed normal rabbit chow (Group I), or normal chow supplemented with 0.25% cholesterol (Group III) Group II animals were fed normal chow, had a clip placed around the left renal artery and were contralaterally nephrectomized (one-kidney-one-clip, 1K-1C). The renal arteries and kidneys of Group IV animals, which were fed a cholesterol diet, were manipulated similarly. Blood pressure and blood chemistry measurements were performed periodically over a 7-month period. The blood pressure was unaffected by either diet; however, PRA and aldosterone levels were greatly reduced in the 1 K-1 C groups (Groups II and IV). No atheroma were observed in any of the animals consuming the normal diet (Groups I and II) despite sharply elevated blood pressure in the Group II animals. Medial hypertrophy of small muscular arteries was observed in several Group II animals. All of the animals fed the atherogenic diet showed extensive aortic atheromata. There was, however, a significantly smaller lesion index for the normotensive cholesterol-fed animals (Group III) than those with increased blood pressure (Group IV). Likewise, microscopic evaluation of the aorta, coronary arteries, renal arteries, and kidneys mirrored this difference in the vascular involvement between the animals of Groups III and IV. We conclude that neither relatively high nor low PRA levels affect the development of atherosclerosis or other cardiovascular lesions. However, hypertension with a concomitantly high cholesterol diet acts synergistically in exacerbating atherogenesis.

The effect of chronic alpha-glycosidase inhibition on diabetic nephropathy in the db/db mouse.

Acarbose, a complex oligosaccharide, is a potent competitive inhibitor of sucrase and decreases postprandial hyperglycemia when administered with food. To evaluate its potential for metabolic control and prevention of diabetic nephropathy, groups of gentically diabetic mice (C57 BLKsJ db/db) were treated with Acarbose for 10 wk. Control mice received normal chow and experimental groups were given Acarbose prepared as a drug-food mixture in doses of 10, 20, and 40 mg/100 g of food. Acarbose did not influence fasting blood glucose, food intake, or the normal development of obesity in the mice. Urinary glucose excretion and glycosylated hemoglobin was significantly reduced in animals receiving high-dose Acarbose (40 mg/100 g food). Immunopathologic examination of the kidneys showed a dose-dependent decrease in glomerular mesangial immunoglobulin deposition. By light microscopy, glomerular mesangial thickening was significantly reduced in the group receiving high-dose Acarbose (40 mg/100 g food). To the extent that Acarbose improves metabolic control in the db/db mouse, chronic treatment with this agent produces a dose-dependent amelioration of diabetic nephropathy. Alphaglycosidase inhibition may be a useful adjunctive therapy for blood glucose control in diabetes mellitus.

Renin as a risk factor for atherogenesis Part 2. Effects of hypercholesterolemia and hyporeninemia in the rabbit

Four groups of New Zealand rabbits were used to study the effect of suppressed plasma renin activity (PRA) on atherogenesis. Control groups were fed normal rabbit chow (Group I) or normal chow supplemented with 0.25% cholesterol-0.75% corn oil (Group III). Group II animals were fed normal chow and received periodic injections of 11-desoxycorticosterone (DOC)pivalate and 0.5% saline to drink, while Group IV animals were treated similarly except that they were also fed the atherogenic diet. Blood pressure and blood chemistry measurements were performed monthly over a 7-month period. The blood pressure was unaffected by either the diet or the DOC-saline treatment, however, the PRA was greatly reduced in the animals receiving DOC-saline (Groups II and IV). Similarly, plasma aldosterone was significantly ( P < 0.05) reduced in the DOC-saline-treated animals. No atheromata were observed in the animals consuming the regular diet, regardless of DOC-saline treatment. All of the animals fed the atherogenic diet showed extensive aortic atheromata. However, there was no difference in the lesion index between the animals with normal PRA levels (Group III) and those with suppressed PRA levels (Group IV). Likewise, microscopic evaluation of the aorta, coronary arteries, and renal arteries failed to show a consistent difference in the vascular involvement between animals of Groups III and IV. We therefore conclude that the suppression of PRA does not have a protective effect on atherogenesis in the cholesterol-fed normotensive rabbit.

Renin as a risk factor for atherogenesis: Effects of hypercholesterolemia and two-kidney-one-clip hypertension in the rabbit

Four groups of New Zealand rabbits were used to study the effect of plasma renin activity (PRA) on atherogenesis. Control groups were fed normal rabbit chow (Group I) or chow supplemented with 0.25% cholesterol and 0.75% corn oil (Group II). The two-kidney-one-clip (2K-1C) hypertensive model was produced in 2 additional groups; Group III (normal diet) and Group IV (atherogenic diet). The latter 2 groups were subgrouped according to PRA levels. Each group was examined over a 7-month period. Group II became hyperlipidemic and developed extensive lipoidal vascular lesions. Mean arterial pressure remained normal throughout the experimental period; PRA fell below normal. Group III and Group IV rabbits developed sustained hypertension irrespective of circulating PRA. The atheromas of Group III were predominantly microscopic and fibromuscular; the extent of aortic and coronary artery involvement was independent of renin response. The most extensive and complicated atheromas were seen in the 2K-1C rabbits consuming the atherogenic diet (Group IV). The lesions were mostly lipoidal, although some were fibromuscular. These results demonstrated that cardiovascular lesions and atherogenesis were exacerbated in the 2K-1C rabbits on a high cholesterol diet; however, PRA was excluded as the cause.