[Update on current care guidelines. Prolonged epileptic attack].
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Adolescent↗
Biomedical subjects
Eero Mervaala
Publications and source records attributed to Eero Mervaala.
Vasopeptidase inhibition has beneficial cardiac effects in spontaneously diabetic Goto-Kakizaki rats.
In this study we examined diabetes- and hypertension-induced changes in cardiac structure and function in an animal model of type 2 diabetes, the Goto-Kakizaki (GK) rat. We hypothesized that treatment with omapatrilat, a vasopeptidase inhibitor, which causes simultaneous inhibition of angiotensin converting enzyme and neutral endopeptidase, provides additional cardioprotective effects, during normal- as well as high sodium intake, compared to treatment with enalapril, a selective inhibitor of angiotensin converting enzyme. Fifty-two GK rats were randomized into 6 groups to receive either normal-sodium (NaCl 0.8%) or high-sodium (NaCl 6%) diet and enalapril, omapatrilat or vehicle for 12 weeks. The GK rats developed hypertension, cardiac hypertrophy and overexpression of cardiac natriuretic peptides and profibrotic connective tissue growth factor compared to nondiabetic Wistar rats. The high dietary sodium further increased the systolic blood pressure, and changed the mitral inflow pattern measured by echocardiography towards diastolic dysfunction. Enalapril and omapatrilat equally decreased the systolic blood pressure compared to the control group during normal- as well as high-sodium diet. Both drugs had beneficial cardioprotective effects, which were blunted by the high dietary sodium. Compared to enalapril, omapatrilat reduced the echocardiographically measured left ventricular mass during normal-sodium diet and improved the diastolic function during high-sodium diet in GK rats. Furthermore, omapatrilat reduced relative cardiac weight more effectively than enalapril during high sodium intake. Our results suggest that both the renin-angiotensin and the neutral endopeptidase system are involved in the pathogenesis of diabetic cardiomyopathy since vasopeptidase inhibition was shown to provide additional benefits in comparison with selective angiotensin converting enzyme inhibition alone.
Aldosterone↗
Angiotensin II and vascular inflammation.
Vascular inflammation is involved in the initiation and progression of atherosclerosis, and is also present in hypertension- and diabetes-induced vascular complications. Angiotensin II (Ang II), the key effector of the renin-angiotensin system (RAS), plays a central role in the regulation of blood pressure and electrolyte homeostasis. There is accumulating evidence to indicate that Ang II is also capable of inducing inflammatory response in the vascular wall. This review summarizes the current understanding of the molecular mechanisms and signal transduction pathways of Ang II-induced vascular inflammation. The roles of modulators of Ang II-induced inflammatory response, such as nitric oxide (NO), bradykinin, cyclooxygenase-2 (COX-2), endothelin-1 (ET-1), and epoxyeicosatrienoic acids (EETs), are also discussed. The current data suggest that Ang II modifies several steps of inflammatory response, such as increase of vascular permeability, leukocyte infiltration, tissue hypertrophy/proliferation, and fibrosis. Ang II, via the type 1 (AT1) receptors, enhances the production of reactive oxygen species (ROS) through stimulation of NAD(P)H oxidase in the vascular wall. Increased oxidative stress contributes to endothelial dysfunction and to vascular inflammation by stimulating the redox-sensitive transcription factors (NF-kappaB) and by upregulating adhesion molecules, cytokines, and chemokines. The pro-inflammatory action of Ang II may help us to understand the molecular mechanisms of hypertension- and diabetes-induced vascular complication as well as the pleiotropic actions of drugs interfering with RAS.
Angiotensin II↗
Vascular and renal effects of vasopeptidase inhibition and angiotensin-converting enzyme blockade in spontaneously diabetic Goto-Kakizaki rats.
BACKGROUND: The renin-angiotensin system plays an important role in the pathogenesis of diabetes-induced vascular and renal complications. Vasopeptidase inhibitors simultaneously inhibit angiotensin-converting enzyme (ACE) and neutral endopeptidase. OBJECTIVE: To compare the effectiveness of vasopeptidase inhibition and ACE inhibition in preventing hypertension, endothelial dysfunction and diabetic nephropathy in spontaneously diabetic Goto-Kakizaki (GK) rats. METHODS: Eight-week-old GK rats received omapatrilat (40 mg/kg) or enalapril (30 mg/kg) for 12 weeks, either during a normal-sodium or high-sodium diet (7% w/w). Blood pressure, arterial functions and renal morphology were determined. RESULTS: Blood pressure and albuminuria were increased in GK rats compared to non-diabetic Wistar controls. Endothelium-dependent vascular relaxation in response to acetylcholine (ACh) and endothelium-independent vascular relaxation in response to sodium nitroprusside (SNP) were impaired in GK rats. Experiments with N-nitro-L-arginine methyl ester (L-NAME), diclofenac, and L-NAME + diclofenac suggested that cyclooxygenase and endothelium-derived hyperpolarizing factor components of endothelium-dependent vascular relaxation were also impaired. A high-sodium diet aggravated hypertension and diabetes-induced vascular and renal complications. Omapatrilat and enalapril normalized blood pressure and albuminuria during the normal-sodium diet, and effectively ameliorated diabetes-induced renal complications also during the high-sodium diet. However, omapatrilat improved endothelium-dependent relaxation to ACh to a greater extent (85 +/- 5%) than enalapril (68 +/- 6%, P < 0.05). Diclofenac pre-incubation eliminated this difference between omapatrilat and enalapril in ACh-induced vascular relaxation, suggesting that it was mediated, at least in part, via the cyclooxygenase pathway. CONCLUSIONS: Despite comparable blood pressure-lowering and renoprotective properties, omapatrilat may be more effective in preventing vascular dysfunction during diabetes compared to enalapril in GK rats.
Acetylcholine↗
High calcium diet down-regulates kidney angiotensin-converting enzyme in experimental renal failure.
BACKGROUND: Calcium salts are used as phosphate binders in renal failure, while high calcium diet also improves vasorelaxation and enhances natriuresis. The influences of calcium intake on renal renin-angiotensin system (RAS) are largely unknown. METHODS: Four weeks after NTX, rats were put on 3.0% or 0.3% calcium diet for 8 weeks (12-week study). In additional experiments, 15 weeks after NTX, rats were put on similar diets for 12 weeks (27-week study). Appropriate blood, urine, and kidney samples were taken. Renal angiotensin-converting enzyme (ACE) and angiotensin II receptors (AT1, AT2) were examined using autoradiography, ACE also using Western blotting, and connective tissue growth factor (CTGF) using immunohistochemistry. RESULTS: In the 12-week study, albuminuria increased 5-fold in NTX rats, but only 2-fold in calcium NTX rats on 3.0% calcium. In the 27-week study, high calcium intake decreased blood pressure, retarded progression of renal failure, reduced glomerulosclerosis, interstitial damage, and aortic calcifications, and improved survival from 50% to 92% in NTX rats. In both experiments plasma parathyroid hormone and phosphate were elevated after NTX, and suppressed by high calcium diet, while kidney ACE was down-regulated by 40% or more after increased calcium intake. In the 27-week study renal CTGF was decreased and cortical AT1 receptor density reduced after high calcium diet. CONCLUSION: High calcium diet down-regulated kidney ACE, reduced albuminuria and blood pressure, and favorably influenced kidney morphology in experimental renal failure. These findings suggest a link between calcium metabolism and kidney ACE expression, which may play a role in the progression of renal damage.
Albuminuria↗
Cardioprotective effects of vasopeptidase inhibition vs. angiotensin type 1-receptor blockade in spontaneously hypertensive rats on a high salt diet.
The aim of our study was to compare the cardioprotective effects of vasopeptidase inhibition with those of angiotensin type 1 (AT1)-receptor blockade, a diuretic and the combination of AT1-receptor blockade and a diuretic in an experimental rat model of essential hypertension on a high salt diet. Spontaneously hypertensive rats (SHR) (n =73) were divided into 6 groups to receive the following diet and drug regimens for 8 weeks: 1) low salt controls (NaCl 0.5%); 2) high salt controls (NaCl 6%); 3) omapatrilat (40 mg/kg/d) on a high salt diet; 4) losartan (30 mg/kg/d) on a high salt diet; 5) hydrochlorothiazide (HCTZ; 10 mg/kg/d) on a high salt diet; and 6) losartan+HCTZ (30+10 mg/kg/d) on a high salt diet. Blood pressure was measured by tail-cuff plethysmography. The histological score of myocardial damage, myocardial collagen volume fraction (CVF), connective tissue growth factor (CTGF) expression and cardiomyocyte apoptosis were determined. As an antihypertensive, omapatrilat showed greater efficacy than monotherapy with losartan or HCTZ, and was equally effective as the combination of losartan+HCTZ. Assessed by myocardial damage score, omapatrilat and losartan protected cardiac morphology better than HCTZ or the drug combination. Omapatrilat decreased CVF to a greater extent than the other therapies, whereas losartan was most effective in decreasing CTGF expression. All drug treatments, except HCTZ, decreased cardiomyocyte apoptosis. Our findings provide evidence that both vasopeptidase inhibition and AT1-receptor blockade exert cardioprotective properties beyond their blood pressure-lowering effects. Cardioprotection was associated with prevention of cardiomyocyte apoptosis and inhibition of extracellular matrix formation.
Aldosterone↗
Angiotensin II induces connective tissue growth factor gene expression via calcineurin-dependent pathways.
Connective tissue growth factor (CTGF) is a polypeptide implicated in the extracellular matrix synthesis. Previous studies have provided evidence that angiotensin II (Ang II) promotes collagen synthesis and regulates collagen degradation. We investigated whether or not CTGF mediates the profibrotic effects of Ang II in the heart and kidneys and the role of calcineurin-dependent pathways in CTGF gene regulation. In transgenic rats harboring human renin and angiotensinogen genes, Ang II induced an age-dependent increase in myocardial CTGF expression, which was 3.5-fold greater compared to normotensive Sprague Dawley (SD) rats. CTGF overexpression correlated closely with the Ang II-induced rise in blood pressure. CTGF mRNA and protein were located predominantly in areas with leukocyte infiltration, myocardial, and vascular lesions and co-localized with TGFbeta(1), collagen I, and collagen III mRNA expressions. Ang II induced CTGF mRNA and protein to a lesser extent in the kidneys, predominantly in glomeruli, arterioles, and in the interstitium with ample inflammation. However, no expression was found in the right ventricle or pulmonary arteries. Blockade of calcineurin activity by cyclosporine A completely normalized Ang II-induced CTGF overexpression in heart and kidney, suppressed the inflammatory response, and mitigated Ang II-induced cell proliferation and apoptosis. In contrast, blockade of mTOR (target of rapamycin) pathway by everolimus, further increased the expression of CTGF even though everolimus ameliorated cell proliferation and T-cell-mediated inflammation. Our findings provide evidence that CTGF mediates Ang II-induced fibrosis in the heart and kidneys via blood pressure and calcineurin-dependent pathways.
Angiotensin II↗
Lipoic acid supplementation prevents angiotensin II-induced renal injury.
BACKGROUND: Angiotensin II (Ang II)-induced renal injury is associated with perivascular inflammation, cell proliferation, and increased superoxide production in the vascular wall. We tested whether lipoic acid, an endogenous antioxidant, protects against the Ang II-induced inflammatory response and end-organ damage. METHODS: Light microscopy, immunohistochemistry, electrophoretic mobility shift assay, Northern blots, and high-pressure liquid chromatography (HPLC) were used in kidneys from double transgenic rats (dTGR) harboring human renin and angiotensinogen genes and normotensive Sprague Dawley (SD) rats. The effects of lipoic acid supplementation for three weeks were examined in dTGR and SD rats. RESULTS: Lipoic acid effectively prevented Ang II-induced glomerular and vascular damage in the kidneys and completely prevented the development of albuminuria. Ang II-induced leukocyte infiltration and cell proliferation in the kidney were attenuated. The redox-sensitive transcription factors nuclear factor (kappa) B (NF-kappa B) and activator protein-1 (AP-1) in the kidneys were increased in dTGR compared with SD, and were effectively reduced. Renal glutathione levels were much higher in dTGR than in SD, while the opposite was true for cysteine levels. These results suggested increased renal glutathione oxidation in dTGR, leading to cysteine shortage. Lipoic acid partly prevented renal cysteine depletion and increased hepatic cysteine and glutathione concentrations. This effect was accompanied by increased hepatic gamma-glutamylcysteine synthetase mRNA expression. CONCLUSION: Our in vivo results suggest that lipoic acid protects against Ang II-induced renal injury through anti-inflammatory/antioxidative mechanisms. The effects are associated with decreased NF-kappa B and AP-1 activation, as well as improved thiol homeostasis.
Albuminuria↗
Effects of microcrystalline plant sterol suspension and a powdered plant sterol supplement on hypercholesterolemia in genetically obese Zucker rats.
Because dietary fat appears to be an effective vehicle for dispensing plant sterols into the diet, a special plant-sterol-containing ingredient has recently been developed. This ingredient is a plant sterol suspension in oil in which the sterols are in microcrystalline form. The objective of the present study was to analyse the cholesterol-lowering effects and safety of two different plant sterol preparations, an orally administered microcrystalline plant sterol suspension (MPS) in rapeseed oil and a powdered plant sterol supplement, in obese Zucker rats. Dietary plant sterol supplements (0.5%, w/w) were given concurrently with a high cholesterol diet (HCD, 1% cholesterol and 18% fat, w/w). No significant changes in serum triglyceride, blood glucose, serum glutamate oxaloacetic transaminase and glutamic pyruvic transaminase values or body and liver weights were observed. The powdered plant sterol supplement lowered the serum cholesterol by 25% (P < 0.05) and the MPS diet by 35% (P < 0.001) compared with HCD by the end of the 12-week experiment. Interestingly, the plant sterol supplements also produced a marked reduction in serum ubiquinone levels, suggesting a possible effect on isoprene synthesis. Unlike the powdered plant sterol, both MPS and plain rapeseed oil decreased the serum baseline diene conjugation values, suggesting that they protect against oxidative stress-induced lipid peroxidation in rats. This lipid peroxidation diminishing effect is probably due to some antioxidative components in rapeseed oil. These findings indicate that an unesterified plant sterol, such as the microcrystalline suspension in oil, effectively prevents cholesterol absorption in obese Zucker rats.
Administration, Oral↗
Sodium load increases renal angiotensin type 1 receptors and decreases bradykinin type 2 receptors.
The regulation of both angiotensin receptors and bradykinin receptors during sodium intake is poorly understood. We hypothesized that an altered balance between renal angiotensin type 1 (AT1) receptors and bradykinin type 2 (B2) receptors might contribute to an increase in blood pressure during periods of high-sodium intake. We studied the effects of high-sodium intake on renal AT1 receptors and B2 receptors in 5-6-week-old spontaneously hypertensive rats (SHR) receiving high-sodium chloride (6% NaCl) or mineral salts (10.5%, composition: 57% NaCl, 28% KCl, 12% MgSO4) compared to those receiving a low-sodium (NaCl 0.125%) diet for 10 weeks. Mineral salt intake was included due to its beneficial effects on blood pressure and cardiac hypertrophy. Receptor densities were measured by quantitative autoradiography. AT1 receptors were quantified using incubation with 125I-Sar1-Ile8-angiotensin II and displacement was measured with PD123319 (10 micromol/l), whereas B2 receptors were quantified using 125I-HPP-icatibant and displacement was measured with icatibant (3 micromol/l). Compared to the SHR controls, a further increase in blood pressure occurred after 2 weeks in the 6% NaCl group and after 6 weeks in the mineral salt group. AT1 receptor density increased in the renal cortex by 41% (p<0.01) in the 6% NaCl group and by 26% (p<0.05) in the mineral salt group. B2 receptor density decreased in the renal medulla by 26% (p<0.01) in the 6% NaCl group, and decreased even more i.e., by 45% (p<0.001), in the mineral salt group. It was shown that a 6% NaCl or a 10.5% mineral salt loading was capable of increasing renal AT1 receptor density and decreasing renal B2 receptor density. An altered balance between these receptors might be associated with hypertension under conditions of sodium loading.
Animals↗
Immunosuppressive treatment protects against angiotensin II-induced renal damage.
Angiotensin (Ang) II promotes renal infiltration by immunocompetent cells in double-transgenic rats (dTGRs) harboring both human renin and angiotensinogen genes. To elucidate disease mechanisms, we investigated whether or not dexamethasone (DEXA) immunosuppression ameliorates renal damage. Untreated dTGRs developed hypertension, renal damage, and 50% mortality at 7 weeks. DEXA reduced albuminuria, renal fibrosis, vascular reactive oxygen stress, and prevented mortality, independent of blood pressure. In dTGR kidneys, p22phox immunostaining co-localized with macrophages and partially with T cells. dTGR dendritic cells expressed major histocompatibility complex II and CD86, indicating maturation. DEXA suppressed major histocompatibility complex II+, CD86+, dendritic, and T-cell infiltration. In additional experiments, we treated dTGRs with mycophenolate mofetil to inhibit T- and B-cell proliferation. Reno-protective actions of mycophenolate mofetil and its effect on dendritic and T cells were similar to those obtained with DEXA. We next investigated whether or not Ang II directly promotes dendritic cell maturation in vitro. Ang II did not alter CD80, CD83, and MHC II expression, but increased CCR7 expression and cell migration. To explore the role of tumor necrosis factor (TNF)-alpha on dendritic cell maturation in vivo, we treated dTGRs with the soluble TNF-alpha receptor etanercept. This treatment had no effect on blood pressure, but decreased albuminuria, nuclear factor-kappaB activation, and infiltration of all immunocompetent cells. These data suggest that immunosuppression prevents dendritic cell maturation and T-cell infiltration in a nonimmune model of Ang II-induced renal damage. Ang II induces dendritic migration directly, whereas in vivo TNF-alpha is involved in dendritic cell infiltration and maturation. Thus, Ang II may initiate events leading to innate and acquired immune response.
Angiotensin II↗
Effects of calcium and plant sterols on serum lipids in obese Zucker rats on a low-fat diet.
Ca may interfere with fat and cholesterol metabolism through formation of insoluble soaps with fatty and bile acids in the intestine. In the present study, we examined the effects of different dietary Ca levels on the serum lipid profile and cholesterol metabolism in obese Zucker rats fed a low-fat diet. We also tested whether dietary Ca interfered with the lipid-lowering effects of a pine oil-derived plant sterol mixture. Increase in dietary Ca intake from 0.2 to 0.8%, and further to 2.1% (w/w) dose-dependently decreased serum total cholesterol (r -0.565, P=0.002, n 27), LDL-cholesterol (r -0.538, P=0.006, n 25), and triacylglycerol (r -0.484, P=0.014, n 25) concentrations, and increased HDL-cholesterol (r -0.478, P=0.016, n 25) and HDL: LDL cholesterol (r 0.672, P<0.001, n 25) in rats fed a 1% cholesterol diet. Analysis of serum campesterol: cholesterol and sitosterol: cholesterol suggested that Ca dose-dependently increased intestinal cholesterol absorption (r 0.913, P<0.001, n 18), whereas serum desmosterol: cholesterol and lathosterol: cholesterol indicated that Ca dose-dependently increased endogenous cholesterol synthesis (r 0.691, P=0.003, n 18). Therefore, the decrease of serum LDL-cholesterol appeared to be due to Ca-induced increase in the conversion of cholesterol to bile acids. The increase in Ca intake did not interfere with the beneficial effects of plant sterols on serum total cholesterol, LDL-cholesterol and HDL-cholesterol concentrations. The high-Ca diet with plant sterol supplementation further increased the HDL-cholesterol concentration and HDL: LDL cholesterol. The present findings indicate that the beneficial effects of dietary Ca on the serum lipid profile during a low-fat diet are dose-dependent, and resemble those of bile acid sequestrants. Increased dietary Ca did not impede the lipid-lowering effects of natural plant sterols.
Animals↗
Supplementation of plant sterols and minerals benefits obese Zucker rats fed an atherogenic diet.
In most hypertensive rat models, serum total cholesterol is typically low and the cholesterol is primarily in the HDL rather than the LDL fraction. This difference from humans usually makes these animals unsuitable for experimental atherosclerosis studies. In the present study, we induced severe hypercholesterolemia including a 10-fold increase in serum LDL cholesterol, endothelial dysfunction and hypertension as well as vascular and renal damage in obese Zucker rats by feeding a human-type high fat, high cholesterol and high salt diet (butter 18, cholesterol 1 and NaCl 6 g/100 g dry weight). Supplementation of this atherogenic diet with plant sterols (1 g/100 g) and replacing the NaCl partially by calcium, magnesium and potassium effectively prevented the diet-induced increases in total and LDL cholesterols and 24-h systolic and mean blood pressures, and markedly improved endothelial function. Plant sterols and the minerals also protected against vascular and renal damage and extended the life span of the obese Zucker rats by 60% compared with the rats fed the atherogenic diet. Our findings suggest that human-type cardiovascular disorders can be induced in obese Zucker rats by feeding a human-type atherogenic diet. This seems to be a suitable animal model for experimental studies on atherosclerosis and hypertension as well as for evaluating new dietary approaches to reducing cardiovascular risk.
Animals↗
Sodium intake and hypertension.
In current diets, the level of sodium is very high, whereas that of potassium, calcium, and magnesium is low compared with the level in diets composed of unprocessed, natural foods. We present the biologic rationale and scientific evidence that show that the current salt intake levels largely explain the high prevalence of hypertension. Comprehensive reduction of salt intake, both alone and particularly in combination with increases in intakes of potassium, calcium, and magnesium, is able to lower average blood pressure levels substantially. During the past 30 years, the one-third decrease in the average salt intake has been accompanied by a more than 10-mm Hg fall in the population average of both systolic and diastolic blood pressure, and a 75% to 80% decrease in both stroke and coronary heart disease mortality in Finland. There is no evidence of any harmful effects of salt reduction. Salt-reduction recommendations alone have a very small, if any, population impact. In the United States, for example, the per capita use of salt increased by approximately 55% from the mid-1980s to the late 1990s. We deal with factors that contribute toward increasing salt intakes and present examples of the methods that have contributed to the successful salt reduction in Finland.
Blood Pressure↗