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Blockade of the renin-angiotensin system (RAS) is considered to be among the most important interventions for the prevention and management of diabetic kidney disease (1). Drugs that inhibit ACE or [...], OBJECTIVE--The degradation of angiotensin (Ang) II by ACE2, leading to the formation of Ang 1-7, is an important step in the renin-angiotensin system (RAS) and one that is significantly altered in the diabetic kidney. This study examines the role of ACE2 in early renal changes associated with diabetes and the influence of ACE2 deficiency on ACE inhibitor--mediated renoprotection. RESEARCH DESIGN AND METHODS--Diabetes was induced by streptozotocin in male c57b16 mice and ACE2 knockout (KO) mice. After 5 weeks of study, animals were randomized to receive the ACE inhibitor perindopril (2 mg x [kg.sup.-1] x [day.sup.-1]). Wild-type mice were further randomized to receive the selective ACE2 inhibitor MLN-4760 (10 mg x [kg.sup.-1] x [day.sup.-1]) and followed for an additional 5 weeks. Markers of renal function and injury were then assessed. RESULTS--Induction of diabetes in wild-type mice was associated with a reduction in renal ACE2 expression and decreased Ang 1-7. In diabetic mice receiving MLN-4760 and in ACE2 KO mice, diabetes-associated albuminuria was enhanced, associated with an increase in blood pressure. However, renal hypertrophy and fibrogenesis were reduced in diabetic mice with ACE2 deficiency, and hyperfiltration was attenuated. Diabetic wild-type mice treated with an ACE inhibitor experienced a reduction in albuminuria and blood pressure. These responses were attenuated in both diabetic ACE2 KO mice and diabetic mice receiving MLN-4760. However, other renoprotective and antifibrotic actions of ACE inhibition in diabetes were preserved in ACE2-deficient mice. CONCLUSIONS--The expression of ACE2 is significantly modified by diabetes, which impacts both pathogenesis of kidney disease and responsiveness to RAS blockade. These data indicate that ACE2 is a complex and site-specific modulator of diabetic kidney disease.

2017 APR 15 (NewsRx) -- By a News Reporter-Staff News Editor at Obesity, Fitness & Wellness Week -- Data detailed on Angiotensins have been presented. According to news reporting from [...]

OBJECTIVE -- ACE inhibitors are known to be effective in preventing the progression of diabetic nephropathy. Activation of the renin-angiotensin system (RAS) is reported to contribute to intrarenal hemodynamic abnormality [...]

Objective: To investigate matrix metalloproteinases (MMP-2 and MMP-9) in heart failure caused by ischaemic and idiopathic dilated cardiomyopathy, and the impact of angiotensin converting enzyme (ACE) inhibition on MMP. Design [...]

In the treatment of diabetic nephropathy, ACE inhibitor therapy reduces albumin excretion and slows the rate of decline in glomerular filtration rate (GFR). Our study was designed to investigate whether [...]

Transforming growth factor-Β (TGF-Β) and the renin-angiotensin system (RAS) have both been implicated in the pathogenesis of glomerulosclerosis in diabetic kidney disease. However, tubulointerstitial pathology may also be an important [...]

We explored the relative roles of the suppression of angiotensin II and the prevention of bradykinin degradation in mediating the renoprotective effects of ACE inhibitors in experimental diabetic nephropathy. Over [...]

To evaluate the effect of angiotensin-converting enzyme inhibition on spontaneous and insulin-stimulated endothelin-1 (ET-1) secretion in vitro and in vivo, human endothelial cells derived from umbilical cord veins were cultured [...]

Insulin rapidly stimulates the uptake and metabolism of glucose in skeletal muscle (1). People with non-insulin-dependent diabetes mellitus (NIDDM) show a markedly decreased sensitivity of glucose metabolism to insulin in [...], We measured the sensitivity of glucose metabolism to insulin in soleus muscle preparations isolated from spontaneously hypertensive (SH) rats and normotensive age-matched Wistar-Kyoto (WKY) rats. SH rats were treated with the angiotensin-converting enzyme (ACE) inhibitor trandolapril (1 mg(/kg) and/or a second antihypertensive drug, the calcium antagonist verapamil, alone (100 mg/ kg) or as combination therapy (50 mg/kg). Treatment of SH rats with trandolapril or trandolapril in combination with verapamil for 6 weeks normalized the blood pressure. The estimated concentration of insulin required for half-maximal stimulation of glycogen synthesis (i.e., [EC.sub.50 values) was ~500 μU/ml for muscles from both WKY and SH rats. This value is five times higher than the value obtained from soleus muscle preparations isolated from insulin-sensitive Wistar rats. This indicates that glycogen synthesis is insensitive to insulin in SH and WKY rat soleus muscle. Treatment of SH rats with trandolapril with or without verapamil improved the sensitivity of glycogen synthesis to insulin in soleus muscle. Further experiments investigated whether acute exposure (1 h) of insulin-sensitive skeletal muscle with either trandolaprilat (the active metabolite of trandolapril) or bradykinin (levels of which may be raised by ACE inhibition) could affect the insullin-stimulated rate of glucose metabolism. These results show that both trandolaprilat and bradykinin caused a small but significant increase in the rates of glucose metabolism. In conclusion, 1) SH and WKY rat skeletal muscle was insulin resistant, 2) chronic treatment of SH rats with trandolapril with or without verapamil normalized blood pressure and improved the response of glycogen metabolism to insulin, and 3) bradykinin and trandolaprilat acutely caused a small but significant increase in the rate of glycogen synthesis to a submaximal physiological concentration of insulin. Diabetes 45 (Suppl. 1):S120-S124, 1996

Syndrome X, or the metabolic syndrome (1), describes the clustering of atherogenic risk factors in the hypertensive patient, including insulin resistance of whole-body glucose disposal, hyperinsulinemia, obesity, and dyslipidemia. In [...], Insulin resistance of skeletal muscle glucose disposal underlies the pathogenesis of NEDDM and is associated with hypertension, obesity, and dyslipidemia. Angiotensin-converting enzyme (ACE) inhibitors are used primarily in antihypertensive therapy but also are known to improve whole-body insulin-mediated glucose disposal. However, the exact site of action is not well characterized. We have used the isolated epitrochlearis muscle from a well-established animal model of skeletal muscle insulin resistance, the obese Zucker rat, to test the effect of oral administration of ACE inhibitors on insulin-sensitive muscle glucose transport activity. Both acute and chronic administration of a sulfhydryl-containing ACE inhibitor (captopril) or a non-sulfhydryl-containing ACE inhibitor (tran-dolapril) significantly enhanced in vitro insulin-mediated muscle glucose transport activity. In addition, the acute effect of oral captopril administration was completely abolished by pretreatment of the animal with a bradykinin [B.sub.2] receptor antagonist (HOE 140). These findings indicate that ACE inhibitors may improve whole-body glucose metabolism by acting on the insulin-sensitive skeletal muscle glucose transport system. In addition, bradykinin or one of its metabolites may be involved in the action of the ACE inhibitor captopril on insulin-resistant muscle. Diabetes 45 (Suppl. 1):S125-S128, 1996

Various physiological and/or pathological stimuli that imposed increased workload on the left ventricle,, such as exercise aging, hypertension, and heart failure, will finally result in left ventricular hypertrophy (LVH). LVH [...], Left ventricular hypertrophy is considered to be an independent risk factor giving rise to ischenda, arrhythmias, and left ventricular dysfunction. Slow movement of intra-cellular calcium contributes to the impaired contraction and relaxation function of hypertrophied myocardium. Myofibril content may also be shifted to fetal-type isoforms with decreased contraction and relaxation properties in left ventricular hypertrophy. Myocyte hypertrophy and interstitial fibrosis are regulated independently by mechanical and neurohumoral mechanisms. In severely hypertrophied myocardium, capillary density is reduced, the diffusion distance for oxygen, nutrients, and metabolites is increased, and the ratio of energy-production sites to energy-consumption sites is decreased. The metabolic state of severely hypertrophied myocardium is anaerobic, as indicated by the shift of lactate dehydrogenase marker enzymes. Therefore, the hypertrophied myocardium is more vulnerable to ischemic events. As a compensatory response to severe cardiac hypertrophy and congestive heart failure, the ADP/ATP carrier is activated and atrial natriuretic peptide is released to increase high-energy phosphate production and reduce cardiac energy consumption by vasodilation and sodium and fluid elimination. However, in severely hypertrophied and failing myocardium, vasoconstrictor and sodium- and fluid-retaining factors, such as the renin-angiotensin system, aldosterone, and sympathetic nerve activity, play an overwhelming role. Angiotensin-converting enzyme inhibitors (ACEIs) are able to prevent cardiac hypertrophy and improve cardiac function and metabolism. Under experimental conditions, these beneficial effects can be ascribed mainly to bradykinin potentiation, although a contribution of the ACEI-induced angiotensin II reduction cannot be excluded. Diabetes 45 (Suppl. 1):S59-S65, 1996

A reduced ability of the myocardium to take up and metabolize glucose has been demonstrated in clinical and experimental studies and seems to be characteristic for insulin-dependent and -independent types [...], There is some evidence that inhibition of angiotensin-converting enzyme (ACE) activity can improve the uptake and conversion of glucose by heart and skeletal muscle in diabetes. To study the underlying mechanisms, we treated streptozotocin-induced diabetic rats with the angiotensin type 1 receptor ([AT.sub.1]) antagonist ICI D8731 and the ACE inhibitor fosinopril for 4 months and determined the expression of the myocardial glucose transporter proteins. In diabetic rats, the expression of the insulin-regulated glucose transporter (GLUT4) was strongly diminished as shown by Western and Northern blots. ICI D8731 prevented the decrease of GLUT4 protein in diabetes but had no influence on the amount of mRNA encoding for GLUT1 and GLUT4. GLUT1 protein was hardly detected in the rat heart and was affected neither by diabetes nor by treatment with the ATL antagonist. Additionally, ICI D8731 influenced the translocation of GLUT4 from the intracellular pool to the plasma membrane, because treatment increased the amount of GLUT4 protein in the plasma membranes as well as in intracellular membrane fractions compared with membranes of untreated diabetic control rats. In contrast, inhibition of ACE by fosinopril influenced neither the expression nor the translocation of the glucose transporter proteins. These observations indicate that angiotensin II has a distinct influence on the post-transcriptional regulation of the GLUT4 transporter protein, presumably indirectly as a consequence of hemodynamic effects and structural alterations of the vessel wall. Diabetes 45 (Suppl. 1):S82-S87, 1996

1996 The nonapeptide bradykinin (BK) is released from high-molecular weight precursors, the kininogens, by limited proteolysis via kallilkreins mainly in response to tissue injury, inflammation processes, and increasing energy demand [...], Receptors for bradykinin (BK) were characterized in primary cultures of beating neonatal rat cardiomyocytes using [³H]BK as radioligand. Degradation studies demonstrated that [³H]BK was stable for at least 2 h when incubated with cardiomyocytes at 2 and 37°C in the presence of bacitracin in combination with captopril or ramiprilat. Without these inhibitors, >80% of the [³H]BK was degraded within 2 h at 37°C. This indicates that angiotensin-converting enzyme (ACE) is responsible for the main BK-degrading activity in cardiomyocytes. Scatchard plots were linear and gave a [K.sub.d] of 1.5 ± 0.8 nmol/l (mean ± SD, n = 4) and a maximum binding capacity of 55-125 fmol/mg protein. Association and dissociation studies showed that binding of [³H]BK was saturable and reversible. Binding of [³H]BK at 37°C led to internalization of the ligand. Competition studies with [B.sub.1] and [B.sub.2] agonists And antagonists were consistent with a [B.sub.2] subtype of receptor. Addition of BK to beating cardiomyocytes (>1 nmol/l) at 37°C gave a strong but transient negative chronotropic effect. This response was paralleled by changes in the pulsation amplitude, which indicated a simultaneous negative inotropic effect of BK. These results provide a basis for the hypothesis that ACE inhibition exerts its cardioprotective effect at the level of a population of cardiomyocytes by virtue of kinin receptor-mediated mechanisms. Diabetes 45 (Suppl. 1):S44-S50,

Despite a decline in its incidence in recent years, coronary heart disease (CHD) is still the major cause of death in the United States. Recent estimates show that 5.4 million [...], Coronary heart disease (CHD) is the major cause of death in the United States. Major modifiable risk factors for CHD are hypertension, hypercholesterolemia, and cigarette smoking, with concomitant risk factors, especially left ventricular hypertrophy, that act synergistically to significantly increase overall risk. Antihypertensive therapy, while reducing the incidence of stroke, has not consistently reduced the incidence of CHD. This may be a result, in part, of adverse effects on the metabolic profile, especially on blood lipids, which are induced by diuretics and certain β-blockers. Other antihypertensive agents appear to be either lipid neutral such as calcium channel blockers and angiotensin-converting enzyme inhibitors, or lipid positive, such as selective [alpha.sub.1]-blockers. The choice of initial antihypertensive therapy should be made with all of a patient's risk factors in mind. In addition to the drugs recommended in the 1988 Guidelines of the Joint National Committee an Detection, Evaluation and Treatment of High Blood Pressure, selective [alpha.sub.1]-blockers should also be considered since they improve the lipid profile as well as reduce blood pressure.

Q: Should I avoid angiotensin-converting enzyme (ACE) inhibitors in my patients with progressive renal insufficiency? A: This issue is extremely bothersome to clinicians. ACE inhibitors represent a dual-edged sword with [...]

ORLANDO, FLA. -- 'You should accept an increase in serum creatinine of 25%-30% over baseline levels when a patient starts an ACE inhibitor,' according to Dr. George L. Bakris, associate [...]

Angiotensin converting enzyme inhibitors (ACEIs) such as captopril (Capoten) inhibit the production of angiotensin II. One of the end results of this pharmacological action is natriuresis- i.e., increased renal elimination [...]

Benefits seen in type 2 diabetic patients. SAN FRANCISCO -- Angiotensin II inhibitors protect against kidney disease in patients with type 2 diabetes, results of three multinational, randomized, controlled trials [...]

Krishnankutty Sudhir [*] Background: Both angiotensin-converting enzyme inhibitors (ACE-[I.sub.s]) and angiotensin receptor blockers ([ARB.sub.s]) provide vascular protection. This study was designed to compare [ACE-[I.sub.s] with widely differing tissue affinity (captopril [...]

PATIENT PROFILE: The patient is a moderately overweight, 50-year-old, white man with recently diagnosed diabetes mellitus. Initial therapy--with metformin, aspirin, an angiotensin-converting enzyme (ACE) inhibitor, a 'statin,' and moderate dietary [...]

Fibronectin, a glycoprotein homodimer with a critical role in cell adhesion and morphology, is an essential component of glomerular and tubular extracellular matrix (ECM) and may contribute to the development [...]

Concomitant β-blocker/angiotensin-converting enzyme (ACE) inhibitor therapy significantly reduces the risk of death in patients with mild heart failure, according to researchers at the National Heart, Lung, and Blood Institute (NHLBI). [...]

Guidelines on monitoring, on their own, are not sufficient EDITOR--Kalra et al's paper describing an audit of monitoring renal function in general practice suggests that practice is often less than [...]

Aims: Human retinopathy and models of experimental retinopathy of prematurity (ROP) in rodents are related to an hyperproduction of vascular endothelial growth factor (VEGF), a common mechanism also associated with [...]

The beneficial effects of ACE inhibitor (ACED on clinical and experimental diabetic neuropathy have recently been reported. Those effects were mainly explained by the improvement of reduced nerve blood flow. [...]

Reduced nerve conduction velocity (NCV) and blood flow in diabetic rats depends on several factors including increased vasa nervomm vasoconstriction and reduced nitric oxide (NO) mediated vasodilation, which are mutually [...]

There is increasing evidence that pro-inflammatory molecules play an important role in the ventricular remodelling of congestive heart failure (CHF). (1) Among these molecules, intercellular adhesion molecule-1 (ICAM-1) is a [...]

Recently published studies have shown than angiotensin converting enzyme inhibitors can be combined with angiotensin II antagonists and are highly effective in reducing mortality and improving the quality of life [...]

The renin-angiotensin system plays an important part in cardiovascular homoeostasis through the action of angiotensin II on target organs such as the kidneys, the blood vessels, and the adrenals. [1] [...]

Lately I have heard that 'tissue ACE' properties are important in endothelial remodeling and in the prevention of myocardial infarction and stroke. What is the clinical relevance of these properties--and [...]

Angiotensin-converting enzyme inhibitors appears to halt or slow the decline in muscle strength among elderly women who are already moderately to severely physically disabled, reported Dr. Graziano Onder of Wake [...]

Angiotensin converting enzyme (ACE) inhibitors, when taken regularly, show promise for delaying muscle loss and disability, report researchers at Wake Forest University Baptist Medical Center, Winston Salem, North Carolina, who [...]