Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Blood pressure reduction is the most significant factor in delaying onset and progression of renal disease. Blockade of the renin-angiotensin system (RAS) using angiotensin-converting enzyme inhibitors (ACEIs) delays renal disease progression. More recently, agents that block the RAS by preventing angiotensin II from binding to its subtype 1 receptor (ARBs) have been developed in an effort to prevent deleterious consequences of pathologic levels of angiotensin II and to reduce the adverse effects of RAS blockade associated with ACEIs. Human studies with a variety of ARBs have clearly demonstrated the antihypertensive and antiproteinuric efficacy of these agents in patients with progressive renal diseases. Moreover, the effects of ARBs are similar or identical to those of ACEIs. Ongoing long-term clinical trials are designed to determine whether ARBs also preserve renal function similar to ACEIs. Specifically, the role of ARBs in patients with hypertension and type 2 diabetes is being evaluated in 3 large trials, including Appropriate Blood Pressure Control in Diabetes-Part 2 With Valsartan, the Losartan Renal Protection Study, and the Irbesartan Diabetic Nephropathy Trial. Definitive evidence of the long-term protective effects of ARBs in chronic progressive renal disease is expected from these important studies.
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PMID:Angiotensin II subtype 1 receptor blockers and renal function. 1142 96

Activation of the protein kinase C (PKC) family is a potential signaling mechanism by which high ambient glucose concentration modulates the phenotype and physiological function of cells. Recently, the cardiac renin angiotensin system (RAS) has been reported to promote PKC translocation in the diabetic heart via the angiotensin (ANG) II type 1 receptor (AT-1R). To evaluate the molecular events coupled with high glucose-induced PKC translocation and to examine the role of endogenously released ANG II in myocyte PKC signaling, primary cultures of adult rat ventricular myocytes were exposed to normal (5 mmol/l) or high (25 mmol/l) glucose for 12-24 h. Western blot analysis indicated that adult rat ventricular myocytes coexpress six PKC isozymes (alpha, beta(1,) beta(2,) delta, epsilon, and zeta). Translocation of five PKC isozymes (beta(1), beta(2), delta, epsilon, and zeta) was detected in response to 25 mmol/l glucose. Inhibition of phospholipase C with tricyclodecan-9-yl-xanthogenate blocked glucose-induced translocation of PKC-beta(2), -delta, and -zeta. Inhibition of tyrosine kinase with genistein blocked glucose-induced translocation of PKC-beta(1) and -delta, whereas chelation of intracellular Ca(2+) with 1,2-bis(2-aminophenoxy)ethane N,N,N,'N'-tetraacetic acid blocked translocation of PKC-beta(1) and -beta(2). Enzyme-linked immunosorbent assay performed on culture media from myocytes maintained in 25 mmol/l glucose detected a twofold increase in ANG II. Addition of an AT-1R antagonist (losartan; 100 nmol/l) to myocyte cultures blocked translocation of PKC-beta(1), -beta(2), -delta, and -epsilon. Phosphorylation of troponin (Tn) I was increased in myocytes exposed to 25 mmol/l glucose. Losartan selectively inhibited Tn I serine phosphorylation but did not affect phosphorylation at threonine residues. We concluded that 1) 25 mmol/l glucose triggers the release of ANG II by myocytes, resulting in activation of the ANG II autocrine pathway; 2) differential translocation of myocyte PKC isozymes occurs in response to 25 mmol/l glucose and ANG II; and 3) AT-1R-dependent PKC isozymes (beta(1), beta(2), delta, and epsilon) target Tn I serine residues.
Diabetes 2001 Aug
PMID:Angiotensin II promotes glucose-induced activation of cardiac protein kinase C isozymes and phosphorylation of troponin I. 1147 56

The aim of this study was to monitor the effect of the administration of antihypertensive drug losartan on: (1) the antioxidant status of rats with experimental insulin-dependent diabetes mellitus; (2) oxidative damage which is represented by the production of compounds which can react with thiobarbituric acid (TBARP), and (3) some metabolic parameters. Losartan administration did not significantly influence the concentration of glucose, cholesterol, triacylglycerol, and uric acid in the plasma of control and diabetic animals. In the liver tissue, the concentration of triacylglycerols decreased after losartan administration, but the concentration of cholesterol did not change. The present authors have found that losartan administration increased the levels of water solubile antioxidants in the plasma of diabetic rats, which can result in a decrease of the TBARP levels in the plasma of diabetic rats.
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PMID:[Effect of losartan on antioxidant status in rats with diabetes mellitus]. 1147 92

The present investigation was undertaken to study the effects of chronic treatment with losartan (2 mg kg(-1)/ day P.O) in neonatal non-insulin-dependent diabetes mellitus (NIDDM) rats. To induce NIDDM single-dose injection of STZ (70 mg kg(-1); i.p.) was given to 5 day old pups. The animals were weaned at 30 days and after a period of 3 months, they were checked for fasting and fed glucose levels to confirm the status of NIDDM. Losartan (2 mg kg(-1); p.o.) was administered for 6 weeks into the confirmed diabetic rats. A group of control animals were also maintained and this group received saline 5 days after birth. Fasting and fed glucose levels in NIDDM rats were significantly higher than control rats. Treatment with losartan in the NIDDM rats caused a significant decrease in insulin levels and reduction in elevated fasting and fed glucose levels. Results of the oral glucose tolerance test (OGTT) showed a significant increase in AUC(glucose)and AUC(insulin)values in NIDDM control rats. Losartan treatment significantly decreased both AUC(glucose)and AUC(insulin)values. Insulin sensitivity (K(ITT)) index of NIDDM control was significantly low as compared to Wistar control animals followed by significant increase in T(1/2)glucose value. Losartan treatment significantly reversed both K(ITT)and T(1/2)glucose value. Our data indicates that losartan increases insulin sensitivity in NIDDM rats.
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PMID:Improvement in insulin sensitivity by losartan in non-insulin-dependent diabetic (NIDDM) rats. 1171 69

The rising incidence of stroke, congestive heart failure (CHF) and end stage renal disease (ESRD) has signalled a need to increase awareness, treatment and control of hypertension. There continues to be a need for effective antihypertensive medications since hypertension is a major precursor to various forms of cardiovascular disease. The renin-angiotensin (AT) aldosterone system (RAAS) is a key component to the development of hypertension and can be one target of drug therapy. Angotensin II (ATII) receptor blockers (ARBs) are the most recent class of agents available to treat hypertension, which work by by inhibiting ATII at the receptor level. Currently, national consensus guidelines recommend that ARBs should be reserved for hypertensive patients who cannot tolerate angiotensin converting enzyme (ACE) inhibitors (ACEIs). ARBs, however, are moving to the forefront of therapy with a promising role in the area of renoprotection and CHF. Recent trials such as the The Renoprotective Effect of the Angiotensin-Receptor Antagonist Irbesartan in Patients with Nephropathy Due to Type 2 Diabetes Trial (IDNT), the Effect of Irbesartan on the Development of Diabetic Nephropathy in Patients with Type 2 Diabetes (IRMA2), and The Effects of Losartan on Renal and Cardiovascular Outcomes in Patients with Type 2 Diabetes and Nephropathy (RENAAL) study have demonstrated the renoprotective effects of ARBs in patients with Type 2 diabetes. The Valsartan Heart Failure Trial (Val-HeFT) adds to the growing body of evidence that ARBs may improve morbidity and mortality in CHF patients. As a class, ARBs are well tolerated and have a lower incidence of cough and angioedema compared to ACEIs. This article reviews the differences among the ARBs, existing efficacy data in hypertension, and explores the role of ARBs in CHF and renal disease.
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PMID:Angiotensin II receptor blockers for the treatment of hypertension. 1182 17

In hypertensive patients, pulse pressure has been related to hypertension-induced target organ damage and risk of cardiovascular events. However, correlates of pulse pressure reduction during antihypertensive treatment have been less extensively investigated. We related pulse pressure changes to clinical and echocardiographic findings before and after 2 years of antihypertensive treatment in 767 patients aged 55 to 80 years (mean 66) in the Losartan Intervention For End point reduction in hypertension study. Over 2 years, blood pressure and pulse pressure were reduced from 173/98 to 147/84 mm Hg and from 75 to 63 mm Hg, respectively, both p <0.001. In linear multivariate analysis controlling for initial pulse pressure, 2-year reduction in pulse pressure correlated negatively with age and concomitant diabetes mellitus, and positively with body height and 2-year reduction in mean blood pressure (multiple R(2) = 0.42, p <0.01). When dividing the study population into 2 groups using a prognostically validated partition for pulse pressure, patients with pulse pressure > or =63 mm Hg after 2 years of antihypertensive treatment (n = 349) were older and shorter, included more women and patients with isolated systolic hypertension, diabetes mellitus, albuminuria, and echocardiographic left ventricular hypertrophy at baseline, and also had a smaller decrease in mean blood pressure and the urinary albumin/creatinine ratio over 2 years (all p <0.05). Thus, in hypertensive patients with electrocardiographic left ventricular hypertrophy, older age, less reduction in mean blood pressure, concomitant diabetes mellitus, and shorter stature are associated with attenuated pulse pressure reduction during antihypertensive treatment.
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PMID:Correlates of pulse pressure reduction during antihypertensive treatment (losartan or atenolol) in hypertensive patients with electrocardiographic left ventricular hypertrophy (the LIFE study). 1183 19

Angiotensin II receptor blockers represent a class of effective and well tolerated orally active antihypertensive drugs. Activation of AT(1) receptors leads to vasoconstriction, stimulation of the release of catecholamines and antidiuretic hormone and promote growth of vascular and cardiac muscle. AT(1) receptor blockers antagonise all those effects. Losartan was the first drug of this class marketed, shortly followed by valsartan, irbesartan, telmisartan, candesartan, eprosartan and others on current investigation. All these drugs have the common properties of blockading the AT(1) receptor thereby relaxing vascular smooth muscle, increase salt excretion, decrease cellular hypertrophy and induce antihypertensive effect without modifying heart rate or cardiac output. Most of the AT(1) receptor blockers in use controlled blood pressure during the 24 h with a once-daily dose, without evidence of producing tolerance to the antihypertensive effect and being with low incidence of side effects even at long term use. Monotherapy in mild-to-moderate hypertension controls blood pressure in 40 to 50% of these patients; when a low dose of thiazide diuretic is added, 60-70% of patients are controlled. The efficacy is similar to angiotensin-converting enzyme (ACE) inhibitors, diuretics, calcium antagonists and beta-blocking agents. AT(1) receptor blockers are specially indicated in patients with hypertension who are being treated with ACE inhibitors and developed side effects such as, cough or angioedema. The final position in the antihypertensive therapy in this special population and other clinical situations, such as left ventricular hypertrophy, heart failure, diabetes mellitus and renal disease, has to be determined in large prospective clinical trials, some of which are now being conducted and seem promising.
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PMID:Angiotensin II receptor antagonists role in arterial hypertension. 1198 4

Recent trials have helped to clarify indications for the initial pharmacological therapy of hypertension. Both the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI) and World Health Organization-international Society of Hypertension (WHO-ISH) recommendations should be revised. The more recent trials indicate that: (1) diuretics and beta-blockers appear to be as effective in reducing overall morbidity/ mortality as other agents (Swedish Trial in Old Patients with Hypertension [STOP-2], United Kingdom Prospective Diabetes Study [UKPDS], Intervention as a Goal in Hypertension Treatment [INSIGHT], Nordic diltiazem [NORDIL]); (2) the use of an a-blocker results in more cardiovascular events, especially congestive heart failure, when compared with a diuretic (Antihypertensive Therapy and Lipid Lowering Heart Attack Trial [ALLHAT]); (3)the use of an angiotensin-converting enzyme (ACE) inhibitor results in fewer myocardial infarctions and episodes of heart failure than calcium channel blockers in the elderly and in diabetic patients (Fosinopril vs. Amlodipine Cardiovascular Events Randomized Trial [FACET], Appropriate Blood Pressure Control in Diabetes [ABCD], STOP-2) - other data (Captopril Prevention Project [CAPPP]) suggest that the use of an ACE inhibitor is preferred in diabetic patients; (4) overall cardiovascular events are similar with calcium channel blockers compared with a diuretic - however, there are fewer strokes with non-dihydropyridine calcium channel blockers (NORDIL) and a trend towards an increase in heart failure and myocardial infarctions with either a dihydropyridine or non-dihydropyridine calcium channel blockers compared with a diuretic (INSIGHT, NORDIL); (5) angiotensin receptor blockers (ARBs) will decrease proteinuria and slow progression of renal disease in type 2 diabetic patients when compared with regimens that do not include an ARB or an ACE inhibitor (Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan [RENAAL], Irbesartan Type II Diabetic Nephropathy Trial [IDNT], Irbesartan Type II Diabetes with Microalbuminuria [IRMA Il]). The debate over initial therapy may be moot. High-risk hypertensive patients should probably be treated initially with combination therapy, one of which should be a diuretic. The use of diuretics and beta-blockers as well as ACE-inhibitors alone or with a diuretic should be considered as initial therapy (a change from JNCVI). Alpha-blockers should be reserved for special situations, i.e. prostatic hypertrophy (in contrast to WHO-ISH recommendations). An ACE-inhibitor or ARB, usually along with a diuretic, can be considered as preferred therapy in hypertensive diabetic patients. Some data suggest equal or greater reduction in strokes with a calcium channel blocker than other medications.
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PMID:Current recommendations for the treatment of hypertension: are they still valid? 1199 97

Type 2 diabetes is the most common cause of end-stage renal disease in the United States, and type 2 diabetes has been shown to be a myocardial infarction equivalent in regard to risk of death from a cardiovascular event. Proteinuria is a surrogate marker for renal disease progression, and although data favor both the angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) in reducing proteinuria, data for renal outcomes, such as time to dialysis, only exist for the ARBs, which clearly increase the duration to dialysis. Conversely, ACE inhibitors have overwhelming data that show substantial risk reduction from cardiovascular events and death in people with type 2 diabetes. Similar data on cardiovascular risk reduction are not yet available with ARBs, although two trials of renal disease progression did have cardiovascular endpoints as secondary outcomes. There were no significant differences between the ARB and control group except for first hospitalization with heart failure, where losartan reduced the risk by 32%, but there was a trend, albeit not significant, toward reduction of myocardial infarction. The first information regarding ARB effects on cardiovascular events as primary outcomes will come from the Losartan Intervention for Endpoint (LIFE) Reduction in Hypertension study. Therefore, as of this writing, all patients with type 2 diabetes and no evidence of nephropathy, ie, proteinuria and an elevated creatinine > 1.5 mg/dL, should be placed on an ACE inhibitor for cardiovascular risk reduction. If nephropathy is present, the evidence would support an ARB for therapy in concert with a b-blocker for cardiovascular risk reduction and renoprotection.
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PMID:Angiotensin converting enzyme inhibitors or angiotensin receptor blockers in nephropathy from type 2 diabetes. 1200 99

Despite intense investigation and clinical attention, many challenges remain in the management of the hypertensive patient. It is clear that hypertension remains inadequately controlled worldwide, with the control rate in the United States approximating 27%. Furthermore, several recent studies have underscored that it is frequently difficult to attain control at goal blood pressure (BP) with monotherapy and that adequate control of hypertension based on the newer more intensified BP goals necessitates multiple drug therapy. Indeed, in the recently published landmark trials of angiotensin I receptor antagonists, including the Irbesartan Diabetic Nephropathy Trial (IDNT) and Reduction of Endpoints in Non-insulin-dependent Diabetes Mellitus with the Angiotensin II Antagonist Losartan (RENAAL), multiple antihypertensive drugs were required to attain goal. A pivotal class of drug required to comprise this regimen is the calcium antagonists. For example, in RENAAL, 78% of patients randomized to losartan required add-on therapy with a calcium antagonist. Calcium antagonists are an important and often necessary component of this multiple drug regimen.
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PMID:Recent landmark clinical trials: how do they modify the therapeutic paradigm? 1212 Oct 10


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