Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.15.1 (ACE)
18,300 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Detection, treatment and control of hypertension is one of the best proven approaches to prevention of cardiovascular disease. Antihypertensive treatment trials have convincingly demonstrated that diuretics and beta-blockers reduce the risk of stroke and coronary heart disease. Corresponding information is not yet available for newer classes of antihypertensive drug therapy such as calcium channel blockers, angiotensin converting enzyme inhibitors and alpha 1 receptor blockers. Several experimental studies are now addressing this question. The largest such trial (n = 40,000) is the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). This manuscript describes two studies (TOMHS and the VA study on antihypertensive agents) that compared several classes of antihypertensive drugs with regard to blood pressure outcomes and ALLHAT, which is comparing the effect of four first-step approaches to antihypertensive therapy on combined incidence of fatal coronary heart disease and non-fatal myocardial infarction.
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PMID:Experimental approaches to determining the choice of first-step therapy for patients with hypertension. The ALLHAT Research Group Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. 874 44

The increasing role of angiotensin converting enzyme (ACE) inhibitor therapy in cardiovascular disease makes it important for the practising clinician to be aware of the specific benefits afforded by these agents. This article covers the use of ACE inhibitors in hypertension, chronic heart failure, post myocardial infarction, diabetic nephropathy and atherosclerosis, with specific reference to clinical trial data and proposed mechanisms of effect.
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PMID:ACE inhibitors in cardiovascular disease. Which patient? Which drug? Which dose? 876 73

Nitric oxide (NO), derived from the vascular endothelium or other cells of the cardiovascular system, has an important role in physiological regulation of blood flow and has pathophysiological functions in cardiovascular disease. The mechanisms and enzymes involved in the biosynthesis of NO and biological actions of NO, including vasodilatation, cytotoxicity and inflammation, are briefly reviewed. These reactions involving NO cause pathological disturbances of arterial function, coronary blood flow regulation, and may contribute to cardiac myocyte dysfunction. NO and prostacyclin (PGI2), which is also released from the endothelium, act synergistically to inhibit platelet aggregation and adhesion, and in some arteries these mediators also synergise in terms of vasodilatation. In addition, NO is capable of hyperpolarizing vascular smooth muscle, but activation of the endothelium may cause hyperpolarization and may thus promote vasodilatation by an additional mechanism. After myocardial ischemia and reperfusion, production of NO and superoxide radicals represent important mechanisms of cytotoxicity, causing injury to the coronary endothelium and myocytes and compromising ventricular contractile function. Moreover, upon reperfusion endothelium-dependent vasodilatation is impaired and the coronary arteries constrict, leading to irregular myocardial perfusion. This is a consequence of the accumulation of activated leucocytes that we found to generate endogenous inhibitors of NO. These factors have yet to be fully characterised, but clearly they may have a role in irregularities of myocardial reperfusion and cellular injury. Chronic heart failure is associated both with impairment of endothelium-dependent vasodilatation and with excess production of NO via the inducible NO synthase (iNOS), although it is unclear whether the latter assists or compromises ventricular contractile performance under these conditions. Disturbances in the activity of isoforms of NO synthase in the artery wall also accompany the development of atherosclerosis, providing conditions propitious for vasospasm and thrombosis, and perhaps contributing to cell proliferation. Reversing these NO defects with therapeutic agents including angiotensin converting enzyme (ACE) inhibitors offers promise in protecting against some manifestations of vascular disease.
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PMID:Nitric oxide in coronary artery disease: roles in atherosclerosis, myocardial reperfusion and heart failure. 880 87

Atherosclerotic renal artery disease is an important secondary cause of hypertension. Currently, there is great interest in possible genetic determinants of cardiovascular disease. The ACE-D allele has been reported to be associated with increased risk of myocardial infarction as well as coronary re-stenosis after angioplasty. We therefore assessed whether this allele is also linked to renovascular disease by studying 56 Caucasian subjects with atherosclerotic renal artery stenosis and 74 age, sex and race matched control subjects. Genetic analysis for the ACE I/D polymorphism was performed on peripheral leukocytes using PCR techniques, including insertion-specific primers. The distribution of I and D alleles was: renal artery stenosis 8 II, 25 ID, 23 DD; and controls, 16 II, 41 ID, 17 DD. The frequency of the D allele in the renal artery stenosis group was significantly higher (D/total 71/112 = 0.66) than that of the control population [75/148 = 0.51; chi 2 = 4.17, P = 0.04; odds ratio 1.69 (95% CI 1.02 to 2.78)]. Our results suggest that the ACE-D allele may be associated with increased risk of vascular disease at sites other than the coronary circulation.
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PMID:Genetic risk for renal artery stenosis: association with deletion polymorphism in angiotensin 1-converting enzyme gene. 882 41

In the blood-vessel wall, the endothelium plays a key functional role by generating several substances that modulate vascular smooth muscle tone, as well as growth, and platelet function. This review focuses on the role of the endothelial L-arginine/nitric oxide signal transduction pathway in the maintenance of vascular integrity. Functional alterations of this pathway may be important in cardiovascular disease, because depressed activity of this protective mechanism leads to impaired relaxation and is also associated with reduced antithrombotic properties of the endothelial layer. Many of the beneficial effects of ACE inhibitor therapy may be mediated through their ability to enhance the physiological roles of nitric oxide.
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PMID:Maintenance of vascular integrity: role of nitric oxide and other bradykinin mediators. 886 30

The cardiac vasculature and myocardium contain components of the renin-angiotensin system (RAS), which may regulate local growth and cellular function. Alterations in the expression or action of these components, which include angiotensin converting enzyme (ACE), angiotensinogen, and angiotensin II type-1 receptors, may contribute to the development of disease, such as hypertension, left ventricular hypertrophy, myocardial infarction, and end-stage heart failure. ACE is one RAS component found to have genetic variants associated with cardiovascular disease. Molecular variants in any of the RAS components may affect signalling pathways, possibly increasing the risk of heart failure. In addition, variants may exacerbate the deleterious effects of altered RAS expression on cardiac function. Genetic variation in RAS components may affect therapy with ACE inhibitors and receptor-blocking agents. Although at present there is no compelling reason to target molecular variations for treatment, a new era in selective pharmacological therapy for cardiovascular disease may be imminent.
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PMID:The role of genetic variants in angiotensin I converting enzyme, angiotensinogen and the angiotensin II type-1 receptor in the pathophysiology of heart muscle disease. 886 32

Hypertension has been defined and treated as a disease of abnormal systolic and diastolic blood pressure. Recent data have, however, demonstrated that effective blood-pressure control has not resulted in the expected decrease in coronary artery disease. These findings are probably a result of hypertension being a complex inherited syndrome of cardiovascular risk factors, all of which are genetically linked and all of which contribute to the development of cardiovascular disease in these patients. Included in the hypertension syndrome are abnormalities of lipid profile, insulin resistance, changes in renal function, left ventricular hypertrophy and reduced arterial compliance. In many patients, high blood pressure is a late manifestation of this disease process. Since all cardiovascular risk factors contribute to heart disease in these patients, they should all be considered in the management of this disease process. Diuretics and beta blockers, when used at high doses, negatively impact lipid metabolism and insulin sensitivity, while angiotensin converting enzyme (ACE) inhibitors and calcium antagonists tend to have a neutral effect on these metabolic risk factors. These findings have resulted in decreased use of diuretics and beta blockers in favor of newer agents such as ACE inhibitors and calcium antagonists. However, recent data have demonstrated that when used at low doses (6.25 or 12.5 mg of hydrochlorothiazide), diuretics lack significant metabolic side effects while bringing about significant reductions in blood pressure. Thus, at these doses, hydrochlorothiazide is a useful drug in the treatment of hypertension, both as monotherapy and in combination therapy.
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PMID:Metabolic manifestations of low-dose diuretics. 887 77

Premature cardiovascular disease is common in insulin-dependent diabetic (IDDM) patients who develop diabetic nephropathy. Genetic polymorphism within the renin-angiotensin system has been implicated in the aetiology of a number of cardiovascular disorders; these loci are therefore candidate genes for susceptibility to diabetic renal disease. We have examined the angiotensin converting enzyme insertion/deletion polymorphism and angiotensinogen methionine 235 threonine polymorphism in a large cohort of Caucasian patients with IDDM and diabetic nephropathy. Patients were classified as having nephropathy by the presence of persistent dipstick positive proteinuria (in the absence of other causes), retinopathy and hypertension (n = 242). Three groups were examined for comparison: ethnically matched non-diabetic subjects (n = 187); a geographically defined cohort of newly diagnosed diabetic patients (n = 341); and IDDM patients with long duration of disease (> 15 years) and no evidence of overt nephropathy (n = 166). No significant difference was seen in distribution of angiotensin converting enzyme or angiotensinogen genotypes between IDDM patients with nephropathy and recently diagnosed diabetic subjects (p = 0.282 and 0.584, respectively), nor the long-duration non-nephropathy diabetic subjects (p = 0.701 and 0.190, respectively). We conclude that these genetic loci are unlikely to influence susceptibility to diabetic nephropathy in IDDM in the United Kingdom.
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PMID:Examination of two genetic polymorphisms within the renin-angiotensin system: no evidence for an association with nephropathy in IDDM. 887 96

The risk to suffer from cardiovascular events may be modulated, in part, by neurohormonal systems. Neurohormones such as angiotensin II or aldosterone may be activated secondary to congestive heart failure or in the course of an acute myocardial infarction. These systems, if activated, will subject the failing heart to increased hemodynamic load and, thus, further compromise cardiac function. In addition, structural changes of the heart and vessels occurring with pressure or volume overload may be amplified by the growth promoting effects of these agents. Taken together, the interaction of underlying cardiovascular disease and activated neurohormones may often determine clinical symptoms and prognosis. More recently, growing evidence suggests that the basal, genetically determined, activity of the renin angiotensin aldosterone system may relate to the development of cardiovascular disease as well. In particular, variants of the angiotensinogen and angiotensin converting enzyme genes have been associated with essential hypertension, myocardial infarction, or left ventricular hypertrophy. In this regard, the data suggest that the renin angiotensin aldosterone system may be one of the primary causes, rather than only a secondary co-factor, in the pathogenesis of these most important cardiovascular disorders. In light of the various options of pharmacological intervention, it seems important that ongoing clinical and molecular-genetic research will further define the role of the renin angiotensin system in clinical conditions or genetic risk profiles.
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PMID:Adaptive and genetic alterations of the renin angiotensin system in cardiac hypertrophy and failure. 895 47

We propose the following guidelines for treatment of hypertension in the elderly. 1. Indications for Treatment. 1) Age: Lifestyle modification is recommended for patients aged 85 years and older. Antihypertensive therapy should be limited to patients in whom the merit of the treatment is obvious. 2) Blood pressure: Systolic BP > 160 mmHg, diastolic BP > 90 approximately 10 mmHg. Systolic BP < age + 100 mmHg for those aged 70 years and older. Patients with mild hypertension (140-160/ 90-95 mmHg) associated with cardiovascular disease should be considered for antihypertensive drug therapy. 2. Goal of Therapy for BP: The goal BP in elderly patients is higher than that in younger patients (BP reduction of 10-20 mmHg for systolic BP and 5-10 mmHg for diastolic BP). In general, 140-160/< 90 mmHg is recommended as the goal. However, lowering the BP below 150/85 should be done with caution. 3. Rate of Lowering BP: Start with half the usual dose, observe at the same dose for at least four weeks, and reach the target BP over two months. Increasing the dose of antihypertensive drugs should be done very slowly. 4. Lifestyle Modification: 1) Dietary modification: (1) Reduction of sodium intake is highly effective in elderly patients due to their high salt-sensitivity. NaCl intake of less than 10 g/day is recommended. Serum Na+ should be occasionally measured. (2) Potassium supplementation is recommended, but with caution in patients with renal insufficiency. (3) Sufficient intake of calcium and magnesium is recommended. (4) Reduce saturated fatty acids. Intake of fish is recommended. (2) Regular physical activity: Recommended exercise for patients aged 60 years and older: peak heart rate 110/minute, for 30-40 minutes a day, 3-5 days a week. (3) Weight reduction. (4) Moderation of alcohol intake, smoking cessation. 5. Pharmacologic Treatment: 1) Initial drug therapy. First choice: Long-acting (once or twice a day) Ca antagonists or ACE inhibitors. Second choice: Thiazide diuretics (combined with potassium-sparing diuretic). 2) Combination therapy. (1) For patients without complications, either of the following is recommended. i) Ca antagoinst + ACE inhibitor, ii) ACE inhibitor + Ca antagonist (or low-dose diuretics), iii) diuretic + Ca antagonist (or ACE inhibitor), iv) beta-blockers, alpha 1-blockers, alpha + beta blockers can be used according to the patho-physiological state of the patient. (2) For patients with complications. Drug(s) should be selected according to each complication. 3) Relatively contraindicated drugs. beta-Blockers and alpha 1-blockers are relatively contraindicated in elderly patients with hypertension in Japan. Centrally acting agents such as reserpine, methyldopa and clonidine are also relatively contraindicated beta-Blockers are contraindicated in patients with congestive heart failure, arteriosclerosis obliterans, chronic obstructive pulmonary disease, diabetes mellitus (or glucose intolerance), or bradycardia. These conditions are often present in elderly subjects. Elderly subjects are susceptible to alpha 1-blocker-induced orthostatic hypotension, since their baroreceptor reflex is diminished. Orthostatic hypotension may cause falls and bone fractures in the elderly.
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PMID:[Guidelines on treatment of hypertension in the elderly, 1995--a tentative plan for comprehensive research projects on aging and health-- Members of the Research Group for "Guidelines on Treatment of Hypertension in the Elderly", Comprehensive Research Projects on Aging and Health, the Ministry of Health and Welfare of Japan]. 905 55


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