Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0004135 (ATM)
 13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hypertension is one of the major health care problems worldwide since it markedly increases the risk for development of heart disease, stroke, generalized vascular disease, and renal failure. The renin-angiotensin system (RAS) with its major end-product angiotensin II (Ang II) plays a fundamental role in blood pressure regulation through direct and indirect mechanisms. Pharmacologically, we can inhibit the RAS using angiotensin-converting enzyme inhibitors and AT1 receptor blocker. Inhibiting renin directly with a clinically useful drug eluded pharmacologists until recently. However, the once-daily, orally effective, small-molecule, direct renin inhibitor aliskiren has recently changed this state of affairs. Aliskiren, with its 40-h half-life and ideal pharmacokinetics, can now address angiotensin production directly at its rate-limiting step. A novel transgenic rat model outfitted with the human renin and angiotensinogen genes allowed the testing of aliskiren in an animal model. Preclinical data demonstrated that aliskiren prolonged survival, decreased cardiac hypertrophy and the inducibility of arrhythmias, proteinuria, and attenuated inflammation. All these features might result in improved target-organ damage. Studies in humans attest to an effective blood pressure-lowering action, a largely side effect-free profile, and the option of several combination therapies. Aliskiren is the first of a novel antihypertensive drug class. The preclinical data is very promising. Nevertheless, for the evaluation of its potency in humans, we have to wait for more clinical data.
 ...
PMID:Aliskiren--mode of action and preclinical data. 1844 51

The Angiotensin II receptor blockers (ARBs) have been efficacious and safe drugs for the treatment of hypertension, heart failure, diabetic nephropathy and stroke from several short and long term clinical trials. The ARBs exert their effects through selective blockade of the angiotensin II (Ang-II) subtype 1 (AT1) receptor and quite possibly through stimulation by Ang-II of the unoccupied subtype 2 (AT2) receptor. The ARBs are equipotent to other antihypertensive drugs with respect to their effect on blood pressure, heart failure or diabetic nephropathy. They appear to be superior to the other drugs with respect to their stroke protective effect. They exert their stroke protective effect by a dual action, selectively blocking the action of Ang-II on the AT1 receptors, while allowing Ang-II to stimulate the unoccupied AT2 receptors. This dual action is unique to ARBs and results in vasodilation and increase in blood flow to the ischemic zone of the brain leading to improvement and prevention of its extension. All these actions of the ARBs will be discussed in this comprehensive review.
 ...
PMID:Clinical experience with the use of angiotensin receptor blockers in patients with cardiovascular, cerebrovascular and renal diseases. 1866 66

Hypertension is the most common disease affecting humans. Statistical surveys indicate that approximately one billion individuals worldwide suffer from this serious condition. The spotlight of the present review is on the cardiac involvement in patients with hypertension and especially on the possibility that treatment of increased blood pressure may abolish the incidence of cardiac arrhythmia and particularly atrial fibrillation. Modern therapeutic approach based on the electrical and structural remodeling process in the hypertensive heart with a consequent administration of ACE inhibitors and AT1 receptor blockers represent new and more efficient option compared to other antihypertensive drugs, such as calcium channel blockers, beta-blockers and thiazide-type diuretics and might be useful in the prevention of atrial fibrillation and incidence of stroke.
 ...
PMID:Does treatment of hypertension decrease the incidence of atrial fibrillation and cardioembolic stroke? 1932 99

Angiotensin II plays an important role in the cardiovascular continuum starting with risk factors and progressing to atherosclerosis, target organ damage, and ultimately to heart failure, stroke, or death. Inhibiting the renin-angiotensin-aldosterone system (RAAS) represents a cornerstone for the treatment of hypertension and heart failure. In patients with heart failure, the single RAAS blockade with angiotensin-converting enzyme (ACE) inhibitors have been shown to reduce morbidity and mortality, increase life expectancy, and preserve the renal function. AT1 receptor blockers (ARBs) are equally effective in reducing mortality and morbidity in patients with impaired left ventricular function. The combination of ACE inhibitors with ARBs leads to an additive blood pressure lowering effect, better reduction in proteinuria, and to additive benefits in heart failure and left ventricular hypertrophy. But combination therapy is also associated with more side effects. Further investigations evaluating the effect of dual RAAS blockade on fatal and nonfatal cardiovascular events are needed.
 ...
PMID:Dual blockade versus single blockade of the renin-angiotensin system in the light of ONTARGET. 1949 15

Activation of the AT1 angiotensin II (Ang II) receptors has various effects including vasoconstriction, hypertrophy, and possibly hyperplasia of vascular smooth muscle cells and cardiomyocytes and increase in extracellular collagen matrix synthesis. These actions lead to the development of cardiovascular hypertrophy and fibrosis, as well as arterial stiffness, which are some key factors in the development of the cardiovascular and renal complications. In clinical studies, it has been shown that renin-angiotensin blockade has direct and specific implications in the evolution of heart failure, coronary disease, stroke, and hypertensive and diabetic renal disease. The beneficial cardiovascular and renal effects of blocking the renin-angiotensin-aldosterone system reported in numerous clinical trials may be at least partially related to the actions of these drugs on cardiovascular and renal fibrosis, and arterial stiffness. These effects are now well-established and lead the international medical societies to propose the use of the renin-angiotensin system (RAS) blockers as initial treatment (both angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers) in several cardiovascular, metabolic, and renal disorders such as hypertension, heart failure, and proteinuria.
 ...
PMID:Benefits of the RAS blockade: clinical evidence before the ONTARGET study. 1949 20

Angiotensin II receptor blockers (ARBs) have a potent ability to inhibit oxidative stress and advanced glycation, in addition to their protective effects originated from blood pressure lowering and angiotensin II type 1 receptor (AT(1))-blockade. To obtain a pharmacological tool to dissect the mechanisms of ARBs' protective benefits in experimental stroke, we synthesized a novel ARB-derivative, R-147176, which is 6,700 times less potent than olmesartan in AT(1)-binding inhibition and therefore has a minimal antihypertensive effect, but retains marked inhibitory effects on oxidative stress and advanced glycation. We evaluated the effect of R-147176 (10-30 mg/kg per day), administered orally or intravenously, on brain infarct volume in transient thread occlusion and photothrombotic models in rats. The antioxidative and antiinflammatory properties were also investigated. R-147176 significantly reduced infarct volume, without influence on blood pressure, in both models. R-147176 significantly reduced the numbers of ED-1-positive cells and of TUNEL-positive cells, and protein carbonyl formation in the damaged brain. This ARB derivative, despite its significantly lower AT1 affinity and virtually no antihypertensive effect, ameliorated ischemic cerebral damage through antioxidative and antiinflammatory properties. These findings suggest potential usefulness of R-147176 as a pharmacological tool to investigate the ARBs' protective effect in experimental stroke and open new therapeutic avenues.
 ...
PMID:A sartan derivative with a very low angiotensin II receptor affinity ameliorates ischemic cerebral damage. 1953 69

First, an update of the vascular systemic and tissue renin-angiotensin-aldosterone system is provided to explain how it is regulated at the systemic and tissue levels, and how many angiotensin peptides and receptors can be modulated by the various antihypertensive drugs. Second, experimental data is presented to support the hypothesis that antihypertensive drugs that increase angiotensin II formation, such as diuretics, AT1-receptor blockers and dihydropyridines, may have greater brain anti-ischemic effects than antihypertensive drugs that decrease angiotensin II formation, such as beta-blockers and angiotensin-converting enzyme inhibitors, because they increase activation of angiotensin AT2 and AT4 receptors. Indeed, these trigger brain anti-ischemic mechanisms by favouring cerebral blood flow (angiogenesis and recruitment of pre-existing collateral circulation, specifically in the ischemic brain where AT2 receptors are overexpressed) or by directly increasing neuronal resistance to anoxia. Third, we review most of the large primary and secondary stroke prevention trials as well as the ACCESS acute stroke trial in which antihypertensive drugs were evaluated. With the exception of the secondary stroke prevention trial PRoFESS, most trials support the hypothesis that angiotensin II-increasing drugs confer specific blood pressure-independent brain ischemia protection when compared with angiotensin II-decreasing drugs or placebo. A careful analysis of the PRoFESS trial, however, reveals study design limitations, the main one being that diastolic BP (<80 mmHg) in the first month post-stroke may have been too low in at least one third of the population with baseline systolic blood pressure less than 130 mmHg, because a high dose of telmisartan was given after a very short post-stroke delay (median 15 days) without discontinuation of the baseline antihypertensive treatment.
 ...
PMID:Angiotensin AT1-receptor blockers and cerebrovascular protection: do they actually have a cutting edge over angiotensin-converting enzyme inhibitors? 1976 45

Our review of cohort studies and clinical trials evaluating antihypertensive drugs in the prevention of cognition decline and all dementia in patients with hypertension indicates that two antihypertensive drug classes have greater protective effects, independent of blood pressure decrease: dihydropyridine calcium-channel blockers as shown in the Syst-Eur trial and angiotensin-AT1 receptor blockers as found in the MOSES and ONTARGET trials. By contrast, diuretics and angiotensin-converting enzyme-inhibitors (ACEIs) prevent dementia only in patients with a stroke history, provided they are combined, and prevent stroke recurrence. A Japanese cohort study and a small trial in patients already suffering from Alzheimer's disease (AD) suggest, however, that the BBB-penetrating ACEI may slow down cognitive decline. Only cohort studies support the hypothesis that diuretics, (especially potassium-sparing diuretics), may decrease the risk of AD. beta-blockers worsen cognition decline, or are neutral, according to whether or not they cross the BBB. Centrally-acting sympatholytic agent have a negative impact on cognition as BBB-penetrating beta-blockers, probably by blunting the adrenergic pathways. The AD protective effect of DHP appears related to the blockade of neuronal calcium channels. The ambiguous effect of ACEI on cognitive decline and dementia prevention may be explained by the fact that brain ACE is not specific for angiotensin-I. Brain ACE also catabolizes cognition-enhancing brain peptides, amyloid peptides and converts toxic Abeta(42) into less toxic Abeta(40). Therefore, ACEIs may have short-term cognition-enhancing properties and may increase in the long term Abeta(42) brain burden and cognitive decline. The clinical relevance of this scenario, mainly observed in animals, cannot be excluded in man, since the ACE gene has been associated with AD via the human whole genome analysis. To support the hypothesized deleterious effect of ACEI on human AD, confirmation that the ACE gene polymorphism DD is associated with protection against AD is necessary, since this polymorphism increases ACE activity. Independently of their preventive impact on beta-amyloid degenerative neuropathological process by overexpressing insulin degrading enzyme which catabolyses amyloid, the angiotensin AT1-receptor-blockers may have greater cognition protective effects than ACEI (observed in the ONTARGET trial), as they share with ACEI cognition-enhancing effects directly linked with a common AT1-blunting effect. In addition, they increase angiotensin II and IV formation and therefore stimulate non-opposed AT2 and AT4 receptors, whose activation in cognitive processes is well established.
 ...
PMID:Prevention of dementia by antihypertensive drugs: how AT1-receptor-blockers and dihydropyridines better prevent dementia in hypertensive patients than thiazides and ACE-inhibitors. 1976 54

This work aims at studying the possible alteration of renal renin secretion after human ischemic stroke and correlating it to the post stroke neurological and renal function alterations using angiotensin II type 1(AT1) receptor blocker (ARB), candesartan, and beta 1 adrenoreceptor blocker atenolol, which inhibits renin secretion, in Wistar rats subjected to middle cerebral artery occlusion. Methods . This study comprised 21 patients with cerebral ischemic stroke. Seventeen normal persons were used for comparison. Recumbent and standing plasma renin activity (PRA), reflex plasma renin sensitivity, plasminogen activator inhibitor and creatinine clearance (Ccr) were estimated at admission and two weeks later. Moreover, 60 male Wistar rats were divided into two groups SHAM and ischemic. Each of the two groups was further subdivided into three subgroups, non-treated, atenolol treated, and candesartan treated. In all rats, mean arterial blood pressure (MAP), systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse pressure (PP), heart rate (HR), neurobehavioral evaluation, Ccr, PRA, and infarct size were measured. Results . Together with the significant deterioration of the neurological score, focal cerebral ischemia in rats resulted in increased PRA and decreased glomerular filtration rate (GFR). In ischemic stroke patients, GFR was significantly decreased at admission and two weeks later, PRA increased at admission and two weeks later while plasma renin reflex secretion sensitivity had decreased significantly at admission relative to controls, but it increased significantly 2 weeks later. Atenolol caused significant improvement of the neurobehavioral score and renal function and decrease infarct size of rats subjected to focal cerebral ischemia whereas candesartan caused significant improvement of the neurobehavioral score and decreased infarct size with no significant change in GFR. Neither atenolol nor candesartan caused significant change in MAP, SBP, DBP, PP and HR Conclusion . (1) Ischemic stroke seems to be associated with a postischemic increase of the plasma renin secretion, which may increase the infarct size in the brain and may induce acute renal insufficiency. (2) This study confirms that Atenolol and ARBs could benefit ischemic stroke patients without altering blood pressure.
 ...
PMID:Effect of angiotensin II type 1 receptor blocker, candesartan, and beta 1 adrenoceptor blocker, atenolol, on brain damage in ischemic stroke. 2051 Nov 25

Matrix metalloproteinase-9 (MMP-9) which is a member of matrix metalloproteinases family that normally remodel the extracellular matrix, has been shown to play an important role in both animal models of cerebral ischemia and human stroke. The expression of MMP-9 is elevated after cerebral ischemia which is involved in accelerating matrix degradation, disrupting the blood-brain barrier, increasing the infarct size and relating to hemorrhagic transformation. Recently, many drugs, such as tetracycline derivatives, cyclooxygenase inhibitors, ACEI inhibitors and AT1 receptor blockers, etc., have been found to attenuate the elevated expression levels of MMP-9 after ischemia and to reduce the damage of cerebral ischemic. This article reviews the physiological features of MMP-9 and its important role in the genesis, propagation, and therapeutics of cerebral ischemic diseases.
 ...
PMID:Mmp-9, a potential target for cerebral ischemic treatment. 2051 6


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>