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 13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Large-scale clinical trials of vasodilators with nitrates and hydralazine and with angiotensin-converting enzyme (ACE) inhibitors in the 1980s and early 1990s provided the first credible evidence that medical therapy can prolong survival in patients with chronic heart failure (CHF). Moreover, patients treated with ACE inhibitors required fewer hospitalizations for worsening heart failure (HF). Nonetheless, the prognosis in patients with HF remains bleak, and better therapies are urgently needed. Recently, beta-blockers and spironolactone have been shown to reduce mortality when added to ACE inhibitors, diuretics, and digoxin. Digoxin has a neutral effect on overall mortality but does reduce the rate of hospitalization. Angiotensin II receptor blockers (ARB) inhibit the AT1 angiotensin receptor, which mediates the deleterious effects of the renin-angiotensin system, and may provide advantages over ACE inhibitors or advantages when used in combination with ACE inhibitors. Newer drugs that interfere with other mechanisms that contribute to progression of heart failure are also under study. As new therapies prove effective in large populations, they lead to a mandate for polypharmacy. The long-term solution to this clinical problem is to develop sensitive and reliable markers that can predict response in individual patients or monitor effectiveness of therapy.
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PMID:Heart failure: future treatment approaches. 1083 Jul 93

Angiotensin II receptor blockers (ARBs) represent a new class of effective and well tolerated orally active antihypertensive agents. Recent clinical trials have shown the added benefits of ARBs in hypertensive patients (reduction in left ventricular hypertrophy, improvement in diastolic function, decrease in ventricular arrhythmias, reduction in microalbuminuria, and improvement in renal function), and cardioprotective effect in patients with heart failure. Several large long-term studies are in progress to assess the beneficial effects of ARBs on cardiac hypertrophy, renal function, and cardiovascular and cerebrovascular morbidity and mortality in hypertensive patients with or without diabetes mellitus, and the value of these drugs in patients with heart disease and diabetic nephropathy. The ARBs specifically block the interaction of angiotensin II at the AT1 receptor, thereby relaxing smooth muscle, increasing salt and water excretion, reducing plasma volume, and decreasing cellular hypertrophy. These agents exert their blood pressure-lowering effect mainly by reducing peripheral vascular resistance usually without a rise in heart rate. Most of the commercially available ARBs control blood pressure for 24 h after once daily dosing. Sustained efficacy of blood pressure control, without any evidence of tachyphylaxis, has been demonstrated after long-term administration (3 years) of some of the ARBs. The efficacy of ARBs is similar to that of thiazide diuretics, beta-blockers, angiotensin-converting enzyme inhibitors or calcium channel blockers in patients with similar degree of hypertension. Higher daily doses, dietary salt restriction, and concomitant diuretic or ACE inhibitor administration amplify the antihypertensive effect of ARBs. The ARBs have a low incidence of adverse effects (headache, upper respiratory infection, back pain, muscle cramps, fatigue and dizziness), even in the elderly patients. After the approval of losartan, five other ARBs (candesartan cilexetil, eprosartan, irbesartan, telmisartan, and valsartan) and three combinations with hydrochlorothiazide (irbesartan, losartan and valsartan) have been approved as antihypertensive agents, and some 28 compounds are in various stages of development. The ARBs are non-peptide compounds with varied structures; some (candesartan, losartan, irbesartan, and valsartan) have a common tetrazolo-biphenyl structure. Except for irbesartan, all active ARBs have a carboxylic acid group. Candesartan cilexetil is a prodrug, while losartan has a metabolite (EXP3174) which is more active than the parent drug. No other metabolites of ARBs contribute significantly to the antihypertensive effect. The variation in the molecular structure of the ARBs results in differences in the binding affinity to the receptor and pharmacokinetic profiles. The differences observed in lipid solubility, absorption/distribution, plasma protein binding, bioavailability, biotransformation, plasma half-life, and systemic elimination influence the time of onset, duration of action, and efficacy of the ARBs. On the basis of the daily mg dose, the antihypertensive potency of the ARBs follows the sequence: candesartan cilexetil > telmisartan approximately = losartan > irbesartan approximately = valsartan > eprosartan. After oral administration, the ARBs are rapidly absorbed (time for peak plasma levels = 0.5-4 h) but they have a wide range of bioavailability (from a low of 13% for eprosartan to a high of 60-80% for irbesartan); food does not influence the bioavailability, except for valsartan (a reduction of 40-50%) and eprosartan (increase). A limited dose-peak plasma levels/areas under the plasma level-time curve proportionality is observed for some of the ARBs. Most of these drugs have high plasma protein binding (95-100%); irbesartan has the lowest binding among the group (90%). The steady-state volumes of distribution vary from a low of 9 L (candesartan) to a high of 500 L (telmisartan). (ABSTRACT TRUNCATE
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PMID:Clinical pharmacokinetics of angiotensin II (AT1) receptor blockers in hypertension. 1085 85

The treatment of hypertension has evolved in recent years. Blood pressure lowering per se is no longer a sufficient parameter to evaluate its beneficial effects on end-organ damage. Drugs must be considered on the basis of their effects on cellular level and structural alterations that occur in the vasculature, heart and kidney. Angiotensin converting enzyme inhibitors and angiotensin II receptor blockers, two classes of drugs that inhibit angiotensin II effects, may protect target organs from damage and thereby improve outcomes. The mechanisms of action are different even if both counteract all noxious effects of angiotensin II. Angiotensin II receptor blockers selectively inhibit AT1 receptors whose stimulation mediates the hypertensive and proliferative effects of angiotensin II while do not interfere with AT2 receptors. These last ones have a role not well established but it has been postulated that they have antihypertensive and antiproliferative effects. A review will be made on the cellular mechanisms of angiotensin II activity and the effects of AT receptor antagonists.
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PMID:[Rationale for the use of renin-angiotensin inhibitors in the treatment of arterial hypertension and correlated organ damage]. 1196 34

We studied renal AT1 and AT2 receptors in male, female, ovariectomized and ovariectomized-estrogen-treated Wistar-Hanover and Wistar-Kyoto rats. AT1 receptors and AT1A receptor mRNA predominated, with no significant differences between males and females. AT2 receptor expression was restricted in female rats to the capsule, the transition zone between outer and inner medulla, the endothelium lining the papilla, and arcuate arteries and veins. There were no AT2 receptors in male rats, while male mice express substantial numbers of estrogen-dependent AT2 receptors. Arcuate arteries and veins expressed AT1B mRNA in males and females, and AT2 mRNA in females only. AT1 receptor and AT2 receptor expression were estrogen-dependent, with increases in AT1 and AT2 receptor expression after estrogen treatment in ovariectomized rats. Estrogen treatment increased prostaglandin E2 (PGE2) and cGMP concentrations in the renal medulla, and eNOS expression in cortical arteries. In rodents, expression of renal Angiotensin II receptor types is estrogen-dependent, with significant species, strain and area differences. Our results support an important role for AT2 receptors in the regulation of renal function and in the protective effects of estrogen in the kidney.
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PMID:Estrogen upregulates renal angiotensin II AT1 and AT2 receptors in the rat. 1554 36

Angiotensin II receptor density in the brain is elevated when dietary salt intake is raised or in the state of hypertension. The aim of this study was to evaluate whether the angiotensin II modulation of the baroreceptor control of renal sympathetic nerve activity was altered under these conditions. Wistar rats, fed either a regular (0.25% w/w sodium) or high-salt diet (3.1% w/w sodium), or stroke-prone spontaneously hypertensive rats (SHRSPs) were implanted with cannulae in the carotid artery, jugular vein and the cerebroventricle and with recording electrodes on the renal sympathetic nerves. Three days later, baroreceptor gain curves were generated for renal sympathetic nerve activity and heart rate before and following intracerebroventricular (i.c.v.) administration of losartan (15 mug) to block angiotensin AT1 receptors. The rats fed a regular diet had a mean blood pressure of 116 +/- 3 mmHg and heart rate of 467 +/- 25 beats min(-1), which remained unchanged after the i.c.v. administration of losartan. The sensitivity or curvature coefficient of the baroreceptor curve for renal sympathetic nerve activity was increased by 36% (P < 0.05) following losartan. In the rats fed a high-salt diet, all cardiovascular variables and the losartan-induced increase in the baroreceptor curvature coefficient for renal sympathetic nerve activity (29%) were similar to values in rats on the regular sodium diet. The heart rate baroreceptor curvature coefficient was not altered in either the rats fed a regular or a high-salt diet. The slope of the renal sympathetic nerve activity baroreflex gain curve in the SHRSPs was less and the increase following administration of losartan (54%) was greater than in the Wistar rats. These data indicate that in the conscious state, the tonic inhibitory action of brain angiotensin II on the baroreflex regulation of renal sympathetic nerve activity was unaffected by raised dietary sodium, but its role was enhanced in the SHRSPs.
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PMID:The contribution of brain angiotensin II to the baroreflex regulation of renal sympathetic nerve activity in conscious normotensive and hypertensive rats. 1669 Jul 14

Angiotensin II receptor blockers (ARBs) are widely used in patients with hypertension, heart failure, diabetic nephropathy, and other conditions. Over-stimulation of AT2 receptor as a result of AT1 blockade may contribute to the beneficial effects of ARBs through vasodilation and inhibition of cardiac and vascular hypertrophy and fibrosis. Some experimental studies, however, suggested that AT, receptor overstimulation, in addition to beneficial effects, might trigger inhibition of angiogenesis and apoptosis. In a review, some authors suggested that ARBs may increase the risk of myocardial infarction. This position triggered a hot scientific debate and further analyses of existing data. We completed a meta-analysis of randomized clinical trials comparing ARBs with either placebo or active drugs different from ARBs. ARBs were not associated with an excess risk of myocardial infarction (odds ratio 1.03 in a random-effect model and 1.02 in a fixed-effect model). Cardiovascular mortality did not differ between ARBs and drugs different from ARBs (odds ratio 1.00 in a random-effect model and 0.99 in a fixed-effect model) and it was slightly lesser with ARBs than with placebo (odds ratio 0.91; 95% confidence interval 0.83-0.99; p = 0.042) in a prespecified subgroup analysis. Other meta-analyses confirmed these data. In conclusion, evidence from randomized trials does not support the hypothesis that AT2 receptor over-stimulation produces harmful clinical effects. Current indications and contraindications to the use of ARBs in patients with hypertension, heart failure, and diabetic nephropathy should be maintained and probably extended to the entire class of these drugs.
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PMID:[Antihypertensive therapy and cardiovascular prevention. The role of angiotensin II receptor blockers]. 1769

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.
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PMID:Clinical experience with the use of angiotensin receptor blockers in patients with cardiovascular, cerebrovascular and renal diseases. 1866 66

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.
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PMID:A sartan derivative with a very low angiotensin II receptor affinity ameliorates ischemic cerebral damage. 1953 69

Role of reactive oxygen species (ROS)/nitric oxide (NO) balance and renin-angiotensin system in mediating cardiac hypertrophy in hyperthyroidism was evaluated in an in vivo and in vitro experimental model. Male Wistar rats were divided into four groups: control, thyroid hormone, vitamin E (or Trolox, its hydrosoluble analogue), thyroid hormone+vitamin E. Angiotensin II receptor (AT1/AT2) gene expression, immunocontent of AT1/AT2 receptors, angiotensinogen, NADPH oxidase (Nox2), and nitric oxide synthase isoforms, as well as ROS concentration (hydrogen peroxide and superoxide anion) were quantified in myocardium. Thyroid hormone increased ROS and NO metabolites, iNOS, nNOS and eNOS isoforms and it was accompanied by cardiac hypertrophy. AT1/AT2 expression and the immunocontent of angiotensinogen and Nox2 were enhanced by thyroid hormone. Antioxidants reduced ROS levels, Nox2, AT1/AT2, NOS isoforms and cardiac hypertrophy. In conclusion, ROS/NO balance may play a role in the control of thyroid hormone-induced cardiac hypertrophy mediated by renin-angiotensin system.
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PMID:Reactive oxygen and nitrogen species balance in the determination of thyroid hormones-induced cardiac hypertrophy mediated by renin-angiotensin system. 2116 72

The density of Angiotensin II (Ang) receptors on tissue surfaces is regulated by multiple hormones, cytokines and metabolic factors and is profoundly affected by various pathological conditions, such as age, diet and environmental conditions. The participation of several cardiovascular risk factors in the regulation of Angiotensin II receptor expression has been incompletely studied. We performed an ex-vivo study with human aortic postsurgical specimens to test the hypothesis that Ang AT1 and AT2 receptor expression in human aortic arteries is associated with the presence of cardiovascular risk factors. We included 31 Mexican patients with coronary artery disease. We evaluated Angiotensin II receptor expression by immunostaining and angiotensin converting enzyme insertion/deletion (ACE I/D) polymorphisms by polymerase chain reaction. AT1 and AT2 receptor expression was increased in the aortic segments from the cardiovascular patients compared with control arteries and in patients with the DD genotype. There was a correlation between increased AT1 receptor expression and the number of cardiovascular risk factors present in the patient. Furthermore, reduction of AT1 expression correlated with the number of drug combinations used in the patients. These correlations were not present with respect to AT2 receptor expression. We suggest that increased AT1 receptor expression is associated with the DD genotype. Thus the presence of several cardiovascular risk factors as well as DD genotype, induce AT1 expression increasing the probability to develop coronary occlusive disease.
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PMID:Relationship between angiotensin II receptor expression and cardiovascular risk factors in Mexican patients with coronary occlusive disease. 2159 33


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