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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Angiotensin-converting enzyme (ACE) inhibitors have a well-established role in the management of patients with hypertension, diabetes, heart failure and myocardial infarction (MI). ACE inhibitors have been particularly well studied in acute and chronic MI with consistent and substantial survival benefits demonstrated, particularly in the higher risk groups. The recent development of angiotensin II (Ang II) receptor blockers (ARBs) as a well tolerated pharmacological therapy to more completely inhibit the actions of Ang II at the AT1-receptor level raises questions concerning comparative efficacy with the proven ACE inhibitor experience. Two major trials will provide a direct comparison of ARBs with an ACE inhibitor. The Valsartan in Acute Myocardial Infarction (VALIANT) trial is specifically designed to compare and contrast the ARB, valsartan, used both alone as well as in combination with a proven ACE inhibitor regimen, in a high risk MI population. VALIANT, with its three arms targetting 14,500 patients, is uniquely poised to determine whether the pharmacological advance in the development of ARBs confers additional clinical (survival) value in high risk MI patients.
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PMID:Will more complete inhibition of the RAAS with angiotensin receptor blockade improve survival following myocardial infarction? 1719 21

Recently, aldosterone has been shown to activate local renin-angiotensin system in vitro. To elucidate the potential role of local renin-angiotensin system in aldosterone-induced cardiovascular injury, we investigated the effects of selective mineralocorticoid receptor (MR) antagonist eplerenone (EPL), angiotensin (Ang) II type 1 receptor antagonist candesartan (ARB), and superoxide dismutase mimetic tempol (TEM) on the development of hypertension, vascular injury, oxidative stress, and inflammatory-related gene expression in aldosterone-treated hypertensive rats. The increased systolic blood pressure and vascular inflammatory changes were attenuated by cotreatment either with EPL, ARB, or TEM. Aldosterone increased angiotensin-converting enzyme expression in the aortic tissue; its effects were blocked by EPL but not by ARB or TEM. Aldosterone also increased Ang II contents in the aortic tissue in the presence of low circulating Ang II concentrations. Aldosterone induced expression of various inflammatory-related genes, whose effects were abolished by EPL, whereas the inhibitory effects of ARB and TEM varied depending on the gene. Aldosterone caused greater accumulation of the oxidant stress marker 4-hydroxy-2-neonenal in the endothelium; its effect was abolished by EPL, ARB, or TEM. Aldosterone increased mRNA levels of reduced nicotinamide adenine dinucleotide phosphate oxidase components; their effect was abolished by EPL, whereas ARB and TEM decreased only the p47phox mRNA level but not that of p22phox or gp91phox. The present findings suggest that the Ang II-dependent pathway resulting from vascular angiotensin-converting enzyme up-regulation and Ang II-independent pathway are both involved in the underlying mechanisms resulting in the development of hypertension, vascular inflammation, and oxidative stress induced by aldosterone.
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PMID:Angiotensin II receptor type 1-mediated vascular oxidative stress and proinflammatory gene expression in aldosterone-induced hypertension: the possible role of local renin-angiotensin system. 1721 15

The metabolic syndrome is a syndrome characterized by visceral obesity, and is associated with lipid abnormalities, hypertension, and hyperglycemia. The prevalence of this syndrome is increasing in Japan, mainly because of widespread lifestyle changes. Studies from our and other laboratories have shown that early intervention with an ARB can attenuate the development of hypertension in animal models, with a similar trend found in the recent TROPHY clinical study. ARBs also cause inhibition of new-onset diabetes, and may have beneficial effects on insulin resistance and lipid metabolism. The results of multiple laboratory studies and clinical trials suggest that early intervention with ARBs will play an increasing role in preventing progression of the metabolic syndrome and its complications.
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PMID:[Use of angiotensin receptor blockers (ARBs) in the metabolic syndrome]. 1730 87

BP is the most important determinant of the risk of stroke. A small reduction in BP results in a substantial reduction of both ischemic and hemorrhagic stroke. Any of the commonly used antihypertensive drugs lower the incidence of stroke, with larger reductions in BP resulting in larger reductions in risk. Experimental evidence has linked the renin-angiotensin system (RAS) to the development and progression of cerebrovascular disease. Inhibition of the RAS has beneficial cerebrovascular effects and may reduce the risk of stroke in a manner possibly independent from the alterations of BP. Some clinical trials even suggest that ACE inhibitors and angiotensin II type 1 receptor antagonists (angiotensin receptor blockers [ARBs]) exert cerebroprotective effects beyond BP lowering, but the evidence is controversial. Studies on specific protective actions of antihypertensive drugs are generally hampered by the fact that any treatment-related difference in BP may play a dominant role in the prevention of stroke. There are also indications that the protective potency of ARBs might be superior to that of ACE inhibitors, due to their differential activation of angiotensin II type 2 receptors, but the clinical relevance of this mechanism is unclear. Some studies in primary prevention of stroke, acute stroke, and secondary prevention show advantages for ARBs beyond controlling BP alone. In primary prevention, the LIFE randomized trial showed a significant difference in stroke rate in favor of losartan compared with atenolol despite similar reductions in BP. In acute stroke, the role of hypertension and its treatment remains controversial. ACCESS, however, suggested that an ARB is safe in hypertensive acute stroke patients and may offer advantages independent from BP control. In secondary stroke prevention, there are very few antihypertensive trials. These trials show that BP lowering is at least as successful as in primary prevention, but the absolute stroke risk is much higher. An ACE inhibitor was effective compared with placebo in the PROGRESS trial. The MOSES study showed that eprosartan prevented vascular events more effectively than nitrendipine, despite similar BP-lowering effects. Hypertension is not only the most important risk factor for stroke, but is also closely correlated with cognitive decline and dementia. Therefore, prevention of cognitive decline or even improvement of slightly diminished brain function should be an important goal for antihypertensive treatment in the future. Some clinical data suggest advantages for ACE inhibitors, ARBs, and calcium channel antagonists. Currently, however, the existing data are not sufficient for clinical recommendations. Therefore, ongoing trials will further define the exact role of inhibitors of the RAS and are urgently needed in secondary prevention, in acute stroke, and in the prevention of cognitive decline.
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PMID:Inhibition of the renin-angiotensin system and the prevention of stroke. 1735 64

This editorial considers the use of the first selective oral renin inhibitor, aliskiren, in reducing angiotensin (Ang) II reactivation or aldosterone (ALDO) escape during renin-angiotensin-aldosterone system (RAAS) inhibition. RAAS blockade with angiotensin converting enzyme inhibitors (ACEIs) and/or angiotensin receptor AT(1) blockers (ARBs) is very useful for the treatment of arterial hypertension, chronic heart failure (CHF), atherosclerosis and diabetes. 'Ang II reactivation' and 'ALDO escape' or 'breakthrough' have been observed during either ACEI or ARB treatment, and may attenuate the clinical benefit of RAAS blockade. Renin and Ang I accumulate during ACE inhibition, and might overcome the ability of an ACEI to effectively suppress ACE activity. There is also data suggesting that 30 - 40% of Ang II formation in the healthy human during RAAS activation is formed via renin-dependent, but ACE-independent, pathways. Moreover, ACE gene polymorphisms contribute to the modulation and adequacy of the neurohormonal response to long-term ACE inhibition, at least in patients with CHF (up to 45% of CHF patients have elevated Ang II levels despite the long-term use of an ACEI) or diabetes. The reactivated Ang II promotes ALDO secretion and sodium reabsorption. ALDO breakthrough also occurs during long-term ARB therapy, mainly by an AT(2)-dependent mechanism. This was related to target-organ damage in animal models. Oral renin inhibition with aliskiren has showed excellent efficacy and safety in the treatment of hypertension. Aliskiren can be co-administered with ACEIs, ARBs or hydrochlorothiazide. Furthermore, there is evidence suggesting that aliskiren reduces Ang II reactivation in ACE inhibition and ALDO escape during treatment with an ACEI or an ARB, at least to the degree that this is associated with the RAAS. For RAAS-independent ALDO production, the combination of aliskiren with eplerenone might prove useful.
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PMID:Angiotensin II reactivation and aldosterone escape phenomena in renin-angiotensin-aldosterone system blockade: is oral renin inhibition the solution? 1737 10

Olmesartan medoxomil is an angiotensin II (Ang II) receptor blocker (ARB) that has been approved by the US Food and Drug Administration (FDA) for the treatment of hypertension. It is a prodrug that is hydrolysed in the gut into its active metabolite, olmesartan (RNH-6270). Olmesartan is highly selective for the Ang II type 1 receptor (AT1) to which it binds completely and insurmountably and has very little affinity for the other receptor subtypes AT2 and AT4. After oral administration, in animals and humans, it achieves a maximal blood drug concentration within a maximal time of approximately 2 h. It is then slowly eliminated in the urine and faeces. His half-life is approximately 13 h, which makes it suitable for once-daily administration. Olmesartan medoxomil given orally in single daily doses of 20-40 mg has demonstrated significant blood pressure (BP) lowering effects in hypertensive patients. A medline search for the preparation of this manuscript was conducted and revealed 128 references, from 2000 to 2007. Of these, only 16 well-designed prospective clinical trials were selected. The remaining were either animal studies, reviews or studies in progress. In well-designed clinical trials, olmesartan medoxomil has demonstrated similar antihypertensive actions to the other antihypertensive drugs, as well as other members of its class given the highest recommended doses. In addition, the BP lowering effect of olmesartan, like the other members of its class, is greatly enhanced in combination with a diuretic. Its safety profile is similar to the other ARBs and no different than placebo.
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PMID:Treatment of hypertension with olmesartan medoxomil, alone and in combination with a diuretic: an update. 1755 45

Angiotensin II type 1 (AT(1)) receptor blockers (ARBs) are highly selective for the AT(1) receptor, which is a member of the G protein-coupled receptor superfamily (GPCRs), and block the diverse effects (hypertension, hypertrophy, heart failure, proteinuria etc.) of angiotensin II. Many ARBs are in clinical use and have been shown to be safe and effective. Over the past several years, reports have discussed the different degrees of the beneficial effects of ARBs. As ARBs do not all have the same effects, the benefits conferred by ARBs may not be class effects. These different effects may be due to differences in the molecular characteristics of ARBs. The results reported by Le et al. in this issue highlight the different characteristics of two ARBs, olmesartan and telmisartan, and suggest that the higher degree of insurmountability, slower dissociation, and higher affinity of olmesartan compared to telmisartan for AT(1) receptors may help it to form a tight binding complex with this receptor. A better understanding of the different molecular mechanisms for each ARB could be useful for the treatment of patients.
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PMID:Do all angiotensin II type 1 receptor blockers have the same beneficial effects? 1757 2

Angiotensin receptor antagonists (angiotensin receptor blockers; ARBs) are an effective initial antihypertensive monotherapy in many patients. However, when initial ARB monotherapy fails to achieve the recommended BP goal, there is some controversy as to whether dose uptitration or the addition of a diuretic is more appropriate. This article addresses this issue by reviewing the dose-response characteristics of olmesartan medoxomil and other ARBs, as well as the relationship between ARB uptitration and BP goal attainment. Two types of trial designs are used to assess dose response: dose-ranging studies (usually a parallel design using different doses across different patient groups), which are used to establish the optimal dose for US FDA registration purposes, and dose-titration studies (increased dosing within the same patients and treating to goal BP). Since dose titration is within the same patient, it may be considered more appropriate for demonstrating dose-response characteristics and demonstration of BP goal attainment. While results from dose-ranging studies suggest that the dose-response curve for some ARBs may be flat, dose-titration studies indicate that significant improvements in BP control and BP goal attainment can be achieved with ARB uptitration. In an integrated analysis of seven US and European randomized, placebo-controlled, dose-ranging trials involving 3055 patients with stage 2 hypertension treated with olmesartan medoxomil 2.5-80 mg/day or placebo for 8 weeks, all olmesartan medoxomil doses were significantly more effective than placebo in lowering the mean DBP and mean SBP (p<or=0.001); notably, optimal BP-lowering efficacy was observed at higher dosages. In fact, the 20 mg/day (recommended starting dose) and 40 mg/day (maximum approved dose) dosages were significantly (p<or=0.001) more effective in lowering mean BP than the 5 mg/day dosage (optional starting dose in volume-depleted patients), and the 40 mg/day dosage was significantly (p<0.01) more effective than the 20 mg/day dosage. The BP decreases observed with the uptitration of olmesartan medoxomil from 20 to 40 mg/day doses resulted in substantial additional mean BP reductions from baseline. Such BP reductions have been shown to translate into a clinically relevant increase in the number of patients who achieve BP goal. In conventional clinical studies, the shallow dose-response findings often attributed to ARBs may be an artifact resulting from the inclusion of both treatment responders and nonresponders within each dose group. However, this may not accurately reflect the results that are actually obtained in clinical practice. The efficacy of certain ARBs, such as olmesartan medoxomil, is dose-dependent, with greater reductions being attained at higher doses; higher BP goal attainment rates are achieved with the higher doses. Thus, ARB monotherapy, with appropriate uptitration as needed, is an excellent initial treatment option for patients with hypertension.
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PMID:Dose-response characteristics of olmesartan medoxomil and other angiotensin receptor antagonists. 1795 73

Our recent studies have demonstrated that salt excess in the spontaneously hypertensive rat (SHR) produces a modestly increased arterial pressure while promoting marked myocardial fibrosis and structural damage associated with altered coronary hemodynamics and ventricular function. The present study was designed to determine the efficacy of an angiotensin II type 1 (AT(1)) receptor blocker (ARB) in the prevention of pressure increase and development of target organ damage from high dietary salt intake. Eight-week-old SHRs were given an 8% salt diet for 8 wk; their age- and gender-matched controls received standard chow. Some of the salt-loaded rats were treated concomitantly with ARB (candesartan; 10 mg kg(-1) day(-1)). The ARB failed to reduce the salt-induced rise in pressure, whereas it significantly attenuated left ventricular (LV) remodeling (mass and wall thicknesses), myocardial fibrosis (hydroxyproline concentration and collagen volume fraction), and the development of LV diastolic dysfunction, as shown by longer isovolumic relaxation time, decreased ratio of peak velocity of early to late diastolic waves, and slower LV relaxation (minimum first derivative of pressure over time/maximal LV pressure). Without affecting the increased pulse pressure by high salt intake, the ARB prevented the salt-induced deterioration of coronary and renal hemodynamics but not the arterial stiffening or hypertrophy (pulse wave velocity and aortic mass index). Additionally, candesartan prevented the salt-induced increase in kidney mass index and proteinuria. In conclusion, the ARB given concomitantly with dietary salt excess ameliorated salt-related structural and functional cardiac and renal abnormalities in SHRs without reducing arterial pressure. These data clearly demonstrated that angiotensin II (via AT(1) receptors), at least in part, participated importantly in the pressure-independent effects of salt excess on target organ damage of hypertension.
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PMID:AT1 receptor antagonism attenuates target organ effects of salt excess in SHRs without affecting pressure. 1805 16

Hypertension is a multifactorial disorder leading to pathophysiologic changes in target organs over time through diverse mechanisms. In addition, hypertension frequently resists control with monotherapy, necessitating combination therapy with two or more antihypertensive agents. Many currently available fixed-dose antihypertensive combinations combine drugs with different, but complementary, mechanisms of action to improve overall efficacy and tolerability. In addition, it is possible to select drug combinations whereby one drug offsets the negative effects of the other drug. Fixed-dose antihypertensive combinations may provide significant advantages over high-dose monotherapy, such as improved BP-lowering efficacy, reduced adverse event frequency, improved patient compliance, potentially lower treatment costs, and shorter time to BP control. Combination therapy has been recommended as potential first-line therapy in recent consensus guideline statements, especially for higher-risk patients, such as those with stage 2 hypertension. The combination of a renin-angiotensin-aldosterone system-targeting agent, such as an ACE inhibitor or angiotensin II receptor antagonist (ARB), and a diuretic or calcium channel antagonist appears to provide synergy with regard to BP lowering. In addition, ACE inhibitors and ARBs have demonstrated beneficial effects beyond BP reduction, reducing cardiovascular morbidity and mortality, inhibiting development and progression of type 2 diabetes mellitus and the progression of renal disease. Preliminary studies of fixed-dose combinations have shown reductions in left ventricular hypertrophy and improvements in markers of renal function. Additional studies currently underway will compare the effects of available fixed-dose combinations on cardiovascular morbidity and mortality, and markers of renal dysfunction.
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PMID:Fixed-dose combination antihypertensives and reduction in target organ damage: are they all the same? 1807 8


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