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Over the past 4 years, six angiotensin II receptor antagonists (ARBs) were approved for treating essential hypertension. They differ with respect to dosing, metabolism, elimination, clinical efficacy, and investigational applications. Candesartan cilexetil is the only prodrug among the agents. Losartan is distinguished from other ARBs by cytochrome P450 (CYP) 3A4- and CYP2C9-mediated biotransformation to its active metabolite EXP-3174. No ARB requires dosage adjustment for renal impairment, but the initial dose of losartan should be reduced 50% in hepatically impaired patients. None of the drugs is significantly cleared by hemodialysis. Completion of continuing trials will elucidate the drugs' role in treating heart failure, cerebral stroke, and myocardial infarction.
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PMID:Pharmacologic, pharmacokinetic, and therapeutic differences among angiotensin II receptor antagonists. 1067 91

The effects of the angiotensin II receptor blocker candesartan cilexetil on systemic and forearm haemodynamics and baroreceptor sensitivity were evaluated in this randomized, placebo-controlled, double-blind, crossover study. After a 4-week placebo run-in period, 22 patients with essential hypertension (diastolic blood pressure 100-114 mmHg) were randomized to receive either candesartan cilexetil 16 mg or placebo once daily for 6 weeks. At the end of each period, 24 h after the last dose, invasive haemodynamic assessments were performed. Simultaneously, the plasma renin activity and plasma concentrations of angiotensin II, aldosterone and catecholamines were measured. Compared to placebo, candesartan cilexetil significantly reduced mean arterial pressure by 8 mmHg (95% CI: 2.6; 12.3), while cardiac output, stroke volume and heart rate were unchanged. Forearm vascular resistance was reduced by 1 mmHg x ml(-1) x L x min (CI: 0.3; 2.3). The baroreceptor sensitivity was not influenced, but a change in the set-point was noted. Plasma renin activity and angiotensin II concentrations were increased, while the aldosterone concentration was significantly reduced. Plasma catecholamine concentrations were unaffected. In conclusion, 6 weeks' treatment with candesartan cilexetil 16 mg o.d. induced systemic and forearm vasodilatation and a reduction in blood pressure without compromising cardiac performance. The plasma concentration of aldosterone was reduced.
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PMID:Candesartan cilexetil in hypertension: effects of six weeks' treatment on haemodynamics, baroreceptor sensitivity and the renin-angiotensin-aldosterone system. 1069 5

The first effective antihypertensive treatment became available in the 1950s but the early drugs caused intolerable side effects. Drugs with a better side-effect profile became available in the 1960s, and their utility was soon subjected to rigorous clinical trials. In the 1970s, the availability of these drugs opened the door for outcome studies. Most of the results reported in the 1970s and 1980s were rather impressive. Antihypertensive treatment reduced mortality in severe and mild hypertension, in hypertension of the elderly, and in patients with advanced complications of hypertension. A large number of 'hard end point' (mortality and morbidity) trials were organized in the last decade of the 20th century. Most compare the merits of new antihypertensive agents (angiotensin-converting enzyme inhibitor, calcium channel blocker, angiotensin II receptor blocker) versus an older (beta-blocker or diuretic) drug. These trials are rooted in the fact that blood pressure lowering does not equally affect all complications of hypertension. Particularly bothersome is the fact that treatment decreases stroke but fails to substantially reduce coronary events. These variations in treatment outcomes may reflect the multifactorial pathophysiology of hypertension: essential hypertension is frequently associated with pressure-independent coronary risk factors, and the target organ status of a patient (left ventricular hypertrophy, renal dysfunction) greatly affects their prognosis. These new trials investigate whether the mechanism by which a drug decreases the pressure and how it affects various risk factors are of clinical relevance. The practice of medicine in hypertension is evidence bound. Historically, only when the superiority of the treatment had been convincingly shown did physicians alter practice patterns. The effects of systolic blood pressure lowering and of treating mild diastolic hypertension in younger patients have not been sufficiently investigated. Lowering of the systolic blood pressure and treating patients with mild hypertension might have major beneficial effects on public health. We need new studies in this area in order to improve clinical practice in hypertension.
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PMID:Five decades of antihypertensive treatment: the unresolved issues. 1095 81

Although a wide range of antihypertensive agents is available, adequate blood pressure control is achieved in only about 25% of hypertensive patients. Poor control rates are often due to inadequate patient compliance and unacceptable side-effects. The importance of once-daily dosing is now fully acknowledged, but it is crucial that therapy when given once a day must be effective at the end of the dosing interval to order to minimize the likelihood of sudden cardiac death, myocardial infarction and stroke. Ambulatory blood pressure monitoring (ABPM) provides a thorough assessment of the blood pressure-lowering characteristics of an antihypertensive agent throughout the dosing interval and can more accurately evaluate differences in the duration of the antihypertensive effect of different agents. Telmisartan, a new angiotensin II receptor antagonist, has been extensively studied in clinical trials using ABPM. When compared with dihydropyridine calcium antagonists, beta-adrenergic blockers, angiotensin-converting enzyme inhibitors and other angiotensin II receptor antagonists, telmisartan has proved superior in diminishing ambulatory blood pressure throughout the 24-h period between doses. Telmisartan also has excellent tolerability and in clinical trials demonstrates no increase, irrespective of dose level, over placebo in the incidence of adverse events. Thus, telmisartan given once daily provides high efficacy and tolerability, and will hopefully assist in improving both blood pressure control rates and cardiovascular outcomes in the future.
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PMID:Ambulatory blood pressure monitoring to assess the comparative efficacy and duration of action of a novel new angiotensin II receptor blocker--telmisartan. 1133 11

End-stage renal disease (ESRD) comprises an enormous public health burden, with an increasing incidence and prevalence. Hypertension is a major risk factor for progressive renal disease. This escalating prevalence suggests that newer therapeutic interventions and strategies are needed to complement current antihypertensive approaches. Although much evidence demonstrates that angiotensin II mediates progressive renal disease, recent evidence also implicates aldosterone as an important pathogenetic factor in progressive renal disease. Several lines of experimental evidence demonstrate that selective blockade of aldosterone, independent of renin-angiotensin blockade, reduces proteinuria and nephrosclerosis in the spontaneously hypertensive stroke-prone rat model and reduces proteinuria and glomerulosclerosis in the subtotally nephrectomized rat model (i.e. remnant kidney). Whereas pharmacological blockade with angiotensin II receptor blockers and angiotensin-converting enzyme inhibitors reduces proteinuria and nephrosclerosis/ glomerulosclerosis, selective reinfusion of aldosterone restores these abnormalities despite continued renin-angiotensin blockade. Aldosterone may promote fibrosis by several mechanisms, including plasminogen activator inhibitor-1 expression and consequent alterations of vascular fibrinolysis, by stimulation of transforming growth factor-beta 1, and by stimulation of reactive oxygen species. Based on this theoretical construct, randomized clinical studies will be initiated to delineate the potential renal-protective effects of antihypertensive therapy utilizing aldosterone receptor blockade.
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PMID:Aldosterone and the hypertensive kidney: its emerging role as a mediator of progressive renal dysfunction: a paradigm shift. 1139 64

Measurement of vascular compliance has assumed increasing importance as a marker of early disease of the vascular wall, a predictor of future vascular disease, and a way to monitor the effects of vasoactive agents on arterial wall stiffness. Vascular compliance can be estimated by several methods: measurement of the pulse pressure, or pulse pressure-stroke volume ratio; analysis of the systolic pulse wave augmentation index and the diastolic pulse wave contour; ultrasonic echo-tracking; and MRI. Because few comparative studies have been done, the physiologic significance of the measures of compliance obtained by each method is uncertain. Antihypertensive drugs may improve vascular compliance by reducing blood pressure, relaxing vascular smooth muscle, or promoting long-term effects on vascular smooth muscle and cardiomyocyte growth and remodeling. Angiotensin converting enzyme (ACE) inhibitors have been reported to improve vascular compliance in nearly all studies, suggesting a beneficial class effect independent of blood pressure reduction. Favorable changes in the vascular wall-lumen ratio of small vessels from subcutaneous gluteal biopsy specimens after treatment with ACE inhibitors and the persistence of improved vascular compliance after withdrawal of therapy indicate that these agents may produce long-term vascular remodeling. Although few studies have been done, angiotensin II receptor antagonists improve vascular compliance, possibly by blocking angiotensin II-mediated cell proliferation and increasing apoptosis via unopposed AT1 receptor stimulation. In contrast, calcium antagonists and beta-blockers have variable effects on vascular compliance, although beta-blockers with intrinsic sympathomimetic activity improve vascular compliance. Diuretics have little effect on vascular compliance beyond their blood pressure-lowering actions, except for spironolactone, which by improving vascular compliance may have contributed to the reduction in heart failure mortality seen in the Randomized Aldactone Evaluation Study.
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PMID:The effect of antihypertensive drugs on vascular compliance. 1147 12

Tachycardia accompanying exercise shortens the duration of diastole, reducing the time available for the left ventricular (LV) filling. Thus, the LV must fill more rapidly for the stroke volume to increase (or even be maintained) during exercise. Normally, this is accomplished without requiring an excessive increase in left atrial (LA) pressure by an acceleration of LV relaxation and a fall in LV early diastolic pressure during exercise. This response is lost following the development of heart failure due to systolic dysfunction, both in experimental animals and in patients. In fact, in such situations, LV relaxation slows and LV early diastolic pressure increases due to exercise. Thus, any diastolic dysfunction present at rest in CHF during systolic dysfunction is exacerbated during exercise. Similarly, patients with primary diastolic dysfunction heart failure with preserved systolic function may not be able to augment LV filling rates without an abnormal increase in LA pressure. Thus, diastolic dysfunction may contribute to exercise intolerance, both in systolic dysfunction and primary diastolic dysfunction. Acute studies suggest that treatment with angiotensin II receptor blockers or verapamil may improve exercise tolerance in some patients with primary diastolic dysfunction.
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PMID:Diastolic dysfunction as a cause of exercise intolerance. 1149 43

End-stage renal disease (ESRD) comprises an enormous public health burden, with an incidence and prevalence that are increasingly on the rise. This escalating prevalence suggests that newer therapeutic interventions and strategies are needed to complement current therapeutic approaches. Although much evidence demonstrates conclusively that angiotensin II mediates progressive renal disease, recent evidence also implicates aldosterone as an important pathogenetic factor in progressive renal disease. Recently, several lines of experimental evidence demonstrate that selective blockade of aldosterone, independent of renin-angiotensin blockade, reduces proteinuria and nephrosclerosis in the spontaneously hypertensive stroke-prone rat (SHRSP) model and reduces proteinuria and glomerulosclerosis in the subtotally nephrectomized rat model (ie, remnant kidney). Whereas pharmacologic blockade with angiotensin II receptor blockers and angiotensin-converting enzyme (ACE) inhibitors reduces proteinuria and nephrosclerosis/glomerulosclerosis, selective reinfusion of aldosterone restores these abnormalities despite continued renin-angiotensin blockade. Aldosterone may promote fibrosis by several mechanisms, including plasminogen activator inhibitor-1 (PAI-1) expression and consequent alterations of vascular ribrinolysis, by stimulation of transforming growth factor-beta1 (TGF-beta1), and by stimulation of reactive oxygen species (ROS). Based on this formulation, randomized clinical studies will be initiated to delineate the potential renal-protective effects of aldosterone receptor blockade.
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PMID:Aldosterone as a mediator of progressive renal dysfunction: evolving perspectives. 1150 95

In the last few years several large intervention trials have addressed the treatment of hypertension in the elderly and how far blood pressure should be lowered in such patients. The positive results of intervention against high blood pressure in the elderly has resulted in a positive attitude towards treatment and today this is an accepted and highly effective medical intervention. Both stroke and coronary morbidity have been shown to be positively affected as has total mortality. The specific issue, how far to lower blood pressure in the elderly was probably best addressed in the Hypertension Optimal Treatment (HOT) stduy in which about a third of the patients, i.e. >6,000 patients, were > or =65 years of age. In most of the early intervention studies of antihypertensive treatment in elderly patients diuretics or beta-blockers or the two in combination were used as the therapy by which blood pressure was lowered. However, novel therapies, in particular calcium antagonists, have shown benefits of the same magnitude as the older therapies, e.g. in the STONE trial, the Syst-Eur study, the Syst-China study and the STOP-Hypertension-2 study. In the latter study a regimen based on either of two ACE inhibitors was also shown to be equally effective as conventional treatment, based on diuretics and/or betablockers, in the elderly. These trials will be briefly reviewed here as will the SCOPE study which is an ogoing trial in which hypertensive patients aged 70-89 years are being treated with an angiotensin II receptor antagonist under double-blind and placebo-controlled conditions. It can be concluded that a wealth of information, based on large intervention trials, has been accumulated during the last decade. It is quite obvious that the elderly hypertensive patients benefit from antihypertensive treatment to at least the same extent as the young and middle-aged. It appears that blood pressure ought to be lowered down to normotensive values also in the elderly in order to minimize their risk if cardiovascular complications, although more studies would be welcome to address this issue specifically in the elderly.
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PMID:How far should we lower blood pressure in the elderly. 1171 98

Imidapril hydrochloride (imidapril) is a long-acting, non-sulfhydryl angiotensin-converting enzyme (ACE) inhibitor, which has been used clinically in the treatment of hypertension, chronic congestive heart failure (CHF), acute myocardial infarction (AMI), and diabetic nephropathy. It has the unique advantage over other ACE inhibitors in causing a lower incidence of dry cough. After oral administration, imidapril is rapidly converted in the liver to its active metabolite imidaprilat. The plasma levels of imidaprilat gradually increase in proportion to the dose, and decline slowly. The time to reach the maximum plasma concentration (T(max)) is 2.0 h for imidapril and 9.3 h for imidaprilat. The elimination half-lives (t(1/2)) of imidapril and imidaprilat is 1.7 and 14.8 h, respectively. Imidapril and its metabolites are excreted chiefly in the urine. As an ACE inhibitor, imidaprilat is as potent as enalaprilat, an active metabolite of enalapril, and about twice as potent as captopril. In patients with hypertension, blood pressure was still decreased at 24 h after imidapril administration. The antihypertensive effect of imidapril was dose-dependent. The maximal reduction of blood pressure and plasma ACE was achieved with imidapril, 10 mg once daily, and the additional effect was not prominent with higher doses. When administered to patients with AMI, imidapril improved left ventricular ejection fraction and reduced plasma brain natriuretic peptide (BNP) levels. In patients with mild-to-moderate CHF [New York Heart Association (NYHA) functional class II-III], imidapril increased exercise time and physical working capacity and decreased plasma atrial natriuretic peptide (ANP) and BNP levels in a dose-related manner. In patients with diabetic nephropathy, imidapril decreased urinary albumin excretion. Interestingly, imidapril improved asymptomatic dysphagia in patients with a history of stroke. In the same patients it increased serum substance P levels, while the angiotensin II receptor antagonist losartan was ineffective. These studies indicate that imidapril is a versatile ACE inhibitor. In addition to its effectiveness in the treatment of hypertension, CHF, and AMI, imidapril has beneficial effects in the treatment of diabetic nephropathy and asymptomatic dysphagia. Good tissue penetration and inhibition of tissue ACE by imidapril contributes to its effectiveness in preventing cardiovascular complications of hypertension. The major advantages of imidapril are its activity in the treatment of various cardiovascular diseases and lower incidence of cough compared with some of the older ACE inhibitors.
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PMID:Protection of the cardiovascular system by imidapril, a versatile angiotensin-converting enzyme inhibitor. 1217 88


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