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The prevalence of orthostatic hypotension (OH) in hypertensive patients ranges from 3 to 26%. Drugs are a common cause of non-neurogenic OH. In the present study, we retrospectively evaluated the medical records of 9242 patients with essential hypertension referred to our Hypertension Unit. We analysed data on supine and standing blood pressure values, age, sex, severity of hypertension and therapeutic associations of drugs, commonly used in the treatment of hypertension. OH was present in 957 patients (10.4%). Drug combinations including α-blockers, centrally acting drugs, non-dihydropyridine calcium-channel blockers and diuretics were associated with OH. These pharmacological associations must be administered with caution, especially in hypertensive patients at high risk of OH (elderly or with severe and uncontrolled hypertension). Angiotensin-receptor blocker (ARB) seems to be not related with OH and may have a potential protective effect on the development of OH. [ABSTRACT FROM AUTHOR]

In the present study, we tested the hypothesis that up-titrating the dose of an angiotensin receptor blocker (ARB) is superior to combined treatment with an ARB and a calcium channel blocker for the same degree of blood pressure (BP) reduction, with respect to urinary albumin excretion in diabetic patients treated with a standard dose of the ARB. Hypertensive patients with type 2 diabetes mellitus and albuminuria (30 mg g−1 creatinine) were enroled in the study, and were either started on or switched to candesartan (8 mg per day) monotherapy. After a 12-week run-in period, baseline evaluations were performed and patients with BP 130/80 mm Hg were randomly assigned to receive either candesartan (12 mg per day) or candesartan (8 mg per day) plus amlodipine (2.5 mg per day) for a further 12 weeks. The primary end-point was a reduction in urinary albumin levels. Although there was no significant difference in the BP reduction between the two groups, the reduction in urinary albumin was greater in the up-titrated than the combination therapy group (−40±14% vs −9±38%, respectively; P<0.0001). Thus, up-titration of candesartan more effectively reduces urinary albumin excretion than combined candesartan plus amlodipine in hypertensive patients with diabetes for the same degree of BP reduction. [ABSTRACT FROM AUTHOR]

This prospective, 6-week, multicenter, double-blind study examined the benefits of initiating treatment with combination valsartan/hydrochlorothiazide (HCTZ) compared with initial valsartan monotherapy for 648 patients with stage-1 or stage-2 hypertension (age=52.6±10 years; 54% male; baseline blood pressure (BP)=161/98 mm Hg, 32% stage 1). Patients were randomized to valsartan 80 mg (V-low), valsartan 160 mg (V-high) or valsartan/HCTZ 160/12.5 mg (V/HCTZ), and electively titrated after weeks 2 and 4 to the next dosage level (maximum dose valsartan/HCTZ 160/25 mg) if BP remained >140/90 mm Hg. At end of the study, patients initiated with V/HCTZ required less titration steps compared with the initial valsartan monotherapy groups (63 vs 86% required titration by study end, respectively) and reached the target BP goal of <140/90 mm Hg in a shorter period of time (2.8 weeks) (P<0.0001) vs V-low (4.3 weeks) and V-high (3.9 weeks). Initial combination therapy was also associated with higher BP control rates and greater reductions in both systolic and diastolic BP from baseline (63%, −27.7±13/–15.1±8 mm Hg) compared with V-low (46%, −21.2±13/−11.4±8 mm Hg, P<0.0001) or V-high (51%, −24.0±13/−12.0±10 mm Hg, P<0.01). Overall and drug-related AEs were mild to moderate and were similar between V/HCTZ (53.1 and 14.1%, respectively) and the two monotherapy groups, V-low (50.5 and 13.8%) and V-high (50.7 and 11.8%). In conclusion, initiating therapy with a combination of valsartan and low-dose HCTZ results in early, improved BP efficacy with similar tolerability as compared with starting treatment with a low or higher dose of valsartan for patients with stage-1 and stage-2 hypertension. [ABSTRACT FROM AUTHOR]

A clear relationship exists between elevated blood pressure (BP) and various manifestations of cardiovascular disease. Despite the availability of numerous treatment guidelines, hypertension remains inadequately controlled, with only a small proportion of patients achieving target BP levels. Many factors, both patient and physician related, contribute to this poor level of hypertension control. Major determinants include the implementation of inappropriate treatment regimens that do not enable patients to achieve goal and poor patient compliance. For example, it is widely acknowledged that most patients require two or more antihypertensive drugs to achieve BP goal; however, physicians may be reluctant to employ such treatment strategies. The aim of this review is to explore factors that contribute to poor hypertension control rates and how to overcome these, including the rationale for selecting combination therapy, with particular reference to angiotensin II receptor blocker combinations.Journal of Human Hypertension (2006) 20, 841–849. doi:10.1038/sj.jhh.1002079; published online 10 August 2006 [ABSTRACT FROM AUTHOR]

We aimed to compare the effects of two different vasodilating principles, angiotensin II-receptor blockade and calcium channel blockade, on peripheral insulin-mediated glucose uptake in patients with hypertension and other cardiovascular risk factors. Twenty-one hypertensive patients (11 women and 10 men) with mean age 58.6 years (range 46–75 years), body mass index 29.2±1.0 kg/m2 and blood pressure 160±3/96±2 mm Hg entered a 4-week run-in period with open-label amlodipine 5 mg. Thereafter they were randomized double-blindly to additional treatment with amlodipine 5 mg or losartan 100 mg. After 8 weeks of treatment, all patients underwent clinical examination and laboratory testing, and 17 of them underwent a hyperinsulinaemic isoglycaemic glucose clamp. After a 4-week open-label wash-out phase, the participants crossed over to the opposite treatment regimen and final examinations with hyperinsulinaemic isoglycaemic glucose clamp after another 8 weeks. Blood pressure was lowered to the same level in both treatment periods. The glucose disposal rate was significantly higher after treatment with losartan 100 mg+amlodipine 5 mg compared to amlodipine 10 mg (4.9±0.4 vs 4.2±0.5 mg/kg/min, P=0.039). Thus our data suggest that angiotensin II-receptor blockade with losartan improves glucose metabolism at the cellular level beyond what can be expected by the vasodilatation and blood pressure reduction alone.Journal of Human Hypertension (2006) 20, 860–866. doi:10.1038/sj.jhh.1002087; published online 21 September 2006 [ABSTRACT FROM AUTHOR]

In patients with severe hypertension, chronic heart failure or a history of stroke, the lower limit of autoregulation of cerebral blood flow (CBF) is shifted to higher levels of blood pressure (BP) than those observed in healthy subjects. The aim of pharmacotherapy for hypertensive patients with an impaired autoregulation of CBF should be to reduce BP while preserving an appropriate CBF. In the present study, 16 hypertensive patients who had had an episode of stroke more than 4 weeks previously were administered the angiotensin II (AT1) receptor antagonist losartan at daily doses of 25-100?mg for 4 weeks. Systolic and diastolic blood pressures were recorded for 24?h using an ambulatory BP monitoring system. CBF in both hemispheres of the cerebrum and cerebellum was quantified using single photon emission tomography with N-isopropyl-p-[123I]iodoamphetamine. At baseline, CBF was 29.7±6.7?ml/min/100?g in the cerebrum and 31.5±7.5?ml/min/100?g in the cerebellum. At the end of treatment, BP was lower, while CBF increased by 7.7%in the cerebrum, and remained at the baseline level in the cerebellum. Thus, CBF was preserved despite the reduction in BP. We consider the use of losartan is advantageous for hypertensive patients with a history of stroke in whom autoregulation of CBF is potentially impaired.Journal of Human Hypertension (2004) 18, 693-699. doi:10.1038/sj.jhh.1001735 Published online 6 May 2004 [ABSTRACT FROM AUTHOR]

The aim of this study was to compare the effect of the beta-adrenergic blocker atenolol and the Angiotensin II type 1 (AT1) receptor antagonist losartan on cognitive function in very elderly hypertensive patients. A total of 120 mild to moderate essential hypertensive (DBP >90 and <105?mmHg) patients, aged 75-89 years, were studied. After a 4-week wash-out period on placebo, they were randomized to receive atenolol 50?mg or losartan 50?mg for 24 weeks according to a parallel arm design. At the end of the placebo period and of each active treatment period, BP was measured (by mercury sphygmomanometer, Korotkoff I and V) and cognitive function was evaluated through three different tests (word list memory, word list recall and word list fluency). Both atenolol and losartan were equally effective in reducing SBP (-22.1 and -23.1?mmHg, respectively, P< 0.01 vs baseline) and DBP (-10.3 and -11.2?mmHg, respectively, P< 0.01 vs baseline). Atenolol treatment did not induce significant changes in any test score, whereas losartan significantly increased the score of both the word list memory (+2.2, P<0.05 vs baseline) and the word list recall test (+2.1, P<0.05 vs baseline). The comparison between losartan and atenolol was significant (P<0.05) for both memory tests. These data suggest that in very elderly hypertensive patients, chronic AT1 receptor blockade by losartan could improve cognitive function, in particular immediate and delayed memory.Journal of Human Hypertension (2003) 17, 781-785. doi:10.1038/sj.jhh.1001613 [ABSTRACT FROM AUTHOR]

Objective: Angiotensin-converting enzyme (ACE) inhibitors have beneficial effects on arterial compliance and distensibility and favourably modify the arterial pressure waveform in hypertensive patients. The objective of our study was to explore the possible effects of adding an ATII AT[SUB1] (receptor antagonist to an ACE inhibitor on augmentation pressure, a measure of arterial stiffness, and pulse pressure amplification in patients with poorly controlled essential hypertension. Design and methods: We studied a group of 18 patients with poorly controlled hypertension, despite at least three antihypertensive drugs including an ACE inhibitor, before, at 2 h and 2 weeks following the administration of 80 mg of valsartan, an ATII AT[SUB1] receptor antagonist. Haemodynamic responses were measured by cuff sphygmomanometry, arterial pulse-wave analysis and the pulse pressure gradient was calculated as the difference between the brachial pulse pressure (cuff sphygmomanometry) and derived aortic pulse pressure (arterial pulse wave analysis). Results: Blood pressure decreased significantly (P < 0.001) and the effect was more pronounced on central (aortic) pulse pressure than peripheral (brachial) pulse pressure. The pulse pressure amplification increased significantly (from 8 ± 3 at baseline vs 12 ± 7 at 2 h to 14 ± 5 mm Hg at 2 weeks, P < 0.01) and the augmentation pressure decreased from a baseline value of 21 ± 8 to 11 ± 7 at 2 h and 10 ± 5 at 2 weeks, (P < 0.01) following valsartan. Conclusion: The results of our study show that in a group of poorly controlled hypertensives, combining an (ATII AT[SUB1] receptor blocker to an ACE inhibitor induced a significant fall in blood pressure. The decrease in blood pressure was accompanied by a decrease in augmentation pressure in the ascending aorta with a greater decrease in the central pulse pressure than in the peripheral, favourably increasing pulse pressure amplification between... [ABSTRACT FROM AUTHOR]

The objective of this study was to compare the effects of the angiotensin II (ang II) antagonist, losartan and the angiotensin-converting enzyme inhibitor (ACEI), enalapril on haemorheology. Twenty-nine patients with renal parenchymal disease and hypertension were enrolled in the prospective, open, parallel study that involved a 14-day washout period followed by a 120-day treatment period. Patients were allocated randomly to receive either losartan 50-100 mg/day (n = 15) or enalapril 2.5-10 mg/day (n = 14) to achieve blood pressure control <140/90 mm Hg. Blood pressure, haemorheology profile and plasma fibrinogen concentration were measured after the washout phase and after 2, 10, 60, and 120 days of treatment. The data were analysed using ANOVA with repeated measures. Twenty-seven patients completed the study. Treatment with both losartan and enalapril was associated with a significant decrease (P < 0.05) in relative high shear rate whole blood viscosity, indicating an increase in blood cell deformability. In patients taking losartan, the increase in blood cell deformability did not result in a decrease in mean whole blood viscosity due to a concomitant, significant increase in mean plasma viscosity (P < 0.01). In contrast, the improved cell deformability in patients treated with enalapril resulted in a small and statistically insignificant decrease in mean whole blood viscosity (P = 0.06; mean change = -0.15 mPa sec). The mechanism of the increase in blood cell deformability and the rise in plasma viscosity associated with losartan remain unclear. It is possible but unproven that the improvement in intrinsic blood cell rheology with losartan and enalapril may be the result of changes in cation transport systems and/or the consequence of the protective antioxidant properties of drug metabolites. [ABSTRACT FROM AUTHOR]

The objective of this study was to undertake a post-marketing safety surveillance study of losartan, the first specific angiotensin-II receptor antagonist to be marketed in England. It is a non-interventional observational cohort study using the technique of prescription-event monitoring. Subjects who took part in the study were from 14 522 patients treated by general practitioners in England. We recorded adverse drug reactions, adverse events, reasons for stopping the drug, pregnancies and deaths. The results were that general practitioners considered the drug to have been effective in 85.9% of the patients evaluated for effectiveness. Dizziness, malaise, lassitude, nausea, cough and headache were among the most frequently reported adverse drug reactions, reasons for stopping the drug and events of highest incidence density. None of the deaths that occurred were attributed to losartan and no serious unexpected adverse reactions or interactions were identified. In conclusion losartan has an acceptable safety profile and the study confirms the safety information given in the current Summary of Product characteristics for losartan. [ABSTRACT FROM AUTHOR]

The effects of a new angiotensin receptor antagonist, eprosartan (200 or 300 mg b.i.d.) and enalapril (5-20 mg u.i.d.) on cough and blood pressure were compared in a 26-week, double-blind, randomised, parallel-group, multicentre, international study involving 528 patients with hypertension. Uptitration of doses was based on clinic blood pressure measurements during the first 12 weeks, after which hydrochlorothiazide (12.5-25 mg/day) could be added. The frequency and intensity of cough was assessed by a standardised questionnaire administered at each clinic visit. The primary end-point was the incidence of persistent, dry cough not due to upper respiratory infection; change in sitting diastolic blood pressure and overall incidence of cough were secondary end-points. During the first 12 weeks of double-blind therapy, enalapril treatment was associated with a 3.45-fold higher risk of definite cough (14/261 vs 4/259, P = 0.018). Overall cough incidence (from spontaneous reports from patients, or investigator's observation) was also more frequent with enalapril, as compared to eprosartan. Both agents reduced blood pressure significantly compared to baseline, although the eprosartan-treated group had a slightly higher response rate (defined as sitting diastolic blood pressure <90 mm Hg, or at least a 10 mm Hg reduction from baseline), both at end of titration (70.3% vs 62.6%, P < 0.05) and after 26 weeks (81.7% vs 73.5%, P = 0.018). These data suggest that, in unselected hypertensive patients, eprosartan is associated with less cough and a somewhat higher responder rate than enalapril. [ABSTRACT FROM AUTHOR]

Objective: This study compares the antihypertensive efficacy and tolerability of valsartan, a novel angiotensin II antagonist, given with hydrochlorothiazide (HCTZ) vs placebo or vs valsartan or HCTZ alone. Design: 871 adult out-patients with essential hypertension participated in this double-blind study. Patients were randomised in equal number to receive either combination therapy of valsartan (80 mg or 160 mg) and HCTZ (12.5 mg or 25 mg), or valsartan (80 mg or 160 mg) or HCTZ (12.5 mg or 25 mg) alone, or placebo. Patients were treated once daily for 8 weeks and assessed at 2, 4 and 8 weeks after randomisation. Main outcome measures: The primary efficacy variable was change from baseline in mean sitting diastolic blood pressure (MSDBP) at end-point. The secondary variable was change in mean sitting systolic blood pressure (MSSBP) from baseline to end-point. Results: All active treatments produced a statistically significant difference in MSDBP (P < 0.001) from baseline to end-point compared with placebo. Similar results were obtained for MSSBP. All combination regimens produced a statistically significantly greater reduction in MSDPB and MSSBP than the corresponding mono-therapies. Dizziness and headache were the most common treatment-related adverse experiences reported. Hypokalaemia, associated with the use of thiazide diuretics, was more commonly reported in the higher dose HCTZ 25 mg groups. Conclusions: Valsartan 80 mg and 160 mg act additively with HCTZ 12.5 mg or 25 mg to lower MSDBP and MSSBP in patients with essential hypertension. The addition of HCTZ to valsartan 80 mg or 160 mg was well tolerated. [ABSTRACT FROM AUTHOR]

We conducted a randomised, double-blind, parallel design study comparing the efficacy and tolerability of the angiotensin II receptor antagonist, losartan, alone or with low-dose hydrochlorothiazide (HCTZ) to the dihyd-ropyridine calcium channel blocker, nifedipine GITS (gastro-intestinal therapeutic system), in elderly patients (≥ 65 years old) with a diastolic blood pressure (DBP) between 95 and 115 mm Hg. After a placebo wash out period, 140 patients were randomly assigned to receive either losartan 50 mg or nifedipine GITS 30 mg. Patients were evaluated at 4-week intervals during a 12-week treatment period. Patients receiving losartan had HCTZ 12.5 mg added and increased to 25 mg to reduce DBP < 90 mm Hg. Patients receiving nifedipine GITS had their dose increased to 60 mg and 90 mg to reduce DBP < 90 mm Hg. Efficacy, tolerability and quality of life were assessed during the 12 weeks on each regimen. Patients treated with the losartan regimen (n = 73) had reductions in trough sitting DBP of -10, -13, and -13 mm Hg after 4, 8, and 12 weeks of therapy, respectively. Patients receiving the nifedipine GITS regimen (n = 67) had DBP reductions of -14, -15, and -15 mm Hg, respectively. There were no significant differences in the DBP response between the treatment groups except at week 4 (P < 0.05). Similar reductions in systolic BP (SBP) between the two treatment groups were observed at all time points. The percentages of patients in the two treatment groups reaching goal DBP (< 90 mm Hg or DBP >90 mm Hg with a reduction from a baseline of ≥10 mm Hg) were comparable (81% on the losartan regimen and 90% on the nifedipine GITS regimen). There were significantly more adverse events reported in patients receiving nifedipine GITS when compared to the losar-tan regimen (54% vs 36%, P < 0.05). A patient-reported symptom inventory also showed that swollen ankles was bothersome in significantly more patients treated with the nifedipine GITS regimen... [ABSTRACT FROM AUTHOR]

The aim of this study was to evaluate the efficacy and tolerability of valsartan, a new angiotensin II receptor antagonist, versus atenolol in the treatment of severe primary hypertension. A total of 103 adult out-patients were randomised to receive either valsartan 160 mg or atenolol 100 mg once daily for 6 weeks. If necessary, additional blood pressure (BP) control could be provided as add-on therapy. Both valsartan and atenolol decreased mean sitting diastolic BP (DBP) and mean sitting systolic BP (SBP): least squares mean change from baseline in DBP; valsartan, -20.0 mm Hg; atenolol, - 20.4 mm Hg: in SBP; valsartan, -30.0 mm Hg; atenolol, -25.5 mm Hg. There was no statistically significant difference between the treatment groups. Add-on hydrochlorothiazide (HCTZ) 25 mg was required by 97.2% of patients receiving atenolol and 83.6% of patients receiving valsartan; additional verapamil SR 240 mg was also required by 58.3% of patients receiving atenolol and 64.2% receiving valsartan. Valsartan was well tolerated, with a comparable incidence of treatment-related adverse experiences in both groups. In conclusion valsartan 160 mg is as well tolerated and effective as atenolol 100 mg in lowering BP in severely hypertensive patients. [ABSTRACT FROM AUTHOR]

The SILVER (Study of Irbesartan in Left VEntricular hypertrophy Regression) trial is designed to test the hypothesis that the newly developed angiontensin-II receptor antagonist, irbesartan, will produce a greater reduction in left ventricular (LV) mass than felodipine ER, in a population of hypertensive patients defined by seated diastolic blood pressure (SeDBP) in the range 95-115 mm Hg or seated systolic blood pressure (SeSBP) in the range 160-200 mm Hg. A population of 360 men and women of non-childbearing potential, >18 years of age, with hypertension, newly diagnosed or after a 3-week washout from previous anti-hypertensive or vasodilator therapies, will be randomised at approximately 80-90 European sites. Add-on therapy with hydrochlorothiazide and atenolol will be allowed for blood pressure control. Patients will be studied by two-dimensional and M-mode echocardiography at baseline (central validation of LV hypertrophy), on randomisation day, and after 6 and 12 months randomised therapy. Blinded analysis of echocardiograms will be performed at a central laboratory, which will provide measurements of the LV mass index (LVMI), determined by M-mode readings according to Devereux formula and using the Penn convention. The primary end-point of the study will be the change in LVMI from baseline to 12 months. The study power is 90% to detect differences between groups from baseline of approximately 8 g/m[SUP2]. [ABSTRACT FROM AUTHOR]

Candesartan is a new generation angiotensin II type 1 receptor blocker, characterised by tight binding to and slow dissociation from the receptor. In order to delineate the dose-response curve for candesartan cilexetil (the orally administered prodrug), results from six European placebo-controlled, dose-response studies were pooled. These were of a double-blind, randomised, parallel group design, with a treatment duration of 4-12 weeks. A total of 1482 patients with mild to moderate primary hypertension were treated with candesartan cilexetil 2 mg (n = 80), 4 mg (n = 216), 8 mg (n = 455) or 16 mg (n = 294), or with placebo (n = 437). Blood pressure (BP) measurements were performed 24 h after dose. The differences in BP change (baseline vs end of the studies) between the placebo group and the groups treated with candesartan cilexetil were assessed using analysis of covariance and dose response curves were estimated by fitting the data to an Emax model. The placebo-corrected mean reductions in sitting diastolic BP were approximately 2.5 mm Hg with 2 mg, 4.5 mm Hg with 4 mg, 6 mm Hg with 8 mg, and 8 mm Hg with 16 mg of candesartan cilexetil. For sitting systolic BP, the placebo-corrected mean reductions were in the order of 5, 7, 10 and 12 mm Hg, respectively, with 2, 4, 8 and 16 mg of candesartan cilexetil. The BP reductions were similar in the standing position with no indication of postural hypotension. Age or gender did not influence the BP response to candesartan cilexetil. In conclusion, candesartan cilexetil provides a clinically significant, dose-dependent antihypertensive effect in doses ranging from 4-16 mg once daily. [ABSTRACT FROM AUTHOR]

The article discusses the efficacy of angiotensin II antagonists in antihypertensive treatment. Clinical tests have found that angiotensin II antagonists can possibly achieve a greater degree of specificity in blocking the renin angiotensin system. It was also found with arterial hypertension do not demonstrate conclusively that angiotensin II antagonists are more effective than angiotensin-converting enzyme inhibitors at the dosages usually used.

Comments on the effects of antihypertensive agents on fibrinolytic function, which plays an important role in preventing intravascular thrombosis. Process of fibrinolysis; Study by Mugellini et al on the different effect of two combinations of recognized antihypertensive agents; Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor antagonists.

The article cites a study which quantitatively compared in vivo and ex vivo angiotensin II antagonist properties of candesartan cilexetil, an orally administered drug, with those of losartan after single and repeated doses in healthy human volunteers. The study found that plasma pharmacokinetics of candesartan and losartan on Day 1 and Day 8 are almost identical.

A letter to the editor is presented in response to the article "Effect of the angiotensin II receptor antagonist olmesartan on morning home blood pressure in hypertension: HONEST Study at 16 weeks" by K. Kario, I. Saito, T. Kushiro, S. Teramukai, Y. Ishikawa and K. Hiramatsu in the previous issue.

Comments on studies involving the effect of angiotensin II receptor antagonists on hypertensive stroke patients. Treatment with angiotensin converting enzyme inhibitor to normalize dysautoregulation of cerebral circulation; Evaluation of acute candesartan cilexetil therapy in stroke survivors.

A letter to the editor is presented in response to the article "Effect of the angiotensin II receptor antagonist olmesartan on morning home blood pressure in hypertension: HONEST study at 16 weeks" by K. Kario, I. Saito, T. Kushiro, S. Teramukai, K. Hiramatsu and F. Kobayashi in the previous issue.

Comments on the study titled 'Evaluation of Losarton in the Elderly' conducted to evaluate the effect of angiotensin II receptor antagonists, losarton and captopril, on heart failure. Criticism over the use of captopril in the study; Questions raised by the study.

Angiotensin II receptor antagonists (AT-1) represent a new group of orally active anti-hypertensive agents. Activation on AT-1 receptor leads to vasoconstriction, stimulation of the release of catecholamines and anti-diuretic hormone with production of thirst, and promote growth of vascular and cardiac muscle; these effects are blocked by AT-1 antagonist agents. The first chemically useful, orally active AT-1 receptor antagonist was losartan, followed by other agents currently in clinical use, such as: valsartan, eprosartan, irbesartan, telmisartan, candesartan, and many others under investigation. AT-1 receptor antagonists are effective in reducing high blood pressure in hypertensive patients. Monotherapy in mild to moderate hypertension controls blood pressure in 40 to 50% of these patients; when a low dose of a thiazide diuretic is added, 60 to 70% of patients are controlled. The efficacy is similar to angiotensin-converting enzyme inhibitors, diuretics, calcium antagonists and beta-blocking agents. Tolerability has been reported to be very good. AT-1 receptor antagonists would be a drug of choice in otherwise well-controlled hypertensive patients treated with angiotensin-converting enzyme inhibitors who developed cough or angioedema. The final position in the anti-hypertensive therapy in this special population and other clinical situations, such as left ventricular hypertrophy, heart failure, diabetes mellitus and renal disease, has to be determined in large prospective clinical trials, some of which are now being conducted. [ABSTRACT FROM AUTHOR]

Angiotensin II receptor blockers (ARBs) represent a new class of effective and well tolerated orally active antihy-pertensive 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 (AT)1 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, angi-otensin-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 anti-hypertensive 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... [ABSTRACT FROM AUTHOR]

Presents author's remarks at the beginning of a symposium entitled 'Angiotensin II Receptor Antagonists,' held at Amsterdam, Netherlands on June 6, 1998. Objective behind initiating such a symposium; Discussion of research reports by eminent clinicians and researchers on the clinical usage of angiotensin II receptor antagonists in the symposium; Highlights of all the three sessions of the symposium.

There is now abundant evidence that treatment with angiotensin-converting enzyme inhibitors (ACE-I) ameliorates the progression of chronic renal disease. Attention has therefore focused on the role of the renin angiotensin-aldosterone (RAA) system in mediating the development of progressive glomerulosclerosis and angiotensin II (Ang II) has been implicated in several processes thought to be important in the pathogenesis of this entity. Conversely, ACE is also known to catalyse the breakdown of bradykinin. Thus, ACE-I treatment results in elevated bradykinin levels which may cause selective efferent arteriolar dilatation, suggesting an alternative explanation for the beneficial effects of this class of drugs in chronic renal disease. The development of specific angiotensin type 1 receptor antagonists (AT[sub1]RA) has provided a means of testing the relative importance of these two mechanisms. In addition, AT[sub1]RAs differ from ACE-I in their effect on the RAA system in other aspects which may represent therapeutic advantages. This paper reviews studies which have compared ACE-I and AT[sub1]RAs in several rat models of chronic renal disease. Most have found similar beneficial effects including amelioration of proteinuria and glomerulosclerosis, which suggests that the effects of ACE-I are due to a reduction in Ang II activity and not due to increased levels of bradykinin. One long-term study has suggested greater renal protection with candesartan than with enalapril. However, conclusions as regards the relative efficacy of these two groups of agents in ameliorating the progression of chronic renal disease await the results of further long-term studies. [ABSTRACT FROM AUTHOR]

We have investigated the influence of a novel angiotensin II type 1 receptor antagonist, candesartan cilexetil, on the oxidative state of renal tissue and renal function in 5/6 nephrectomized rats, and compared its effects with those of an angiotensin-converting enzyme inhibitor, enalapril. Candesartan cilexetil (1 and 5 mg/kg per day), enalapril (5 mg/kg per day) and vehicle were orally administered once daily for 16 weeks after 5/6 nephrectomy. There was a marked degree of proteinuria evident prior to treatment, an average of 5.69 mg/mg creatinine in the nephrectomized rats, vs 1 to 2 mg/mg creatinine in the control group matched for species and body weight. Inhibition of development of proteinuria by candesartan cilexetil was dose dependent. Enalapril also significantly blunted the rise in urinary protein. Malondialdehyde content in the homogenate from the renal cortex increased significantly in the nephrectomized rats compared to control animals. This elevation of malondialdehyde content was unaffected by administration of either candesartan cilexetil or enalapril. Antioxidative enzyme (glutathione peroxidase, superoxide dismutase, and catalase) activities in the renal tissue were not affected by any active treatment. Elevation of lipid peroxide in remnant renal tissue suggests that oxidative stress may contribute to the progression of renal injury in the nephrectomized rats. Neither candesartan cilexetil nor enalapril affected antioxidant defenses in renal tissue in nephrectomized rats, indicating that mechanisms other than alteration in oxidative stress are involved in the renoprotective effects of candesartan cilexetil and enalapril. [ABSTRACT FROM AUTHOR]

Angiotensin II (Ang II) has diverse physiological actions leading, for example, to increases in extracellular volume, peripheral vascular resistance and blood pressure, and has also been implicated in the regulation of cell growth and differentiation. Molecular cloning and pharmacological studies have defined two major classes of Ang II receptors, designated as AT[sub1] and AT[sub2]. Most effects of Ang II are mediated by AT[sub1] receptors. Much less is known about the physiological role of AT[sub2] receptors. Recent evidence suggests involvement of AT[sub2] receptors in development, cell differentiation, apoptosis and regeneration in various tissues. AT[sub1] and AT[sub2] receptors have been shown to exert counteracting effects on cellular growth and differentiation, vascular tone and the release of arginine vasopressin (AVP). In each condition the AT[sub2] receptor appears to down-modulate actions mediated by the AT[sub1] receptor, resulting in decreased cellular proliferation, decreased levels of serum AVP levels or decreased vasoconstrictor responses. In addition, in neuronal cell lines, the AT[sub2] receptor reportedly exerts antiproliferative effects and promotes neurite outgrowth, an effect accompanied by significant changes in the gene expression pattern of growth- and differentiation-related genes. [ABSTRACT FROM AUTHOR]

Presents excerpts from a discussion among professors of different universities on approaches that can be used in hypertension management. Duration of elevation of angiotensin II-receptor antagonists that are associated with an increase in angiotensin II; Differences in activities of angiotensin converted enzyme and chymase in carotid and femoral artery.

Part I. Presents excerpts from a discussion among professors on the role of angiotensin converted enzymes in the inhibition of cardiomyocyte hypertrophy and fibroblast proliferation. Suggestions for dual inhibition of myocyte hypertrophy and fibroblast hyperplasia; Genetic aspects of renin-angiotensin system receptors; Physiological changes brought out by angiotensin II antagonists.

In an in vivo study, spontaneously hypertensive rats (SHR) were treated with an angiotensin II (Ang II) type 1 receptor antagonist of candesartan or hydralazine. Untreated SHR progressively developed severe hypertension, and treatment with candesartan or hydralazine decreased blood pressure. Candesartan reduced left ventricular (LV) weight, LV wall thickness, transverse myocyte diameter, the relative amount of V3 myosin heavy chain, and interstitial fibrosis, while treatment with hydralazine slightly prevented an increase in LV wall thickness, but did not exert a significant reduction on other parameters. In an in vitro study, neonatal rat cardiomyocytes were cultured on deformable silicone dishes. Stretching cardiomyocytes activated second messengers such as protein kinase C, Raf-1 kinase, and mitogen-activated protein (MAP) kinase, increasing protein synthesis, enhancing endothelin (ET)-1 release, activating the Na[sup+]/H[sup+] ion exchanger. Moreover, pretreatment with candesartan diminished an increase in phenylalanine incorporation, MAP kinase activity, and c-fos gene expression induced by the stretching of cardiomyocytes. This suggests that the cardiac renin-angiotensin system is linked to the formation of pressure-overload hypertrophy and that Ang II increases the growth of cardiomyocytes by an autocrine mechanism. Finally, we examined the signalling pathways leading to MAP kinase activation both in cardiac myocytes and in cardiac fibroblasts. Ang II-evoked signal transduction pathways differed between cell types. In cardiac fibroblasts, Ang II activated MAP kinase through a pathway including the Gβγ subunit of Gi protein, Src, Shc, Grb2, and Ras, while Gq and protein kinase C were important in cardiac myocytes. [ABSTRACT FROM AUTHOR]

Candesartan (8 mg/d) was administered for 2 weeks to eight patients with essential hypertension to investigate the effect of an angiotensin II receptor antagonist on insulin sensitivity. The effect of candesartan on sodium-retaining action and the activation of pressor systems by hyperinsulinaemia, which might be related to pressor mechanisms in essential hypertension, was also investigated in this study. In patients with essential hypertension, candesartan restored insulin sensitivity to the level of that in normotensive subjects. Candesartan treatment attenuated the sodium-retaining action of hyperinsulinaemia. These findings suggest that inhibition of angiotensin II action by candesartan can improve insulin sensitivity and inhibit the sodium-retaining action associated with hyperinsulinaemia in essential hypertension. [ABSTRACT FROM AUTHOR]

Candesartan cilexetil has shown potent and long-lasting antihypertensive effects in clinical trials and in several animal models of hypertension. In spontaneously hypertensive rats, the duration of the antihypertensive effect of candesartan cilexetil was compared to those of losartan, valsartan, eprosartan, and irbesartan at the same degree of maximal blood pressure reduction. A single oral dose of candesartan cilexetil at 0.3 mg/kg reduced maximal blood pressure by about 25 mm Hg, and the antihypertensive effect of candesartan cilexetil lasted the longest, continuing for more than 1 week, without an effect on circadian rhythm. In a rabbit aortic preparation, candesartan, active form of candesartan cilexetil, decreased the maximal contractile response of angiotensin II. This inhibitory mode was different from that of other angiotensin II-receptor antagonists, and showed a shift to the right in the angiotensin II-induced contraction curve and/or a small depression of the maximal response. In kinetic studies using bovine adrenal cortical membrane and tritiated candesartan, both receptor association and dissociation were found to be slow. The dissociation rate of tritiated candesartan binding (t[sub1/2] = 66 min) was five times slower than that of radiolabelled angiotensin II binding (t[sub1/2] = 12 min). The insurmountable inhibition of candesartan in vascular contraction is the result of its tight binding and slow dissociation from angiotensin II AT[sub1] receptors. These characteristics are related to the potency and long duration of action in candesartan cilexetil. [ABSTRACT FROM AUTHOR]

The roles of angiotensin (Ang) II as produced by two different enzymes, angiotensin-converting enzyme (ACE) and chymase, were investigated in a canine experimental model where intima hyperplasia was induced by balloon catheterization in the common carotid and femoral arteries. The animals received oral candesartan cilexetil (3 mg/kg) or enalapril (10 mg/kg) twice a day for 5 weeks. After 1 week of active drug therapy, the common carotid and femoral arteries were unilaterally injured by balloon catheterization. In the common carotid arteries, both ACE and chymase activities were increased by the injury, with the increase in chymase activities being greater than that in ACE activities. In the femoral arteries, ACE, but not chymase, activities were significantly increased by the injury. Both candesartan cilexetil and enalapril reduced blood pressure almost equally. Enalapril increased plasma renin activity more strongly than did candesartan cilexetil, and significantly decreased vascular and plasma ACE activities. Candesartan cilexetil significantly suppressed the formation of intima hyperplasia in both the carotid and femoral arteries, while enalapril significantly suppressed intima hyperplasia in the femoral, but not in the carotid arteries. These results indicate that local Ang II production by ACE and chymase is involved in the hyperplasia seen in injured intima, and the difference in the inhibitory action of candesartan and enalapril reflects the extent of contribution of each enzyme. The effect of the ACE inhibitor, enalapril, depended on the activity of ACE, whereas that of the Ang II receptor antagonist, candesartan, was independent of ACE activity. [ABSTRACT FROM AUTHOR]

Presents author's remarks at the end of a symposium entitled 'Angiotensin II Receptor Antagonists,' held at Amsterdam, Netherlands on June 6, 1998. Review of pre-clinical data about candesartan; Overview of angiotensin converting enzymes versus angiotensin II receptor antagonists; Presentation of a report on the importance of angiotensin II receptor antagonists.

Angiotensin I-converting enzyme (ACE) inhibitors are commonly used for the treatment of hypertension, progressive chronic renal disease, diabetic nephropathy, and congestive heart failure. Because angiotensin II acts through membrane bound type 1 (AT[sub1]) and type 2 (AT[sub2]) receptors, ACE inhibitors and angiotensin II-receptor antagonists have distinct effects. ACE inhibitors inhibit production of angiotensin II thus suppressing the action of angiotensin II on both AT[sub1] and AT[sub2]. In contrast, the effect of AT[sub1]-receptor antagonists is to selectively block the activation of the AT[sub1] receptor. This AT[sub1]-receptor blockade leaves the AT[sub2] receptors unopposed to elevated levels of endogenous angiotensin II. Thus, there may be an advantage of AT[sub1]-receptor blockade over ACE inhibition in the management of a variety of chronic vascular diseases, including chronic glomerulonephritis and other glomerular diseases. In a clinical trial candesartan, an AT[sub1]-receptor antagonist, effectively lowered urinary protein excretion in patients with chronic glomerular nephritis. Evidence indicates that functionally active AT[sub1] receptors, as well as AT[sub2] receptors, are present in both afferent and efferent arteriole of the glomerulus, and that angiotensin II induces afferent and efferent arteriolar dilatation via AT[sub2] receptors. [ABSTRACT FROM AUTHOR]

Current research on angiotensin II AT[sub1]-receptor antagonists (AIIRAs) and selected studies presented at the recent symposium held in Amsterdam, The Netherlands, on 6 June 1998, titled ‘Angiotensin II Receptor Antagonists are NOT all the Same’ are reviewed. AIIRAs offer a number of potential advantages over alternative antihypertensive agents acting via the renin-angiotensin-aldosterone system. They combine blood pressure-lowering effects at least equivalent to those of angiotensin-converting enzyme (ACE) inhibitors, coupled with placebo-like tolerability. Candesartan cilexetil is a novel AIIRA that has demonstrated clinical efficacy superior to losartan, has a sustained duration of action over 24 hours (trough:peak ratio close to 100%) and is well tolerated in patients with essential hypertension. Candesartan cilexetil has a rapid onset of action (approximately 80% of total blood pressure reduction within the first 2 weeks) and dose-dependent effects on blood pressure, is comparable in efficacy to a number of classes of anti-hypertensives, and is effective in combination therapy (eg, with hydrochlorothiazide and amlodipine). This favourable profile may be due in part to the highly selective, tight binding to and slow dissociation of candesartan from the AT[sub1] receptor. Preliminary studies suggest that candesartan cilexetil also protects end organs (kidney, heart, vasculature, and brain) beyond blood pressure control. [ABSTRACT FROM AUTHOR]