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Candesartan is a potent and selective angiotensin II type 1 receptor blocker which binds tightly to and dissociates slowly from the AT1 receptor. It is administered orally as the prodrug candesartan cilexetil, which is rapidly and completely converted to the active compound, candesartan, during gastrointestinal absorption. In hypertensive patients, candesartan cilexetil dose-dependently lowers diastolic and systolic blood pressure (BP) over the 24-h dose interval and it maintains its antihypertensive effects in the long term. Clinical trials indicate that a once-daily dose of 4-16 mg provides a clinically relevant reduction in BP. The usual maintenance doses of candesartan cilexetil are expected to be 8 mg and 16 mg once-daily and dosage adjustment does not appear to be necessary in elderly patients or those with mild to moderate renal or hepatic impairment. Adverse events during treatment with candesartan cilexetil occur at a similar low incidence as with placebo and no dose-dependent events or adverse metabolic effects have been noted. As once-daily monotherapy, candesartan cilexetil 8 mg is as effective as enalapril 10-20 mg, amlodipine 5 mg or hydrochlorothiazide 25 mg, and candesartan cilexetil 16 mg is more effective than losartan 50 mg. The trough to peak ratio for the reduction in BP with candesartan cilexetil has been shown to be in the order of 80-100%, confirming the smooth 24-h BP-lowering profile of the drug. Combined treatment with candesartan cilexetil and hydrochlorothiazide or amlodipine provides an enhanced BP-lowering effect that is useful in patients with inadequate response to initial treatment after step-up titration. Candesartan cilexetil is similarly well tolerated as placebo, both when given as monotherapy, and in combination for example with hydrochlorothiazide. Candesartan cilexetil with its flexible dosage regimen therefore appears to offer an effective and well-tolerated alternative to other established agents in the treatment of a wide range of hypertensive patients. [ABSTRACT FROM AUTHOR]

The long-term efficacy and tolerability of candesartan cilexetil was assessed in two open-label, prospective multicentre studies in patients with mild to moderate essential hypertension. When administered in a flexible dosage regimen of 4-16 mg once-daily, candesartan cilexetil effectively lowered blood pressure (BP) and maintained its antihypertensive effects over the long term (⩽12 months). At the end of treatment, 81.1% of patients showed a clinically significant response (reduction in sitting diastolic BP of ⩾10 mm Hg or reduction to <90 mm Hg), and 73.8% experienced normalisation of sitting diastolic BP (<90 mm Hg). Only a small proportion (10.7%) of patients prematurely discontinued treatment due to lack of efficacy. Candesartan cilexetil was well tolerated and was devoid of clinically relevant biochemical, haematological or cardiac effects. Only 12% of adverse events were judged to be causally related to the drug and only about 5% of patients withdrew from therapy due to adverse events. The most common adverse events were typical of hypertensive patients in general. Most adverse events appeared during the first 3 months of treatment and their incidence decreased steadily with time. Tolerability was unrelated to gender, age (<65 vs ⩾65 years) or dos- age. These results demonstrate that candesartan cilexetil maintains its antihypertensive effects and tolerability during long-term administration. [ABSTRACT FROM AUTHOR]

Several studies have recently been published which have raised doubts over the long-term safety of calcium channel blockers (CCB). These have included retrospective case control studies in hypertension and meta-analyses of small scale studies in unstable angina and myocardial infarction (MI). Most of the reports were primarily concerned with the use of the short acting dihydropyridine nifedipine. Despite wide media coverage of these reports, the results are by no means irrefutable and, because of the nature of the studies themselves, are open to several criticisms. Calcium channel blockers are currently being evaluated in large-scale, prospective, randomised controlled studies, but results are unlikely to be available within the next few years. Meanwhile, the consensus view seems to be that short acting dihydropyridines should in general be avoided and have no place in the management of unstable angina and post MI. In the setting of stable angina, long acting dihydropyridines should generally be used in conjunction with a beta-blocker. In hypertensive patients, long acting dihydropyridines may be used as alternative antihypertensive agents in patients in whom the first line agents (diuretics and beta-blockers) are poorly tolerated, contra-indicated or ineffective.

Thiazide diuretics are widely used to treat hypertension, but their use is associated with impaired glucose tolerance. We propose that the diabetogenic action of thiazides may be due to their ability to open calcium-activated potassium (KCa) channels in pancreatic beta-cells.

Hypertension is a multifactorial disease, and there is growing evidence that implicates a range of environmental factors in its aetiology. These include dietary sodium, obesity, alcohol and stress. Additionally, several genetic abnormalities may predispose an individual to hypertension. The number of hypertensive phenotypes resulting from different environmental-genetic interactions may explain, therefore, why there is marked heterogeneity in response to treatment and why any single antihypertensive agent would be unlikely to control BP in more than 25-50% of patients. This is one rationale for combination therapies in which the component drugs affect different pathophysiological mechanisms.

The retinal vasculature is an accessible region of the microcirculation in humans which undergoes change in essential hypertension. In this study we have examined the effect of nifedipine and glyceryl trinitrate (GTN) on retinal blood flow velocities. Retinal blood flow was measured in 11 subjects using colour Doppler ultrasound. Nifedipine (10 mg orally) or glyceryl trinitrate (0.3 mg, GTN) was given after 30 minutes recumbancy. Systolic retinal arterial blood flow velocity (SRV), diastolic retinal arterial blood flow velocity (DRV), retinal resistive index (RI), SBP, DBP were measured at -10, 0, 5, 10, 15, 20 and 25 minutes following drug administration. Nifedipine significantly increased SRV (peak effect at 15 minutes) but by 25 minutes SRV did not differ significantly from pre-drug values. Nifedipine did not significantly affect DRV, RI, SBP or DBP. GTN significantly increased both SRV and DRV, although both tended to fall towards pre-drug values by 25 minutes. RI, SBP nor DBP were not significantly altered by GTN. Both nifedipine and GTN transiently increase blood flow velocity in the central retinal artery although at the doses used neither agent affected BP or RI. Doppler ultrasound measurement of retinal arterial blood velocity may be a useful technique in the investigation of the retinal microcirculation in essential hypertension.

Hypertension is associated with structural changes in the vascular system and in the heart. This study has examined the relationships between carotid artery intima-media thickness and other risk factors in 52 untreated patients (20 hypertensive). Carotid intima-media thickness was measured bilaterally using a Duplex doppler ultrasonic scanner. In the hypertensive individuals the left ventricle was examined by echo-cardiography and the left ventricular mass index determined. There was a significant association between age and IMT, and both SBP and DBP and IMT. The IMT in the hypertensive group was significantly larger than in the normotensive group and in the hypertensive subjects there was a positive association between left ventricular mass index and IMT. There was no significant difference in calculated media stress between the normotensive and hypertensive groups, probably due to a small increase in carotid intima-media area combined with a small reduction in carotid lumen diameter. Hypertension is associated with a thickening of the intima-media of the carotid artery and an increase in left ventricular mass. Whether these changes in cardiac and arterial structure are in response to similar influences remains to be established.

Small resistance arteries were isolated from human subcutaneous fat and omentum and studied using a myograph. Endothelin-1 induced a concentration-dependent contraction in both type of arteries. In subcutaneous arteries preincubation with calcium antagonists partially inhibited responses to endothelin-1. The effectiveness of the calcium antagonists was nisoldipine > nimodipine > verapamil = flunarizine > diltiazem. In omental arteries nimodipine and diltiazem had no significant effect on endothelin-1-induced contraction and removal of extracellular calcium also had little effect on responses to endothelin-1. The role of influx of extracellular calcium through voltage operated calcium channels in endothelin-1-induced contraction appear to differ between subcutaneous and omental resistance arteries.

We present a case in which a patient, having already sustained an episode of malignant hypertension, was subsequently found to have an underlying Conn's adenoma. Ablation of the adenoma improved control of her hypertension. When a second adenoma developed in her remaining adrenal gland, control of her hypertension deteriorated.

The relationship of left ventricular (LV) filling to the clinical and echocardiographic characteristics of 51 patients with untreated hypertension (borderline hypertension n = 17, essential hypertension n = 34) was investigated using two-dimensional echocardiography and Doppler ultrasound. Twenty-five patients had evidence of abnormal LV filling. Linear regression analysis revealed weak but significant correlations of LV filling with age (r = -0.53; P less than 0.0001), systolic blood pressure (r = -0.38; P less than 0.006), LV septal wall thickness (r = -0.44; P less than 0.0001) and LV mass index (r = -0.33; P less than 0.02). There was no association between LV filling and sex, race, heart rate or LV posterior wall thickness or cavity dimension. After stepwise regression analysis, age was found to be the only independent variable associated with LV filling, indicating that the other variables were dependent on age. This study suggests that a) abnormal LV filling is a frequent observation in hypertension b) LV filling is more dependent on age than blood pressure or LV size and c) other pathophysiological factors, so far undetermined, must contribute to the development of these abnormalities.

Hyperglycaemia, a raised fibrinogen, an increased serum triglyceride and a reduced HDL-cholesterol are common metabolic features of non-insulin dependent diabetes mellitus (NIDDM). Hypertension is frequently associated with NIDDM, however the influence of antihypertensive therapy on these combined factors in the diabetic is at present unclear. In a double-blind placebo-controlled crossover study in 20 stable NIDDM subjects with hypertension, the metabolic effects of 6 weeks' treatment with the alpha-blocker, doxazosin, was compared with treatment with the beta-blocker, atenolol. Similar and significant reductions in BP were produced by both drugs. Significant increases in weight, HbA1, apoprotein B, serum triglyceride and cholesterol/HDL ratio were observed with atenolol therapy. Doxazosin therapy was associated with opposite patterns of changes in fasting glucose, lipids and lipoproteins but only for serum triglyceride was difference between treatments significant. Fibrinogen was not altered by either treatment. Conclusions from this study indicate; 1) adrenergic mechanisms may be an important influence on glucose homeostasis and lipid metabolism in NIDDM and 2) the beta-blocker, atenolol, has a small adverse effect on weight, glycaemic control and the atherogenic lipid profile, whereas the alpha-blocker, doxazosin, has no such effect and may, in part, correct the disturbances of lipoprotein metabolism characteristic of NIDDM.

In a study on 11 stable hypertensive non-insulin dependent diabetic subjects the influence of beta-blocker (atenolol 100mg) withdrawal and reintroduction was assessed. After a three week placebo phase significant increases in pulse rate, high density lipoprotein- and high density lipoprotein2-cholesterol and a significant decrease in triglyceride were observed. Three weeks after recommencement of atenolol therapy the pulse, lipid and lipoprotein changes were reversed and significantly so. Weight and blood pressure remained constant throughout. Results from this study indicate that in non-insulin dependent diabetes, atenolol-induced lipid and lipoprotein changes are reversible in the short term and occur in the absence of significant changes in blood pressure control. The lipoprotein changes observed involved an alteration in high density lipoprotein composition. As a reduced high density lipoprotein cholesterol is associated with macrovascular disease, future studies on the association of lipoproteins and diabetic complications should take into account these changes in lipoproteins with beta-blocker hypotensive therapy.

Fibrinogen and blood viscosity were measured in 72 stable non-insulin dependent diabetic subjects, 31 without hypertension, and 41 who had treated hypertension. The hypertensive group had higher plasma fibrinogen levels and blood viscosity. As both these rheological variables have been associated with micro- and macro-vascular disease, these findings may provide a possible explanation for the mechanism of the increased vascular disease seen in hypertensive compared with normotensive diabetic subjects.