A new class of antihypertensive therapy: angiotensin II receptor antagonists

Despite the availability of safe and efficacious antihypertensive agents, hypertension continues to be a major source of morbidity and mortality in the United States. Losartan, the first of a new class of agents, the angiotensin II receptor antagonists, can be administered as monotherapy in the treatment of hypertension or to complement existing therapy. The angiotensin II receptor antagonists block the effects of angiotensin II through preferential binding to angiotensin II receptor subtype AT1 on the cell membrane. Compared with angiotensin-converting enzyme inhibitors, they may provide more complete blockade of the renin-angiotensin system and be associated with a lower frequency of cough as a side effect.     

Angiotensin receptor antagonists and ACE inhibitors

BACKGROUND: ACE inhibitors are valuable and effective drugs in the treatment of hypertension, heart failure, myocardial infarction and nephropathy. Angiotensin receptor antagonists, which have recently been introduced into clinical practice, have the potential to replace ACE inhibitor therapy in many patients. OBJECTIVE: To review the mechanisms of action, indications and side effects of ACE inhibitors and angiotensin receptor antagonists and to highlight similarities and differences between the two drug classes. DISCUSSION: Angiotensin receptor antagonists have the theoretical advantage of being more effective in blocking the effects of angiotensin II at angiotensin type I receptors. The potential disadvantage of not potentiating bradykinin may be compensated by the unopposed action of angiotensin II on vascular angiotensin type II receptors, which appear to mediate similar beneficial cardiovascular effects to bradykinin. Angiotensin II receptor antagonists have a lower incidence of adverse effects than ACE inhibitors as they do not produce cough and appear much less likely to produce angioedema. Although ACE inhibitors are the most commonly prescribed antihypertensive drug class in Australia, they are underused for the treatment of heart failure and left ventricular dysfunction following myocardial infarction. Angiotensin receptor antagonists may become alternative therapies to ACE inhibitors in these disorders. However, at present they are only indicated for the treatment of hypertension.     

The therapy of arterial hypertension: a comparison between ACE inhibitors and angiotensin-II-receptor antagonists

The efficaciousness of ACE inhibitors in arterial blood hypertension is well known. These drugs decreased the incidence of hypertension and myocardial infarction in population. However, they increase tissue levels of some kinines, that may be responsible of some adverse reactions (cough, etc.). Angiotensin-receptor antagonists can minimize the adverse reactions due to kinine accumulation and may increase the safety of the antihypertensive drug-treatment. Pharmacological and clinical aspects of angiotensin-receptor antagonists are discussed.     

Influence of risk factors and pharmacological treatment on mortality in patients with essential hypertension

BACKGROUND: The V JNC consensus stated that although new antihypertensive agents, such as angiotensin converting enzyme inhibitors and calcium channel blockers, are considered safer drugs, there is no firm evidence from large controlled trials that these drugs are associated with a lower cardiovascular mortality. AIM: To study the association between cardiovascular risk factors, blood pressure levels, pharmacological treatment and mortality in a group of hypertensive patients followed at an hypertension outpatient clinic. PATIENTS AND METHODS: Patients with essential hypertension were treated with different antihypertensive medications, according to physicians criteria, and controlled until death or loss from follow up. Causes of death were obtained from hospital records and death certificates. Survival was analyzed using life tables, comparisons between groups of patients were done using chi square or a Cox's proportional hazards model. RESULTS: Three hundred thirty-nine hypertensive patients aged 33 to 80 years old were followed for a mean period of 9.8 +/- 4.9 years. Eighty-six were treated with beta blockers, 64 with diuretics, 133 with calcium antagonists and 56 with ACE inhibitors. Blood pressure dropped similarly with all medications. During follow up, 79 patients died. Life table analysis showed that patients with a history of angina, diabetes or myocardial infarction had higher mortality rates. Similarly, patients treated with beta blockers and diuretics had higher mortality than patients treated with calcium antagonists or angiotensin converting enzyme inhibitors. The proportional hazards model showed that the effect of treatment modality persisted after correction for the other risk factors for mortality. CONCLUSIONS: In this series of hypertensive patients, those treated with beta blockers or diuretics had higher mortality rates than those receiving calcium channel antagonists or angiotensin converting enzyme inhibitors.     

Does blockade of angiotensin II receptors offer clinical benefits over inhibition of angiotensin-converting enzyme?

Angiotensin AT1 receptor antagonists represent a new class of drugs for the treatment of hypertension. They are specific for the renin-angiotensin system, selective for the angiotensin AT1 receptor, and act independently of the angiotensin II synthetic pathway. Blockade of the renin-angiotensin system at the receptor level should therefore be more complete. The high circulating levels of angiotensin II following angiotensin AT1 receptor blockade could be beneficial in stimulating other unblocked angiotensin receptors, especially the AT2 receptor. It has been proposed that the angiotensin AT2 receptor, which is re-expressed or up-regulated during pathological circumstances, counterbalances the effect of the stimulation of the angiotensin AT1 receptor. Through this mechanism, angiotensin AT1 antagonists may be superior to ACE inhibitors in cardiac and vascular remodelling as well as in kidney insufficiency. Long-term trials are required to demonstrate the possible clinical superiority of this new class of antihypertensive agents.     

Nephrosclerosis: current status

Nephrosclerosis is the most typical and widespread renal manifestation of hypertension and can be judged as the pathological hallmark of essential hypertension. Nephrosclerosis is an important and frequent cause of progressive renal disease, however, information in the literature on the risk of developing renal failure in the course of essential hypertension is sparse. Traditionally, nephrosclerosis was thought to result from glomerular ischemia. Alternatively, glomerular sclerosis in hypertension may result from glomerular hyperperfusion or hypertension. Studies in experimental models of renal disease have identified a promising intervention with either Ca antagonists or angiotensin-converting enzyme inhibitors. Application of these therapies to patients with nephrosclerosis should await the results of careful clinical trials.     

Modern principles of therapy of hypertension in diabetic patients]

Arterial hypertension is the most frequent cardiovascular complication of diabetes mellitus. Diabetes mellitus-type-1 occurs in about 30% of patients and it is connected to development of diabetic nephropathy, while type-2 occurs in as much as 70% of cases, having fast atherosclerosis as a base in its etiopathogenesis. The therapy of arterial hypertension in diabetic patients is specific and in some ways different depending on the type of diabetes mellitus as well as other complications characteristic for diabetes. Apart from drug therapy, it includes: body weight reduction in obese patients, restriction of sodium chloride, proteins and alcohol drinking, as well as other risk factors (smoking, for example). Drug therapy means application of different groups of antihypertensive agents (selective beta-blockers, diuretics, angiotensin-converting enzyme inhibitors, calcium channel antagonists and postsynaptic alpha-1 blockers). Some of them have adverse effects on metabolism of lipids, while some have other adverse effects which must be taken into account when determining therapy. However, angiotensin-converting enzyme inhibitors and calcium channel antagonists are the most preferred today as the most effective and with least adverse effects.     

Angiotensin-converting enzyme inhibitors

ACE inhibitors have achieved widespread usage in the treatment of cardiovascular and renal disease. ACE inhibitors alter the balance between the vasoconstrictive, salt-retentive, and hypertrophic properties of angiotensin II (Ang II) and the vasodilatory and natriuretic properties of bradykinin and alter the metabolism of a number of other vasoactive substances. ACE inhibitors differ in the chemical structure of their active moieties, in potency, in bioavailability, in plasma half-life, in route of elimination, in their distribution and affinity for tissue-bound ACE, and in whether they are administered as prodrugs. Thus, the side effects of ACE inhibitors can be divided into those that are class specific and those that relate to specific agents. ACE inhibitors decrease systemic vascular resistance without increasing heart rate and promote natriuresis. They have proved effective in the treatment of hypertension, they decrease mortality in congestive heart failure and left ventricular dysfunction after myocardial infarction, and they delay the progression of diabetic nephropathy. Ongoing studies will elucidate the effect of ACE inhibitors on cardiovascular mortality in essential hypertension, the role of ACE inhibitors in patients without ventricular dysfunction after myocardial infarction, and the role of ACE inhibitors compared with newly available angiotensin AT1 receptor antagonists.     

Application of plasma scalpel for cholecystectomy

107 male patients with diabetes mellitus type II (DM) combined with hypertension aged 62 to 76 years were divided into 5 groups comparable by DM but different by characteristics of hypertension, ischemic heart disease or other associated diseases the presence of which determined the choice of one or another drugs against hypertension. These drugs belonging to 5 groups (calcium antagonists, inhibitors of angiotensin converting enzymes, beta-blockers, alpha-blockers, agonists of imidasoline receptors) were compared in monotherapy and combined therapy for hypotensive activity and safety. It was found that monotherapy with corinfar, capoten, and cint had a potent hypotensive effect, atenolol and prasosin had moderate hypotensive efficacy and caused side effects more frequently. In differentiated use of the above drugs negative effects on associated diseases did not occur.     

Treatment of arterial hypertension in diabetic nephropathy. Certainties and hypotheses

Clinical observation has long emphasized the importance of arterial hypertension in the course of diabetic nephropathy and recent studies suggest that hypertension might play a decisive pathogenetic role in the course of the disease, hence the necessity of correcting the hypertension of diabetic patients has by now been universally accepted. There is, however, still some uncertainty concerning the usefulness of acting preventively on so-called microhypertension; in other words, whether early antihypertensive drug treatment can prevent diabetic nephropathy. This paper discusses the criteria to be followed in the choice of antihypertensive medication during diabetic nephropathy giving special attention to pathophysiological considerations. Moreover, it also discusses the effects of antihypertensive drugs currently regarded as first-choice agents, i.e. calcium antagonists and the angiotensin converting enzyme inhibitors, on intrarenal hemodynamics.     

Oxidation of the flavonol fisetin by polyphenol oxidase

The rapid development of endothelin-receptor antagonists has made the endothelin pathway a new therapeutic target in the treatment of cardiovascular diseases, only ten years after the report of its discovery. While the first clinical trials will help to position this new family of compounds in our therapeutic armament for the treatment of essential or secondary forms of hypertension, several preclinical chronic studies already provide a picture of what we can expect from these drugs. Endothelin-receptor antagonists are not effective in all experimental models of hypertension, but those that respond present hypertrophy of small arteries, secondary to a local overexpression of the peptide. Although angiotensin II seems to represent a stimulus for endothelin overexpression in some models, other, as yet undetermined, stimuli are likely in others. Besides their narrow spectrum of antihypertensive activity, endothelin-receptor antagonists may also protect from complications of hypertension by improving end-organ function in a pressure-independent manner. This seems to be the case for the structure and reactivity of resistance arteries, as well as for renal damage. However, it is not clear at this point if cardiac structure and function are improved beyond the benefits produced by blood pressure reduction. The first results in essential hypertensive subjects suggest some degree of efficacy of endothelin-receptor antagonists. Other clinical trials will help to determine if secondary forms of the disease benefit equally or more from this new class of drugs, and if end-organ damage can be reduced beyond blood-pressure reduction.     

Glucose and lipid metabolism during long-term antihypertensive treatment with indapamide in non-insulin-dependent diabetic patients

Thirty-nine patients with diabetes and hypertension were treated with indapamide for 24 weeks to study the effects of that drug on glucose and lipid metabolism. The drug was administered at a dose of 2 mg once per day in the morning as a single drug (26 patients) or in combination with other antihypertensive drugs (13 patients), including calcium antagonists, angiotensin-converting enzyme inhibitors, an alpha-blocker, or a beta-blocker. Blood pressure was reduced in both groups during treatment, and no alteration of glycemic control or lipid metabolism was observed. One patient complained of a mild headache, but treatment was continued. The results indicate that indapamide is useful for the long-term treatment of hypertension in diabetic patients, either alone or in combination with other antihypertensive agents.     

Sudden cardiac death in patients with arterial hypertension and left ventricular hypertrophy on antihypertensive therapy

The hypertrophy of the left ventricle in patients with arterial hypertension is an independent risk factor which increases c 9 times the probability of sudden cardiac death. Despite the fact that the incidence of sudden cardiac death in patients with arterial hypertension is low, regarding the high occurrence of hypertension it represents a significant medical problem. The therapy of arterial hypertension is able to decrease the general and cardiovascular mortalities with significant interspecies characteristics of individual antihypertensive drugs, as well as to promote the regression of hypertrophy of the left ventricle. The therapy per se can however increase the risk of cardiovascular complications: until now the complication of the therapy by diuretics rich in potassium and beta-blockers are best distinguished. Calcium antagonists are effective antihypertensive drugs but they do not decrease the total mortality. ACE inhibitors have a marked antihypertensive effect and few adverse effects, but until now there is not a sufficient number of large prospective studies which would definitely confirm the preliminary promising findings. Despite the presented problems the cured patients with arterial hypertension have a substantially better prognosis than patients that are not being cured.     

Regression of left ventricular hypertrophy in hypertension: changing patterns with successive meta-analyses

Left ventricular hypertrophy (LVH) may be an important target for therapy in hypertension, although definitive data in humans are not available. An important question is whether antihypertensive drugs vary in their ability to cause the regression of LVH. Without adequately powered controlled comparisons, meta-analysis provides the best method of assessing the overall results of the numerous smaller published studies. A succession of meta-analyses have indicated a strong relationship between changes in blood pressure and LVH regression. We have reviewed studies conducted for 5 years since the first major meta-analysis. Methodology was found to have improved, and the overall ranking of drug classes according to their effects on LVH regression were: calcium antagonists, angiotensin converting enzyme inhibitors, diuretics, alpha-blockers, beta-blockers, and lifestyle changes. Changes from earlier reports may reflect the use of new preparations within some classes of drugs and large studies are required to define whether this will be reflected in clinical outcomes.     

Endothelin and arterial hypertension

Endothelins (ETs) are peptides of 21 amino acids synthesized and released by variety of cells. Endothelin (now this peptide is called endothelin-1 (ET-1)) was isolated and identified in 1988 by Yanagisawa et al. Following studies revealed two other isoforms of endothelin': Endothelin-2 (ET-2) and endothelin-3 (ET-3). All of them bind to two types of receptors (A and B (ET-A r, ET-Br). ET-A r are responsible for concentration mediating. Two subtypes of ET-B r are known. ET-B1 r mediates vasorelaxation; ET-B2 vasoconstriction. ETs (especially ET-1) have variety of biological actions but the most important are vasoconstrictor and mitogenic action. Through these two mechanism ETs may participate in the pathogenesis and/or in the maintenance of hypertension in both experimental animal models and human essential hypertension. The intravenous infusion of synthetic ET induces a long-lasting elevation of blood pressure in experimental animals and in healthy humans. Number of studies have shown enhanced responses to ET in hypertensive subjects but decreased responses have also been reported. Similarly, plasma levels of ET-1 are either normal or elevated in experimental and human essential hypertension. Numerous investigators have suggested an interaction between ET and angiotensin-converting enzyme inhibitors through the renin-angiotensin system or through the accumulation of endogenous bradykinin. Also calcium antagonists of different classes prevent endothelin-induced contractions. Endothelin- converting enzyme inhibitor (phosphoramidon) and ET-A/B r antagonists (bosentan, BQ-123, FR139317) may have potential role as vasodilators in the treatment of hypertension.     

Response of hypertension to conventional antihypertensive treatment and/or steroidogenesis inhibitors in Cushing's syndrome

OBJECTIVES: To evaluate the effect of conventional antihypertensive drugs and/or inhibitors of steroid production in the management of hypertension in Cushing's syndrome. DESIGN: A retrospective open clinical study with pre- and post-treatment assessment. SETTING: A university hospital, where patients were initially admitted and then followed-up in an ambulatory clinic over a period of 6 years. SUBJECTS: Forty consecutive hypertensive patients with Cushing's syndrome. INTERVENTIONS: Patients were divided into two groups according to the different management of hypertension. The first group (group 1) of 28 patients included those treated with antihypertensive drugs at full dose (diuretics, calcium antagonists, angiotensin converting enzyme [ACE] inhibitors, as single agents or in combination). The second group (group 2) of 12 patients received ketoconazole alone. MAIN OUTCOME MEASURES: Blood pressure variations compared to pre-treatment levels. RESULTS: Blood pressure normalization was obtained in four of the 28 patients of group 1. In 12 of the remaining patients, ketoconazole, an inhibitor of steroid production, was subsequently added and this normalized blood pressure in all but the one in whom cortisol was not decreased. In the 12 patients of group 2, ketoconazole alone lowered blood pressure within normal limits in all but one who had long-standing hypertension. CONCLUSIONS: In hypertensive patients with Cushing's syndrome, conventional antihypertensive therapy is mostly ineffective. Blood pressure response is satisfactory only after the restoration of normal cortisol levels, indicating the need for a specific treatment for hypertension in this disorder.     

Calcium antagonists and mortality risk in men and women with hypertension in the Framingham Heart Study

BACKGROUND: Several recent studies have suggested that calcium antagonist drugs, which are widely used for the treatment of hypertension, are associated with increased risk of cardiovascular disease. These studies have cast doubts on the long-term safety of calcium antagonists. OBJECTIVE: To examine the association of calcium antagonist use with mortality in subjects with hypertension followed up in the Framingham Heart Study. SUBJECTS AND METHODS: We stratified 3539 subjects (mean+/-SD age, 64+/-13 years) from the Framingham Heart Study who had hypertension at routine clinic examinations, according to the use of calcium antagonists and presence of coronary heart disease at the baseline examination. At each follow-up examination (every 2-4 years), subjects were reclassified with regard to the use of calcium antagonists. The end point of the study was all-cause mortality. Hazard ratios and 95% confidence intervals associated with the use of calcium antagonists were obtained using Cox proportional hazards regression models. RESULTS: There were 970 deaths during follow-up. Hazard ratios for mortality associated with the use of calcium antagonists were 0.93 (95% confidence interval, 0.72-1.21; P=.59) for subjects with hypertension without coronary heart disease, and 0.92 (95% confidence interval, 0.69-1.24; P=.58) for those with coronary heart disease at baseline. All models were adjusted for age, sex, current smoking, systolic and diastolic blood pressure, use of beta-blockers, and use of other antihypertensive medications. CONCLUSIONS: In this cohort of 3539 subjects with hypertension there were no differences in mortality among subjects with hypertension using a calcium antagonist compared with those who were not. Results were similar among subjects with hypertension with and without coronary heart disease. The results of ongoing long-term, randomized clinical trials will provide more definitive data on the safety of calcium antagonists.     

Isolated systolic hypertension in the elderly subject

Interest in isolated systolic hypertension in the elderly has increased in the last few years. The definition of this disorder remains controversial: according to most authors, the systolic blood pressure has to be above 160 mm Hg and the diastolic under 90 mm Hg. The prevalence depends on number of visits, as well as on sex, age and race. The elderly is characterized by haemodynamic and neurohormonal features, which have to be pointed out: cardiac output and renal blood flow as well as hepatic blood flow are significantly lower than those of younger adults; great vessels compliance is diminished, baroreflex is impaired and cerebral autoregulation curve is shifted towards the right. From a prognostic point of view, systolic hypertension is now recognized as an independent risk factor for cardio-vascular morbidity and mortality. Recently, the SHEP study has demonstrated that the treatment of isolated systolic hypertension with diuretics alone or associated with beta-blockers resulted in a significant reduction in the incidence of stroke and major cardio-vascular events. The effectiveness of angiotensin-converting enzyme inhibitors and calcium antagonists is still under evaluation.     

Main objectives and new aspects of combination treatment of hypertension

AIM: To review the various pharmacological approaches currently proposed for the treatment of hypertension. RESULTS: With the evolution of pharmacological treatment of hypertension, various classes of agent (diuretics, beta-blockers, angiotensin converting enzyme inhibitors, calcium antagonists and alpha 1-blockers) have become available for the initiation of antihypertensive therapy. As monotherapy, each type of agent will normalize blood pressure in about half of all hypertensive patients. Replacing one drug with another that acts through a different mechanism improves the probability of controlling blood pressure. Another way to increase the number of responders is to increase the dose; however, this often results in more side effects. A preferable way of improving efficacy is to combine low doses of drugs that have different impacts on the cardiovascular system, thus opposing the compensatory responses that tend to limit the blood pressure drop. CONCLUSION: Low-dose drug combinations are generally well tolerated and the treatment of hypertension can be simplified by using fixed-dose combinations. These combinations have the potential to become a valuable alternative in the initiation of antihypertensive therapy.     

Sex differences in the pharmacological treatment of hypertension: a review of population-based studies

OBJECTIVE: To summarize all available literature on sex differences in the pharmacological treatment of hypertension with respect to the percentage of hypertensive patients treated pharmacologically and the selection of antihypertensive drugs. The influences of the calendar period, age, definition of hypertension, prevalence of hypertension and country on these sex differences were examined. DATA IDENTIFICATION: A secondary analysis of data from 46 population-based studies in 22 countries on the prevalence of pharmacologically treated hypertension was conducted to estimate sex ratios for the prevalence of drug treatment for hypertension. RESULT: Overall, women with hypertension were 1.33-fold [95% confidence interval (CI) 1.32-1.34] more likely to be treated pharmacologically for hypertension than were hypertensive men. With increasing age, the female: male ratio for pharmacological treatment of hypertension decreased from 2.26 (95% CI 1.56-3.27) at ages 20-29 years to 1.22 (95% CI 1.11-1.34) at ages 60-69 years. In all countries more women than men were treated for hypertension, with the biggest difference observed in the USSR (1983-1986), where about twice as many women as men were treated for hypertension. Women more frequently used diuretics, whereas men more often used beta-blockers, angiotensin converting enzyme inhibitors and calcium antagonists. CONCLUSIONS: Hypertensive women are more often treated for hypertension than hypertensive men and their pattern of use of antihypertensive drugs differs from that of men. Further research is required in order to explain sex differences in the treatment of hypertension with respect to the prevalence of pharmacological treatment of hypertension and choice of antihypertensive drugs, and to investigate the consequences of this difference for long-term outcomes.