Journal of hypertension. Supplement : official journal of the International Society of Hypertension最新文献

Stroke is a burden of modern civilization, causing death and disability. Nowadays it is universally accepted that inhibition of the renin-angiotensin system by angiotensin-converting enzyme inhibitors or angiotensin II type 1 (AT1) receptor blockers (ARBs) can effectively decrease the incidence of stroke in patients at risk. Here, we summarize current knowledge concerning the molecular mechanisms of the beneficial effects of inhibition of the renin-angiotensin system in stroke, with an emphasis on mechanisms beyond blood pressure reduction; in particular, neuroprotection. All major clinical studies comparing the effectiveness of ARBs with placebo or other blood pressure decreasing drugs in stroke are mentioned and commented on. These clinical data are complemented by data from a selection of animal experiments pivotal for the understanding of neuroprotective actions of ARBs. Clinical studies have shown that ARBs can be superior to other antihypertensive drugs in the prevention of stroke, even if there are no differences in blood pressures. Findings from animal experiments suggest that the underlying mechanisms include not just inhibition of the detrimental peripheral and central actions of angiotensin II mediated by AT1-receptors, but also stimulation of unopposed angiotensin II type 2 (AT2) receptors that are upregulated in the area of ischaemia. ARBs have been proven to be effective in the prevention of stroke via mechanisms that are both dependent on and independent of the antihypertensive abilities of the drugs.

Objective: To present a cost-effectiveness analysis of the Antihypertensive Treatment and Lipid Profile in a North of Sweden Efficacy Evaluation study (ALPINE).

Design: In newly diagnosed hypertensive individuals as yet untreated with drugs, the ALPINE study compared the 1-year metabolic effects of inexpensive treatment with a diuretic (hydrochlorothiazide), alone or in combination (84%) with a beta-adrenoceptor blocker (atenolol), with that of newer but also more expensive antihypertensive treatment with an angiotensin II receptor blocker (candesartan), alone or in combination (71%) with a calcium antagonist (felodipine). No crossover of medication was allowed. The cost-effectiveness analysis included costs for antihypertensive treatment during follow-up, and lifetime costs for care of diabetes mellitus diagnosed during follow-up. Cost per patient was calculated using Swedish prices and costs, translated into US dollars (US$), at 2004 prices.

Results: Diabetes mellitus was diagnosed in nine patients during the 1-year follow-up period of the study, eight in the hydrochlorothiazide group (4.1%) and one (0.5%) in the candesartan/felodipine group (P < 0.05). The cost of antihypertensive treatment per patient was US$92 in the hydrochlorothiazide/atenolol group and US$422 in the candesartan/felodipine group. Lifetime cost for care of diabetes mellitus per patient in the two groups was US$1013 and US$127, respectively. Total cost per patient was US$556 less in the candesartan/felodipine group. In sensitivity analyses, the outcome for the candesartan/felodipine group ranged from cost savings to an incremental cost of US$30 000 per case of diabetes mellitus prevented. In all analyses but one, the additional cost for antihypertensive treatment in the candesartan/felodipine group could be balanced by the reduced lifetime cost for care of diabetes mellitus.

Conclusions: The results suggest that an antihypertensive treatment strategy with candesartan and felodipine may have a favourable health economic impact in the longer term.

Diabetic retinopathy is characterized by both functional and morphological changes in the retinal microvessels that can lead to macular edema, neovascularization, and vision loss. Hypertension has been identified as a major risk factor for diabetic retinopathy and randomized clinical trials have shown that reduction of blood pressure using angiotensin converting enzyme (ACE) inhibitors reduces the progression of diabetic retinopathy. The major components of the renin-angiotensin system have been identified in ocular tissues. Activation of angiotensin II type 1 (AT1) receptors expressed on retinal endothelial cells and pericytes has been implicated in contributing to the microvascular abnormalities in diabetic retinopathy. We have examined the experimental and clinical evidence for the role of the renin-angiotensin system in the pathogenesis of diabetic retinopathy, including the effects of ACE inhibition and AT1-receptor antagonism on diabetes-induced abnormalities in retinal hemodynamics, vascular permeability, and leukostasis; retinal neovascularization in rodent models of oxygen-induced retinopathy; and results from randomized clinical trials that have investigated the effects of ACE inhibitors on the progression of diabetic retinopathy in diabetic patients in the absence or presence of hypertension. The effects of AT1-receptor antagonism on the retina have been attributed to decreases in systemic blood pressure and the concomitant reduction in mechanical vascular stretch, in addition to the intraocular effects blocking AT1-receptor stimulation of retinal endothelial cells and pericytes. Results from the current DIabetic REtinopathy Candesartan Trials program will evaluate the potential of the AT1-receptor as a therapeutic target for diabetic retinopathy.

Background: Blood pressure, as well as blood volume homeostasis, depends to a large extent on humoral influences stemming from the renin-angiotensin axis and the sympathetic nervous system. Evidence has been provided that a large part of this homeostatic modulation is effected by the complex interactions between the two systems.

Objectives: The present review will focus on three major issues. First it will examine the physiological and pathophysiological relevance of angiotensin-sympathetic crosstalk discussing possible sites, mechanisms and effects of the interaction. It will then address the clinical relevance of these inter-relationships by reviewing data collected in cardiovascular and non-cardiovascular diseases. Finally, the influences of angiotensin II on adrenergic function will be examined as possible targets of cardiovascular drug treatment.

Conclusions: By interrupting the influences of angiotensin II on sympathetic function, therapeutic interventions aimed at blocking the renin-angiotensin system exert favourable effects on the haemodynamic, metabolic and renal profile. This has important implications for the treatment of hypertension, congestive heart failure, renal insufficiency and metabolic syndrome.

Migraine is a common episodic headache that predominantly affects young adults, particularly women in their most productive years. Many of the prophylactic agents available today have side-effects that are not compatible with long-term use. The discovery that drugs influencing the renin-angiotensin system (RAS), which have few side-effects, were effective in some patients with migraine led to several studies investigating a possible link between the angiotensin system and migraine pathophysiology. Clinical trials indicated that angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) are effective in the prophylactic treatment of migraine. These findings are further supported by pharmacoepidemiological, genetic, and physiological studies. In addition, it is known that the RAS has neurophysiological, chemical, and immunological effects that are of relevance in migraine pathophysiology. On the basis of evidence presented in this review, we find it likely that the RAS has a clinically important role in migraine pathophysiology. The effect of ARBs and ACEIs on migraine is probably not attributable to their effect on blood pressure. The RAS has several actions that may be relevant in migraine pathophysiology, but the reason for the prophylactic effect of ARBs/ACEIs in migraine remains a matter of speculation.

Background: The therapies developed to treat heart failure over the years have resulted in a significant improvement in clinical outcome. The 1-year mortality following hospital discharge remains unacceptably high, however. Furthermore, a significant number of patients are unable to tolerate angiotensin-converting enzyme (ACE) inhibitors. Clearly, scope remains for the improvement of neurohormonal blockade in patients with heart failure, and there is a particular need for alternative therapies in patients who are unable to tolerate ACE inhibitors. The use of angiotensin II receptor blockers may provide a means of fulfilling these needs.

Objectives: This paper reviews the studies examining the angiotensin II receptor blocker candesartan in comparison with placebo, in comparison with ACE inhibitors, and in combination with ACE inhibitors.

Conclusions: Overall the review found candesartan was effective and safe in various clinical settings. These initial data were used to design the Candesartan in Heart failure--Assessment of Reduction in Mortality and morbidity (CHARM) programme. The mechanistic studies performed prior to the CHARM programme supported the rationale to design a large trial examining the effects of candesartan on clinical events.

In addition to controlling systemic blood pressure, angiotensin II (Ang II) has several roles in the brain, including the regulation of cerebrovascular flow and the reaction to stress. In order to clarify the central effects of Ang II and its type 1 (AT1) receptors, we reviewed the literature reporting recent research on the effects of pretreatment with the AT1-receptor blocker, candesartan, on experimental ischemia, cerebrovascular remodeling, and inflammation in spontaneously hypertensive rats (SHRs), and the responses to stress induced by isolation and by cold-restraint. Angiotensin II regulates the brain circulation through stimulation of AT1-receptors located in the cerebrovascular endothelium and central pathways. SHRs express greater numbers of endothelial AT1-receptors and a central sympathetic overdrive, resulting in pathological cerebrovascular growth, inflammation, decreased cerebrovascular compliance, and enhanced vulnerability to brain ischemia. Sustained central AT1-receptor antagonism reverses these effects. Sustained reduction of AT1-receptor stimulation before stress prevents the hormonal and sympathoadrenal stress responses during isolation and prevents the gastric ulceration stress response to cold-restraint, indicating that increased AT1-receptor stimulation is essential to enhance the central sympathetic response and the formation and release of corticotropin-releasing factor (CRF) and arginine vasopressin that occur during stress. AT1-receptor blocking agents reverse the cortical alterations in CRF1 and benzodiazepine receptors characteristic of isolation stress, effects probably related to their anti-anxiety effect in rodents. Sustained reduction of Ang II tone by AT1-receptor antagonism could be considered as a preventive and therapeutic approach for brain ischemia and stress-related and mood disorders. Additional preclinical studies and controlled clinical trials are necessary to confirm the efficacy of this novel therapeutic approach.

Background: The important role of the endothelium for regulation of vascular tone, growth, inflammatory response, coagulation and thrombocyte adhesion has now been recognized. Endothelial function has largely been assessed as endothelium-dependent vasodilation, assuming that endothelium-dependent vasomotion represents a surrogate marker for other important endothelial functions. An important rational for this approach has been the observation that both endothelium-dependent vasomotion and other protective endothelial functions are at least partially mediated by nitric oxide. Accumulating clinical studies have now demonstrated a close and independent association of impaired endothelium-dependent vasodilation with cardiovascular events and prognosis. These findings have stimulated interest in treatment options to improve endothelial function in patients at high cardiovascular risk.

Discussion: This article describes recent insights into endothelial effects of both angiotensin-converting enzyme (ACE) inhibition and angiotensin II type 1 (AT1) receptor blockade, which have both been shown to improve endothelial function (i.e. by increasing endothelial nitric oxide availability via bradykinin-dependent endothelial nitric oxide release). ACE has a high affinity for bradykinin and degrades the peptide, so ACE inhibition may increase bradykinin-dependent effects by preventing bradykinin degradation. Interestingly, AT1-receptor blockade appears to stimulate the bradykinin-nitric oxide pathway by increased angiotensin II type 2 receptor activation. Moreover, both treatment strategies prevent increased inactivation of endothelial nitric oxide by oxygen radicals, by reducing AT1-receptor-dependent activation of the oxidant enzyme NADPH oxidase and increasing the activity of the vascular antioxidant enzyme extracellular superoxide dismutase. These beneficial effects of ACE inhibition and AT1-receptor blockade are likely to contribute to their effects on cardiovascular events.

Patients with essential hypertension are at increased risk of type 2 (non-insulin-dependent) diabetes. Recent large studies have been unable to delineate any superiority in one class of antihypertensive drug over another, independent of their effects in reducing blood pressure; however, in the longer term, antihypertensive agents that are able to reduce the risk of diabetes may have a theoretical advantage. To this end, the findings of several recent clinical trials have suggested that blockade of the renin-angiotensin system (RAS) may protect against the development of de-novo diabetes in 'at risk' patients. This beneficial effect appears to outweigh both the adverse metabolic effects of agents used in the control arm of these studies and the control of blood pressure achieved. Furthermore, recent evidence suggests that the RAS may have a direct role in the pathogenesis of diabetes. Angiotensin-mediated increases in oxidative stress, inflammation, and free fatty acids concentrations potentially contribute to beta-cell dysfunction in diabetes. In addition, activation of the RAS appears to potentiate the action of other pathogenic pathways, including glucotoxicity, lipotoxicity, and advanced glycation. In experimental models of type 2 diabetes, blockade of the RAS with angiotensin-converting enzyme inhibitors or angiotensin receptor antagonists also results in the improvement of islet structure and function. At least three large controlled trials are currently under way to study the utility of blockade of the RAS in the development of diabetes, including studies of combination therapy. It is hoped that these studies will demonstrate the true potential of blockade of the RAS for the prevention of diabetes.

Cerebral ischaemia-reperfusion injury is associated with an inflammatory response, with contributions from leucocytes and microglia. Formation of free radicals and nitric oxide contributes to the development of cerebral infarction and of the neurological deficit that follows transient focal ischaemia. The circulating and cerebral renin-angiotensin systems contribute, via stimulation of the angiotensin II (Ang II) types 1 (AT1) and 2 receptors, to the initiation or progression of inflammatory processes, and blockade of AT1-receptors prevents irreversible tissue injury and improves outcome from stroke in animal experiments. Such cerebral protection can be achieved even when treatment is initiated hours after established reperfusion. Blockade of AT1-receptors also reduces the incidence of stroke and cardiovascular mortality associated with stroke in patients; however, the mechanisms underlying the prevention of stroke by AT1-receptor blockade in patients remain to be elucidated. In this review we summarize the existing experimental and clinical data demonstrating that the renin-angiotensin system contributes to the inflammation and subsequent irreversible injury after cerebral ischaemia-reperfusion. We conclude that AT1-receptor blockade reduces cerebral ischaemia-reperfusion injury in part by attenuating inflammatory processes.