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Most antihypertensives have advantages and disadvantages. The ideal antihypertensive drug should be effective in lowering blood pressure, well tolerated, safe in the long term, and easy to use. Ideally, it should be relatively inexpensive. Most importantly it should reduce the risk of the adverse effects of high blood pressure, such as myocardial infarction, sudden death, stroke, heart failure, renal damage, and retinal changes. Most antihypertensive drugs effectively reduce blood pressure, are available as once daily preparations, and are safe long-term. Unfortunately, most antihypertensive drugs cause adverse effects in some patients and for few drugs is there good evidence that they protect the heart, the brain, the kidney, and the eye? Reducing the effects of Angiotensin II (using an ACE inhibitor) has been shown to reduce the incidence of coronary events, sudden death, heart failure, renal damage, and fundal changes. AT1 blocking drugs offer the same pharmacological advantages but also very good tolerability, in particular no cough. Therefore, they have the potential to meet all the criteria for an ideal antihypertensive drug.
Basic Res Cardiol 1998
PMID:Therapeutic advantages of AT1 blockers in hypertension. 983 62

The main goal of the treatment of hypertension is to decrease cardiovascular morbidity and mortality. Since this has been demonstrated for betablocker and diuretics only, other antihypertensive agents should be recommended for initial single-drug therapy only if they demonstrate that their antihypertensive potency, and their tolerability is at least comparable to that of the other established drug classes. From this latter perspective AT1 blockers should become one of the most favored anti-hypertensive drugs, since it can be shown that their efficacy is comparable to all other classes of antihypertensive drugs and their tolerability is undoubtedly better. Candesartan seems to be the most efficient AT1 blocker with regard to molar potency. Moreover, it has been shown that Candesartan achieves an impressively long duration of action presumably due to its special receptor binding properties with a peak trough ratio of more than 0.9. An other advantage of this special AT1 blocker may be its dose response curve which demonstrates a continuous increase of efficacy between 2 and 16 mg daily.
Basic Res Cardiol 1998
PMID:Clinical efficacy of a new AT1 blocker. 983 63

We studied cerebral blood flow autoregulation by laser Doppler flowmetry, and expression of brain angiotensin II AT1 receptors by quantitative autoradiography, after administration of an angiotensin AT1 receptor antagonist, CV-11974 (Candesartan, 0.5 or 1.0 mg/kg.day) for two weeks via subcutaneously implanted osmotic pumps in adult normotensive Wistar Kyoto and spontaneously hypertensive male rats (SHR). In SHR, the autoregulation curve was shifted towards higher blood pressures, when compared with that of normotensive Wistar Kyoto rats. Administration of CV-11974 shifted the autoregulation curve toward lower blood pressures in both Wistar Kyoto and SHR, partially normalizing the autoregulation curve in SHR. CV-11974 treatment markedly decreased the expression of AT1 receptors in Wistar Kyoto rats, both in areas outside the blood brain barrier (subfornical organ, 95% decrease) and inside the blood brain barrier (nucleus of the tractus solitarius, 87% decrease, and paraventricular nucleus, 96% decrease). Our results demonstrate that blockade of AT1 receptors tends to normalize the shift to higher pressures in the autoregulation curve of genetically hypertensive rats, and has a profound modulatory role in brain angiotensin II AT1 receptors.
Basic Res Cardiol 1998
PMID:The angiotensin AT1 receptor antagonist CV-11974 regulates cerebral blood flow and brain angiotensin AT1 receptor expression. 983 66

The renin-angiotensin system is activated during myocardial ischemia, and local angiotensin II formation occurs in ischemic hearts. At least two angiotensin II receptor subtypes, the AT1 and AT2 receptor, have been identified. The cardiovascular effects of angiotensin II have been largely attributed to activation of AT1 receptors. In ventricular preparations from normal rat and pig hearts, the density of AT1 receptors is higher than that of AT2 receptors, whereas data on the AT receptor subtype density and its distribution in human hearts remain controversial. AT1 receptor blockade increases coronary blood flow during ischemia in dogs and during reperfusion in rats. It also reduces the incidence of ischemia-related arrhythmias in rats and guinea pigs, limits infarct size in pigs, improves functional and metabolic recovery following myocardial ischemia, and attenuates ventricular remodelling post-myocardial infarction in rats. The potential mechanisms responsible for the cardioprotection by AT1 receptor blockade remain to be elucidated in detail, but appear to involve AT2 receptor activation and the subsequent action of bradykinin, prostaglandins, and/or nitric oxide. Patients under treatment with AT1 receptor antagonists for indications such as hypertension and ventricular dilatation after myocardial infarction are likely to have improved prognosis when suffering an acute myocardial infarction.
Basic Res Cardiol 1998
PMID:AT1 receptor blockade in experimental myocardial ischemia/reperfusion. 983 69

Ventricular remodeling following nonfatal myocardial infarction includes an excentric hypertrophy of the surviving myocardium, associated with hemodynamic overload. Disseminated cardiomyocyte apoptosis and phenotype changes of the surviving myocardium, such as a labile calcium homeostasis of the hypertrophied cardiomyocytes, impaired beta-adrenergic signal transduction, interstitial fibrosis, and reduced coronary reserve are typical features of the overloaded, distended ventricular wall. They are considered as relevant for the myocardial dysfunction progressing to overt cardiac failure and for the enhanced mortality risk. Hemodynamic load and trophic angiotensin effects are assumed to cause this excentric hypertrophy, since systemic and local angiotensin formation in the overloaded myocardium is activated. In isolated rat cardiomyocytes, cultured on distensible membranes, overload is mimicked by distension, and causes enhanced formation and release of angiotensin II, which results in AT1 receptor mediated trophic reactions of distended neonatal cardiomyocytes and in AT1-mediated apoptosis in distended adult cardiomyocytes. In experimental models of postinfarct remodeling, therapy with ACE inhibition or with AT1 blockade similarly normalizes myocardial hypertrophy, interstitial fibrosis, and impaired coronary reserve. In patients with terminal heart failure, a reduction of apoptotic signs and a normalization of antiapoptotic gene expression is obtained by myocardial unloading under ventricular assist devices or by treatment with ACE inhibitors, and the latter therapy has been shown to improve survival. In contrast to general assumptions and to predictions from data in vitro, the improvements obtained by AT1 blocker therapy in vivo are mediated by bradykinin, as are those obtained under ACE inhibitors. Under AT1 blockade, bradykinin is probably activated due to stimulation of AT2 and other AT receptors.
Basic Res Cardiol 1998
PMID:Role of ACE inhibition or AT1 blockade in the remodeling following myocardial infarction. 983 70

An activated renin-angiotensin system is a major risk factor for cardiovascular events. Angiotensin II acts on AT1 and AT2 receptors. Stimulation of AT1 receptors is associated with endothelial dysfunction, mainly as the consequence of an increased vascular production of superoxide radicals, vasoconstriction, platelet activation, enhanced release of plasminogen activator inhibitor-1, activation of immediate early genes c-fos and c-jun, myocyte hypertrophy, connective tissue formation, endothelin-1 synthesis, and activation of growth factors like PDGF and TGF-beta 1. Stimulation of AT2 receptors can mitigate or abolish the growth promoting effects of AT1 receptor stimulation. The contribution of these effects--single or in combination--on the progression of atherosclerotic lesions, the phenomenon of restenosis and the process of remodeling in heart failure is being progressively elucidated. With increasing knowledge about these relationships the inhibition of AT1 receptors appears as a main target in preventive and reparative strategies in cardiovascular diseases.
Basic Res Cardiol 1998
PMID:Angiotensin II and coronary artery disease, congestive heart failure, and sudden cardiac death. 983 71

Morbidity and mortality due to end-stage renal failure has become a major health concern in recent years and there is clear evidence that arterial hypertension constitutes a powerful risk factor for the progression of renal disease. Several studies have documented the benefit of blood pressure control on renal function, and it is increasingly recognized that antihypertensive therapy aimed at reducing blood pressure well below the target value of 140/90 mmHg further improves the overall renal survival rate. Different classes of antihypertensive agents show disparate specific nephroprotective properties that are unrelated to their blood pressure lowering properties. ACE inhibitors and calcium channel blockers have been reported to ameliorate renal function by favorably modifying renal and intraglomerular hemodynamics. In addition, both drugs exert beneficial effects on non-hemodynamic parameters of renal function. In contrast, beta-blockers and diuretics, although still being solely recommended as first line drugs in the management of arterial hypertension, can have adverse effects on renal function. Recently, long-term randomized controlled trials have consistently demonstrated the superior nephroprotective value of ACE inhibitors on renal function outcome. Whether AT1 receptor antagonists have similar effects on long-term renal survival is still under investigation. The outcome of forthcoming clinical trials is likely to influence clinical guidelines and optimize the medical regimen of human essential hypertension in patients with chronic renal insufficiency.
Basic Res Cardiol 1998
PMID:Nephroprotection by antihypertensive therapy. 983 72

Diabetic nephropathy has become the single most important cause of endstage renal failure in most countries of the Western world. Against this background, the role of the renin-angiotensin system (RAS) and its blockade command considerable interest. In diabetic patients and in diabetic animals, the circulating components of the RAS are suppressed. Although the evidence is not completely uniform, there are indirect arguments (renal hemodynamic response to RAS blockade, AT1 receptor expression), however, which would be consistent with increased intrarenal action of angiotensin (ANG) II. There is solid evidence that ACE inhibitors effectively interfere with progression of micro-albuminuria both in IDDM and NIDDM. They also prevent progression of advanced renal failure in IDDM, while there is only preliminary evidence in this respect for NIDDM. ACE inhibitors are superior to conventional antihypertensive agents (with the possible exception of some calcium channel blockers), but such superiority is seen only when the levels of blood pressure are relatively high. In diabetic animals, treatment with ANG II receptor blockers interferes with the development of glomerular lesions. In acute and subacute studies on diabetic patients, ANG II receptor blockers reduced albuminuria (or proteinuria) more than beta-blockers. Head-on comparison of equipotent doses ACE inhibitors and ANG II receptor blockers in non-diabetic patients produced equal reductions in proteinuria. The long-term effects of ANG II receptor blockers on progression of advanced diabetic nephropathy is the object of two large international studies. The results will not be available before the year 2000.
Basic Res Cardiol 1998
PMID:Diabetes--renal function--what are the special problems? 983 74

The AT1 receptor mediates many biological effects of the renin angiotensin system such as vasoconstriction and cell proliferation. The expression level of the AT1 receptor is subjected to various pathophysiological influences. Insulin, which is elevated in the metabolic syndrome, induces a overexpression of vascular AT1 receptors leading to an enhanced biological efficacy of angiotensin II. This heterologous regulation of the AT1 receptor by insulin may explain the fact that the metabolic syndrome is frequently associated with hypertension and atherosclerosis.
Basic Res Cardiol 1998
PMID:Interaction between insulin and AT1 receptor. Relevance for hypertension and arteriosclerosis. 983 76

In a multicenter, randomized, double-blind, placebo-controlled clinical trial the effects of candesartan cilexetil (cand.cil.), a novel angiotensin II antagonist selective for the AT1 receptor with long-lasting antihypertensive activity, on glucose homeostasis--and the serum lipid profile--were assessed in patients with mild hypertension and stable type II diabetes mellitus. A total of 161 men and women, 30-75 years old, with mild hypertension (sitting diastolic blood pressure 90-100 mmHg) and type II diabetes (HbA1c 5.5-9.0%), both measured after a 4-week placebo run-in period, were randomized to double-blind treatment with cand.cil. 8 mg o.i.d. (n = 83) or placebo (n = 78). Dose was increased to 16 mg o.i.d., if diastolic blood pressure remained > or = 90 mmHg. At randomization and after 12 weeks of treatment HbA1c (primary effect variable), blood glucose and the serum lipid profile (including total cholesterol, HDL and LDL cholesterol, triglycerides) were assessed. The statistical analysis of the differences between treatments was based on changes from randomization to the end of the study. Cand.cil. had no significant effect on HbA1c, blood glucose, and serum lipids compared to placebo. The median HbA1c both at baseline and after 12 weeks was 7.1% in patients on cand.cil., and 7.2% and 7.1% in patients on placebo. The 95% confidence interval for the median difference in change between the groups was narrow (-0.25; 0.16), including zero, which excluded any clinically important difference. The same held true for blood glucose (-1.10; 0.20), total cholesterol (-0.40; 0.20), and the other lipid parameters. More than 60% of the patients reached a diastolic blood pressure < 90 mmHg; adverse events and withdrawals were similar in both groups. Thus, in patients with mild hypertension and type II diabetes, cand.cil. 8 to 16 mg o.i.d. for 12 weeks does not affect glucose homeostasis respectively serum lipids. Blood pressure was controlled in most patients and cand.cil. was well tolerated.
Basic Res Cardiol 1998
PMID:Effects of candesartan cilexetil on glucose homeostasis. Multicenter Study Group. 983 77


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