Effect of an angiotensin II receptor antagonist, candesartan, on insulin resistance and pressor mechanisms in essential hypertension

Higashiura, Katsuhiro; Ura, Nobuyuki; Miyazaki, Yoshinori; Shimamoto, Kazuaki

doi:10.1038/sj.jhh.1000748

Cited by 45 publications

(27 citation statements)

References 22 publications

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“…In contrast, recent studies have shown that TCV-116 is clinically superior to losartan in reducing blood pressure by tight binding and slow dissociation to the AT 1 receptor. 21,22 Furthermore, Higashiura et al 23 have demonstrated that treatment with the agent increases insulin sensitivity assessed by the M-value in patients with essential hypertension. These results may have enhanced the amelioration of insulin resistance in the present study.…”

Section: Discussionmentioning

confidence: 99%

Candesartan Inhibits Carotid Intimal Thickening and Ameliorates Insulin Resistance in Balloon-Injured Diabetic Rats

et al. 2001

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Abstract-This study investigates the effects of candesartan, an angiotensin II type 1 receptor blockade, on carotid arterial intimal thickening and glucose tolerance in balloon-injured male Wistar fatty rats and their littermates (Wistar lean rats). Candesartan was orally administered to 12-week-old rats for 21 days, and age-matched rats without the agent were used as the respective controls. Balloon catheterization in the left common carotid artery was performed on day 7, and the artery was removed on day 14 for histological analysis. Compared with the area ratios of the neointima/media in fatty rats without treatment, the ratios in fatty rats treated with candesartan at 1 mg · kg Ϫ1 · d Ϫ1 and lean rats without treatment were significantly decreased to 65%; on the other hand, the ratios of fatty rats treated with candesartan at 10 mg · kg Ϫ1 · dϪ1 and lean rats treated with 1 mg · kg Ϫ1 · d Ϫ1 were reduced to 35%, and those of lean rats treated with 10 mg · kg Ϫ1· d Ϫ1 were reduced to 28%. The administration of candesartan also decreased the level of plasma glucose time-and dose-dependently in fatty rats. In an intragastric glucose load, the levels of both glucose and insulin at 30 and 60 minutes were significantly decreased when fatty rats were treated with candesartan at 10 mg · kg Ϫ1 · d Ϫ1. In cultured vascular smooth muscle cells from fatty rats, insulin-stimulated Akt (New England Biolabs) phosphorylation and 2-deoxy-Dglucose uptake were inhibited to 59% and 68%, respectively, by angiotensin II, but the effects were ameliorated by the addition of 10 Ϫ7 mol/L candesartan. We conclude that candesartan could be effective for the suppression of vascular smooth muscle cell growth dose-dependently in Wistar fatty and lean rats. Furthermore, the agent could improve insulin resistance in Wistar fatty rats. Key Words: angiotensin II Ⅲ receptors, angiotensin II Ⅲ rats Ⅲ balloon injury Ⅲ insulin resistance M ultiple epidemiological and clinical studies have established that diabetes mellitus and hypertension are the most crucial risk factors in the pathogenesis of atherosclerosis, including cardiovascular disease and subsequent sudden death. 1-3 Considerable evidence supports the view that insulin resistance, its concomitant compensatory hyperinsulinemia, and the related glucose intolerance are associated with hypertension, 4,5 although the mechanisms of interaction still need to be completely clarified. Therefore, for the prevention of atherosclerosis and diabetic complications, it is necessary to identify the hypotensive agents that are beneficial for glucose metabolism.The renin-angiotensin system plays a key role in the pathogenesis of hypertension and atherosclerosis. In this pathological process, the universal underlying abnormality, which is mainly concerned with alterations in the structure and function of vascular smooth muscle cells (VSMCs), is enhanced by circulating and locally generated angiotensin (Ang) II, which affects the contractility and growth of VSMCs and the sympathetic nervous system. 6 Recen...

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Section: Discussionmentioning

confidence: 99%

Candesartan Inhibits Carotid Intimal Thickening and Ameliorates Insulin Resistance in Balloon-Injured Diabetic Rats

et al. 2001

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“…90 The benefits of ARB therapy of hypertension go beyond the reduction in blood pressure. The additional advantages of ARB therapy include: (1) reduction in left ventricular hypertrophy; 5,22,48,[91][92][93][94][95] (2) improvement in diastolic function; 96 (3) decrease in ventricular arrhythmias; 97 (4) reduction in the abnormal QT dispersion; 98 (5) improvement in endothelial dysfunction; 99 (6) improvement in large artery compliance; 95 (7) reduction in microalbuminuria; 29,35,45,89,100,101 (8) preservation of or improvement in renal function; 36,39,45,[84][85][86][87][88][89] except in patients with severe congestive heart failure or renal artery stenosis; (9) increase in insulin sensitivity; 102,103 and (10) decrease in serum uric acid levels (by only losartan); [104][105][106] hyperuricaemia is associated with increased risk for stroke and heart attack in hypertensive patients. 107 …”

Section: Advantages Of Angiotensin Receptor Blocker Therapy In Hypertmentioning

confidence: 99%

Clinical pharmacokinetics of angiotensin II (AT1) receptor blockers in hypertension

2000

J Hum Hypertens

285

215

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Angiotensin II receptor blockers (ARBs) represent a new class of effective and well tolerated orally active antihypertensive 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, angiotensin-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 antihypertensive 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 (candesartan cilexetil, eprosartan, irbesartan, telmisartan, and valsartan) and three combinations with hydrochlorothiazide (irbesartan, losartan and valsartan) have been approved as antihypertensive agents, and some 28 compounds are in various stages of development.The ARBs are non-peptide compounds with varied structures; some (candesartan, losartan, irbesartan, and valsartan) have a common tetrazolo-biphenyl structure. Except for irbesartan, all active ARBs have a carboxylic acid group. Candesartan cilexetil is a prodrug, while losartan has a metabolite (EXP3174) which is more active than the parent drug. No other metabolites of ARBs contribute significantly to the antihypertensive effect.Keywords: angiotensin receptor blockers; candesartan; eprosartan; irbesartan; losartan; telmisartan; valsartan; pharmacokinetics After oral administration, the ARBs are rapidly absorbed (time for peak plasma levels ‫؍‬ 0.5-4 h) but they have a wide range of bioavailability (from a low of 13% for eprosartan to a high of 60-80% for irbesartan); food does not influence the bioavaila...

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“…19 In contrast, chronic administration of Ang II receptor antagonists to insulin-resistant fructose-fed 12 or spontaneously hypertensive 20 rats or to human subjects with essential hypertension 21 leads to significant improvements in whole-body insulin sensitivity. Moreover, Rao 22 and Richey et al 23 have reported that acute infusion of Ang II leads to substantial reduction in glucose disposal in normal skeletal muscle, which could not be attributed to hemodynamic alterations.…”

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confidence: 99%

Selective Angiotensin II Receptor Antagonism Reduces Insulin Resistance in Obese Zucker Rats

et al. 2001

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Abstract-Effects of oral administration of the angiotensin II receptor antagonist (selective AT 1 -subtype) irbesartan on glucose tolerance and insulin action on skeletal-muscle glucose transport were assessed in the insulin-resistant obese Zucker rat. In the acute study, obese rats received either vehicle (water) or irbesartan 1 hour before the experiment. Although irbesartan had no effect on glucose transport (2-deoxyglucose uptake) in the epitrochlearis muscle, which consists mainly of type IIb fibers, acute angiotensin II receptor antagonism led to a dose-dependent increase in insulin action in the predominantly type I soleus muscle. Irbesartan at 25 and 50 mg/kg induced significant increases (41% and 50%, respectively; PϽ0.05) in insulin-mediated glucose transport. Moreover, these acute irbesartan-induced improvements in soleus-muscle glucose transport were associated with enhancements in whole-body insulin sensitivity (rϭϪ0.732; PϽ0.05), as assessed during an oral glucose tolerance test. After chronic administration of irbesartan (21 days at 50 mg · kg), glucose tolerance was enhanced further, and insulin-mediated glucose transport was significantly elevated in both epitrochlearis (32%) and soleus (73%) muscle. Chronic angiotensin II receptor antagonism was associated with significant increases in glucose transporter-4 (GLUT-4) protein expression in soleus (22%) and plantaris (20%) muscle and myocardium (15%). Chronic irbesartan-induced increases in whole-body insulin sensitivity were associated with increased insulin-mediated glucose transport in both epitrochlearis (rϭϪ0.677; PϽ0.05) and soleus (rϭϪ0.892; PϽ0.05) muscle. In summary, angiotensin II receptor (AT 1 -subtype) antagonism, either acutely or chronically, improves glucose tolerance, at least in part because of an enhancement in skeletal-muscle glucose transport, and the effect of chronic angiotensin II receptor antagonism on type I skeletal-muscle glucose uptake is associated with an increase in GLUT-4 protein expression. Key Words: irbesartan Ⅲ glucose Ⅲ muscle, skeletal Ⅲ transport, glucose Ⅲ rats, Zucker Ⅲ receptors, angiotensin I ndividuals with essential hypertension frequently display a clustering of additional atherogenic risk factors, including insulin resistance of skeletal-muscle glucose uptake, hyperinsulinemia, dyslipidemia, and central adiposity, in a condition described as "insulin resistance syndrome." 1 Angiotensin (Ang) II is a potent vasoconstrictor and can contribute to the pathogenesis of hypertension. 2 Reductions in formation of Ang II, as results from treatment with ACE inhibitors or inhibition of the cellular actions of Ang II by the use of specific Ang II (AT 1 -subtype) antagonists, are effective interventions for lowering blood pressure. [3][4][5] Although both animal model studies 6 -12 and clinical investigations 6,[13][14][15][16][17][18] have demonstrated that ACE inhibitor treatment can ameliorate peripheral insulin resistance, the role of a specific reduction in Ang II action on whole-body and skeletal-muscle ins...

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Effect of an angiotensin II receptor antagonist, candesartan, on insulin resistance and pressor mechanisms in essential hypertension

Cited by 45 publications

References 22 publications

Candesartan Inhibits Carotid Intimal Thickening and Ameliorates Insulin Resistance in Balloon-Injured Diabetic Rats

Candesartan Inhibits Carotid Intimal Thickening and Ameliorates Insulin Resistance in Balloon-Injured Diabetic Rats

Clinical pharmacokinetics of angiotensin II (AT1) receptor blockers in hypertension

Selective Angiotensin II Receptor Antagonism Reduces Insulin Resistance in Obese Zucker Rats

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