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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study was designed to determine the effects of angiotensin II type 1 (AT(1)) receptor inhibition on coronary hemodynamics and ventricular mass and hydroxyproline content and the additive effects of angiotensin II type 2 (AT(2)) receptor inhibition in spontaneously hypertensive rats (SHR). The selective AT(1) receptor antagonist candesartan (10 mg/kg per day) was administered alone or in combination with the AT(2) receptor antagonist PD 123319 (50 mg/kg per day) for 12 weeks. Control SHR received placebo for the same period. Left and right ventricular coronary blood flow, blood flow reserve, and minimal coronary vascular resistance were determined by using radiomicrospheres in male 35-week-old rats. Mean arterial pressure; total peripheral resistance; left and right ventricular, renal, and aortic weights; and hydroxyproline concentration were also determined. Candesartan reduced mean arterial pressure and left ventricular, renal, and aortic masses, as well as hydroxyproline concentration and minimal coronary vascular resistance of both ventricles. PD 123319 partially prevented the hypotensive effect of AT(1) receptor inhibition and reversed the effect on myocardial hydroxyproline concentration. These data suggest that AT(2) receptors contribute to the hypotensive and antifibrotic effects but not the coronary hemodynamic improvement or reduced left ventricular mass of AT(1) receptor inhibition in these adult SHR.
Hypertension 2001 Jun
PMID:Coronary hemodynamic and ventricular responses to angiotensin type 1 receptor inhibition in SHR: interaction with angiotensin type 2 receptors. 1140 84

The antihypertensive efficacy and tolerability of the novel angiotensin-II (A-II) receptor blocker candesartan cilexetil and the prototype A-II receptor blocker, losartan, were compared in an 8-week, multicenter, double-blind, randomized, parallel-group, titration-to-effect study of 332 adults (42% women, 12% black) with systemic hypertension (sitting diastolic blood pressure [DBP] 95-114 mmHg, inclusive). In patients with a mean trough (24 +/- 3 hours after dose) sitting DBP of 90 mmHg or higher after 4 weeks of once daily administration of candesartan 16 mg or losartan 50 mg, dose was titrated up to candesartan 32 mg or losartan 100 mg once daily. The candesartan regimen was significantly more effective than the losartan regimen in reducing trough sitting DBP at week 8 (11.0 mmHg versus 8.9 mmHg). Candesartan also produced numerically greater reductions in secondary blood pressure parameters, including sitting systolic blood pressure (SBP), trough standing DBP and SBP, and peak (6 +/- 2.5 hours after dose) sitting and standing DBP and SBP. Responder rates (sitting DBP < 90 mmHg or reduction in blood pressure of > or = 10 mmHg) and control rates (sitting DBP <90 mmHg) were higher with candesartan (64% versus 54% and 54% versus 43%, respectively). A total of 1.9% of the patients taking candesartan and 6.5% of those taking losartan discontinued prematurely because of adverse events or lack of efficacy.
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PMID:Comparative effects of candesartan cilexetil and losartan in patients with systemic hypertension. Candesartan Versus Losartan Efficacy Comparison (CANDLE) Study Group. 1172 Jun 4

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(-1). d(-1) 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(-1). d(-1) and lean rats treated with 1 mg. kg(-1). d(-1) were reduced to 35%, and those of lean rats treated with 10 mg. kg(-1). d(-1) 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(-1). d(-1). In cultured vascular smooth muscle cells from fatty rats, insulin-stimulated Akt (New England Biolabs) phosphorylation and 2-deoxy-D-glucose uptake were inhibited to 59% and 68%, respectively, by angiotensin II, but the effects were ameliorated by the addition of 10(-7) 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.
Hypertension 2001 Dec 01
PMID:Candesartan inhibits carotid intimal thickening and ameliorates insulin resistance in balloon-injured diabetic rats. 1175 99

Hypertension induced by long-term infusion of angiotensin II (Ang II) is associated with augmented intrarenal Ang II levels to a greater extent than can be explained on the basis of the circulating Ang II levels. Although part of this augmentation is due to AT(1) receptor-dependent internalization, the intracellular compartments involved in this Ang II accumulation remain unknown. In the present study, we sought to determine whether Ang II trafficking into renal cortical endosomes is increased during Ang II hypertension, and if so, whether the AT(1) receptor antagonist, candesartan, prevents this accumulation. Compared with controls (n=12; 114+/-2 mm Hg), Ang II-infused rats (n=12; 80 ng/kg/min, SC, for 13 days) developed hypertension with systolic blood pressure rising to 185+/-4 mm Hg by Day 12. In Ang II hypertensive rats, plasma renin activity was suppressed, whereas plasma and kidney Ang II levels were increased by 3-fold (348+/-58 versus 119+/-16 fmol/mL) and 2-fold (399+/-39 versus 186+/-26 fmol/g). Intracellular endosomal Ang II levels were increased by more than 10-fold (1100+/-283 versus 71+/-12 fmol/mg protein), whereas intermicrovillar cleft Ang II levels were increased by more than 2-fold (88+/-22 versus 37+/-7 fmol/mg protein). Flow cytometric analysis detected significant increases in AT(1A) receptor antibody binding in endosomal and intermicrovillar clefts of Ang II-infused rats. The hypertension induced by Ang II was prevented in rats treated concurrently with candesartan (2 mg/kg/d, 119+/-3 mm Hg). Candesartan treatment (n=8) also prevented increases in kidney (215+/-19 fmol/g), endosomal (96+/-29 fmol/mg protein), and intermicrovillar cleft Ang II levels (11+/-2 fmol/mg protein). These results indicate that there is substantial intracellular accumulation of angiotensin peptides in renal cortical endosomes during Ang II-dependent hypertension via an AT(1) receptor-mediated process.
Hypertension 2002 Jan
PMID:Ang II accumulation in rat renal endosomes during Ang II-induced hypertension: role of AT(1) receptor. 1179 89

Candesartan cilexetil is the prodrug of candesartan, an angiotensin II type 1 (AT1) receptor antagonist. Absorbed candesartan cilexetil is completely metabolised to candesartan. Oral bioavailability is low (about 40%) because of incomplete absorption. Plasma protein binding in humans is more than 99%. The volume of distribution in healthy individuals is 0.13 L/kg. CV-15959 is the inactive metabolite of candesartan. Candesartan that reaches the systemic circulation is mainly cleared by the kidneys, and to a smaller extent by the biliary or intestinal route. The apparent oral clearance of candesartan is 0.25 L/h/kg after a single dose in healthy individuals. Oral clearance (3.4 to 28.4 L/h) is highly variable among patients. No relevant pharmacokinetic drug-food or drug-drug interactions are known. The terminal elimination half-life remains unclear, but appears to be longer than the currently used range of 4 to 9 hours. Non-compartmental models do not appear to be appropriate for the analysis of candesartan pharmacokinetic data. A 2-compartment analysis revealed a much longer half-life of 29 hours using data from patients with hypertension. However, a further indepth analysis has never been performed. The concentration-effect relationship is unaffected by age. No gender or race differences have been shown in the effect or pharmacokinetics of candesartan. Renal function affects the pharmacokinetic profile of candesartan. For patients with creatinine clearances of >60 ml/min x 1.73m(2), 30 to 60 ml/min x 1.73m(2) and 15 to 30 ml/min x 1.73m(2), the elimination half-life is 7.1, 10.0 and 15.7 hours, respectively, at a dose of 8 mg/day. However, at 12 mg/day an accumulation factor of 1.71 was found. Thus, a maximum daily dose of up to 8mg appears suitable in patients with severe renal dysfunction. No significant elimination of candesartan occurs with haemodialysis. In patients with mild to moderate hepatic impairment, no relevant pharmacokinetic alterations have been observed. Dosages of up to 12 mg/day do not require precautions in patients with mild to moderate liver disease. Clinically effective dosages range between 8 and 32 mg/day. The response rate of monotherapy with candesartan in patients with hypertension increases with dosage, but never exceeds 60% at a daily dosage of 16mg of candesartan. Dosages up to 32 mg/day do not increase this response rate.
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PMID:Clinical pharmacokinetics of candesartan. 1182 94

Angiotensin II (Ang II) regulates cerebral blood flow by stimulating cerebral vasoconstriction via AT1-receptors. In adult spontaneously hypertensive rats (SHR), the cerebrovascular autoregulatory curve is shifted to the right, in the direction of higher blood pressures, an indication of excessive cerebrovascular vasoconstriction. A restricted capacity to dilate cerebral blood vessels may be responsible for the enhanced vulnerability to cerebrovascular ischaemia during hypertension. We found that chronic treatment with the AT1-receptor antagonist, candesartan, (0.5 mg/kg/day for 14 days, via osmotic minipumps implanted in the subcutaneous tissue) blocked Ang II binding to AT1-receptors in cerebral blood vessels and in brain areas involved in the regulation of cerebrovascular flow, and increased the ratio of lumen-wall area in the middle cerebral artery. Candesartan treatment normalised the lower part of the autoregulatory curve in SHR, and markedly decreased cerebral ischaemia as a consequence of middle cerebral artery occlusion with reperfusion. Protection from ischaemia is related to arterial remodelling, enhanced compensatory vasodilatation in the peripheral area of ischaemia, decreased reduction in cerebral blood flow following the occlusion of a major cerebral blood vessel, and protection from injury in the periphery of the lesion. Our results indicate that pre-treatment with AT1-antagonists such as candesartan could be of benefit in the prevention and treatment of brain ischaemia.
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PMID:Pre-treatment with candesartan protects from cerebral ischaemia. 1188 Nov 19

Although current hypertension management guidelines recommend increasingly stringent blood pressure targets, these targets are seldom achieved in clinical practice. Even in patients with mild-to-moderate hypertension, monotherapy is only effective in approximately 50-70% of patients, and thus there is a clear need for combination therapy if stringent blood pressure targets are to be achieved. Drugs used in combination therapy should satisfy a number of prerequisites, including complementary mechanisms of action, enhanced efficacy in combination, and maintained (or improved) tolerability. Evidence is accumulating that combination therapy with an AT(1)-receptor blocker and a diuretic represents a rational and effective treatment option. In clinical trials, the combination of candesartan cilexetil, 16 mg, and hydrochlorothiazide, 12.5 mg, has been shown to be more effective in lowering blood pressure than either agent alone. Furthermore, this combination has been shown to reduce blood pressure to a greater extent, and control blood pressure in a higher proportion of patients, than the combination of losartan, 50 mg, and hydrochlorothiazide, 12.5 mg, both when used instead of or in addition to previous antihypertensive therapy. The placebo-like tolerability of AT(1)-receptor blockers was maintained when these drugs were used in combination with hydrochlorothiazide. The combination of candesartan and a dihydropyridine calcium antagonist has also been shown to be more effective than either component alone. Furthermore, in the Candesartan and Lisinopril Microalbuminuria (CALM) Study, the combination of candesartan and lisinopril reduced blood pressure to a greater extent than either agent alone, and tended to have a greater effect on microalbuminuria.
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PMID:Combination therapy with AT(1)-receptor blockers. 1214 Jul 24

Hypertension is an established risk factor for stroke and other cerebrovascular disorders. Both stroke and small lacunar infarcts or white matter lesions can cause cognitive impairment and dementia, and there is evidence that vascular risk factors play a major role in the development of both Alzheimer's disease and vascular dementia. Several large epidemiological studies have shown that raised blood pressure in midlife is a strong risk factor for dementia later in life; however, blood pressure often decreases following the development of dementia. The cognitive function hypothesis proposes that elevated blood pressure increases the risk of decline of cognitive function, and that this can be reversed by active lowering of blood pressure. Evidence in support of this hypothesis comes from the Syst-Eur Dementia project, and from a number of smaller studies. SCOPE (Study on Cognition and Prognosis in the Elderly) is a large prospective study involving almost 5000 elderly patients (age 70-89 years), who are randomised to receive candesartan cilexetil, 8-16 mg, or placebo. Candesartan was chosen for this study because it is effective and well tolerated in elderly patients. SCOPE should provide important information on the long-term effects of AT(1)-receptor blocker treatment with candesartan on morbidity-including effects on cognitive function-and cardiovascular mortality in elderly hypertensive patients.
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PMID:Potential for antihypertensive treatment with an AT(1)-receptor blocker to reduce dementia in the elderly. 1214 Jul 32

Guidelines for antihypertensive therapy by World Health Organization/International Society of Hypertension(WHO/ISH) and the Joint National Committee(JNC) have been widely accepted by doctors in the world. In Japan, those for Japanese patients(JSH2000) were prepared last year by Japanese Society of Hypertension considering the difference in the drug metabolism, life style, frequencies of complications, etc. in the elderly. Although angiotensin II receptor antagonists are recommended as one of the first line treatment in JSH2000, no large-scale studies have been conducted in Japan. Therefore, CASE-J study has been designed in order to examine the efficacy of Candesartan Cilexetil, an angiotensin II receptor antagonist, comparing with that of amlodipine besilate, a calcium antagonist, in high-risk hypertensive patients using the incidence of cardiovascular events as an endpoint. The study was started in September 2001 and 4,000 patients will be recruited by December 2002. The results are expected to be presented at the meeting of International Hypertensive Society held in Fukuoka in 2006.
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PMID:[A megatrial of ARB in Japan--CASE-J]. 1239 5

We carried out semiquantitative immunoblotting of kidney to identify apical sodium transporter proteins whose abundances are regulated by angiotensin II. In NaCl-restricted rats (0.5 mEq Na/200 g BW/d), the type 1 angiotensin II receptor (AT1 receptor) antagonist, candesartan, (1 mg/kg of body weight per day SC for 2 days) markedly decreased the abundance of the alpha subunit of the epithelial sodium channel (ENaC). This subunit has been shown to be rate-limiting for assembly of mature ENaC complexes. In addition, systemic infusion of angiotensin II increased alphaENaC protein abundance in rat kidney cortex. The decrease in alphaENaC protein abundance in response to AT1 receptor blockade was associated with a fall in alphaENaC mRNA abundance (real-time RT-PCR), consistent with transcriptionally mediated regulation. The effect of AT1 receptor blockade on alphaENaC expression was not blocked by spironolactone, suggesting a direct role of the AT1 receptor in regulation of alphaENaC gene expression. Candesartan administration was also found to increase the abundances of the beta and gamma subunits. The increase in beta and gammaENaC protein abundance was not associated with a significant increase in the renal abundances of the corresponding mRNAs, suggesting a posttranscriptional mechanism. Immunocytochemistry confirmed the increase in beta and gammaENaC protein abundance and demonstrated candesartan-induced ENaC internalization in collecting duct cells. The results support the view that the angiotensin II receptor regulates ENaC abundance, consistent with a role for angiotensin II in regulation of collecting duct function.
Hypertension 2003 May
PMID:Long-term regulation of ENaC expression in kidney by angiotensin II. 1268 79


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