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

The angiotensin II receptor blockers (ARBs) are safe and effective agents in the treatment of hypertension, and they have potential in treating other cardiovascular disorders such as heart failure. These drugs share a common mechanism of action: They selectively block the angiotensin type 1 (AT1) receptor. A new ARB, candesartan cilexetil is a prodrug that is converted completely into the active metabolite candesartan during gastrointestinal absorption, whereas losartan is converted partially by hepatic metabolism into the more active compound EXP 3174. Valsartan and irbesartan are active in their own right. These ARBs differ pharmacologically in terms of their affinity for the AT1 receptor, the mechanism by which they block the receptor, and the duration of their receptor-blocking activity. In radioligand-binding studies, candesartan had a slightly higher affinity for the AT1 receptor than the other ARBs. In the rabbit aorta, candesartan blocked angiotensin II-induced contractions in an insurmountable manner, whereas losartan blocked the contractions competitively, and EXP 3174, valsortan and irbesartan blocked the contractions in a manner intermediate between competitive and insurmountable antagonism. The insurmountable antagonism exhibited by candesartan likely reflects its long-lasting blockade of the AT1 receptor due to a slow dissociation rate. This suggests that candesartan will exhibit a longer duration of action than would be predicted simply from its pharmacokinetic elimination half-life. Comparative clinical trials with several ARBs are needed to define the clinical significance of these pharmacologic differences.
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PMID:Significance of angiotensin type 1 receptor blockade: why are angiotensin II receptor blockers different? 1058 89

Angiotensin type 2 (AT(2)) receptors for angiotensin II suppress cell growth and induce apoptosis in vitro, but their role is poorly defined in vivo. We reported that transient induction of smooth muscle cell (SMC) apoptosis precedes DNA synthesis inhibition and aortic hypertrophy regression in spontaneously hypertensive rats treated with the AT(1) antagonist losartan or the converting-enzyme inhibitor enalapril. Although both drugs are equipotent in reducing SMC number, apoptosis occurs significantly earlier with losartan than enalapril. To examine the role of AT(2) receptors in this model, spontaneously hypertensive rats were given valsartan, an AT(1) antagonist, or enalapril, in combination or not with the AT(2) antagonist PD123319 for 1 or 2 weeks. Control rats received vehicle. Systolic blood pressure was reduced similarly by valsartan and enalapril but it was not significantly affected by PD123319. Angiotensin II plasma levels were increased (6-fold) with valsartan and reduced (80%) with enalapril but unaffected by PD123319. Valsartan significantly increased internucleosomal DNA fragmentation indicative of apoptosis at 1 week only (2.7-fold) and significantly reduced aortic mass (18%), SMC number (33%), and DNA synthesis (24%, measured by (3)H-thymidine incorporation) at 2 weeks. These valsartan-induced changes were prevented by PD123319. In contrast, enalapril-induced DNA fragmentation (2-fold increase at 2 weeks) was not affected by PD123319. PD123319 given alone did not affect growth or apoptosis. AT(1) and AT(2) receptor mRNAs were detected in the aorta by reverse transcription-polymerase chain reaction. Together, these results provide the first evidence that AT(2) receptors mediate vascular mass regression by stimulating SMC apoptosis in vivo, an effect seen during AT(1) receptor blockade but not during converting-enzyme inhibition.
Hypertension 2000 May
PMID:Proapoptotic and growth-inhibitory role of angiotensin II type 2 receptor in vascular smooth muscle cells of spontaneously hypertensive rats in vivo. 1081 66

Successful treatment of hypertension entails not only normalizing high blood pressure, but also addressing the associated risk factors that increase the likelihood of cardiovascular morbidity and mortality. Hypertension often occurs in a setting of insulin resistance, hyperinsulinemia, dyslipidemia, and a prothrombotic state. A number of epidemiologic studies have shown that the clustering of these abnormalities is associated with increased risk of cardiovascular morbidity and mortality. Therefore, it is rational to direct therapy at moderating these risk factors as well as at lowering blood pressure in hypertensive patients. This is particularly important in patients with comorbidities such as diabetes, cardiovascular disease, or renal insufficiency. Many physicians prescribe only diuretics and beta-blockers, agents that have demonstrated efficacy in long-term randomized controlled trials. However, this approach does not consider the potential benefits of newer agents for which long-term outcome data are not yet available. The ongoing Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial, in which the angiotensin II subtype 1 receptor blocker valsartan is compared with the third-generation calcium channel blocker amlodipine, should provide important evidence on the long-term efficacy of these newer agents. A unique feature of VALUE is that it is specifically enrolling into the only current trial, now under way, hypertensive men and women at a relatively high risk for a cardiovascular event to determine the benefits of complete blockade of angiotensin II beyond those of the control of blood pressure.
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PMID:Treating high-risk hypertensive patients. 1083 Jul 92

Tissue factor (TF), a main initiator of clotting, is up-regulated in vasculopathy. We tested the hypothesis that chronic in vivo angiotensin (ANG) II receptor AT(1) receptor blockade inhibits TF expression in a model of ANG II-induced cardiac vasculopathy. Furthermore, we explored the mechanisms by examining transcription factor activation and analyzing the TF promoter. Untreated transgenic rats overexpressing the human renin and angiotensinogen genes (dTGR) feature hypertension and severe left ventricular hypertrophy with focal areas of necrosis, and die at age 7 weeks. Plasma and cardiac ANG II was three- to fivefold increased compared to Sprague-Dawley rats. Chronic treatment with valsartan normalized blood pressure and coronary resistance completely, and ameliorated cardiac hypertrophy (P < 0.001). Valsartan prevented monocyte/macrophage infiltration, nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1) activation, and c-fos expression in dTGR hearts. NF-kappaB subunit p65 and TF expression was increased in the endothelium and media of cardiac vessels and markedly reduced by valsartan treatment. To analyze the mechanism of TF transcription, we then transfected human coronary artery smooth muscle cells and Chinese hamster ovary cells overexpressing the AT(1) receptor with plasmids containing the human TF promoter and the luciferase reporter gene. ANG II induced the full-length TF promoter in both transfected cell lines. TF transcription was abolished by AT(1) receptor blockade. Deletion of both AP-1 and NF-kappaB sites reduced ANG II-induced TF gene transcription completely, whereas the deletion of AP-1 sites reduced transcription. Thus, the present study clearly shows an aberrant TF expression in the endothelium and media in rats with ANG II-induced vasculopathy. The beneficial effects of AT(1) receptor blockade in this model are mediated via the inhibition of NF-kappaB and AP-1 activation, thereby preventing TF expression, cardiac vasculopathy, and microinfarctions.
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PMID:Angiotensin II (AT(1)) receptor blockade reduces vascular tissue factor in angiotensin II-induced cardiac vasculopathy. 1088 Mar 68

1. The structure of the basilar artery and the relationship of structure to blood pressure and ventricular hypertrophy was examined in genetically hypertensive (GH) rats, their control normotensive (N) Wistar strain, GH given the nitric oxide synthase (NOS) inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME) and GH given L-NAME and either valsartan or enalapril. 2. Systolic blood pressure (SBP; tail-cuff) was measured weekly from age 7-12 weeks. At the end of the experiment at 12 weeks, the basilar artery was fixed by perfusion and embedded in Technovit (Heraeus Kulzer GmbH, Werheim, Germany). Serial sections were cut and stained and stereological analysis applied to quantify the morphology of the vessels. Left ventricular (LV) mass was determined. 3. Both SBP and LV mass were significantly increased in GH compared with N (P < 0.001) and increased further in GH given L-NAME (P < 0.05). The GH L-NAME + valsartan and GH L-NAME + enalapril groups had significantly lower (P < 0.001) SBP and LV mass than the GH L-NAME group. 4. Basilar arteries in GH (which are frankly hypertensive, but have no apparent endothelial defect) showed hypotrophic inward remodelling compared with the N control group with no change in media to lumen ratio. 5. In the GH L-NAME group, further inward remodelling occurred and the media to lumen ratio was increased compared with N (P < 0.01) and GH (P < 0.05). Valsartan treatment in GH L-NAME rats caused eutrophic outward remodelling. Enalapril caused hypertrophic outward remodelling, suggesting that the angiotensin II-stimulated growth was not entirely suppressed with an angiotensin-converting enzyme inhibitor or that there was a bradykinin effect with enalapril. 6. In GH with an endothelial defect induced by treatment with L-NAME, the further remodelling, together with an increased media to lumen ratio and the development of a stroke-like syndrome, indicates the NOS-inhibited GH rat may be a useful model for essential hypertension (where it is known that endothelial abnormalities exist) and where stroke can develop as a consequence of the hypertension.
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PMID:Basilar artery remodelling in the genetically hypertensive rat: effects of nitric oxide synthase inhibition and treatment with valsartan and enalapril. 1090 98

(1) Valsartan is a antihypertensive drug belonging to the family of angiotensin II receptor antagonists. (2) At a dose of 40 mg/day its antihypertensive effect is inconsistent. (3) At 80 mg/day its effect on blood pressure, its adverse effects and its contraindications (mainly pregnancy and renal artery stenosis) are similar to those of angiotensin-converting-enzyme (ACE) inhibitors, except that coughing is rarer with valsartan than with ACE inhibitors. (4) Valsartan has no demonstrated advantage over losartan, another angiotensin II antagonist. (5) Valsartan has not been shown to prevent the complications of arterial hypertension, and its use is therefore less well validated than that of diuretics and betablockers.
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PMID:Valsartan: new preparation. Just a second-line antihypertensive drug. 1091 19

We examined whether xanthine oxidoreductase (XOR), a hypoxia-inducible enzyme capable of generating reactive oxygen species, is involved in the onset of angiotensin (Ang) II-induced vascular dysfunction in double-transgenic rats (dTGR) harboring human renin and human angiotensinogen genes. In 7-week-old hypertensive dTGR, the endothelium-mediated relaxation of noradrenaline (NA)-precontracted renal arterial rings to acetylcholine (ACh) in vitro was markedly impaired compared with Sprague Dawley rats. Preincubation with superoxide dismutase (SOD) improved the endothelium-dependent vascular relaxation, indicating that in dTGR, endothelial dysfunction is associated with increased superoxide formation. Preincubation with the XOR inhibitor oxypurinol also improved endothelium-dependent vascular relaxation. The endothelium-independent relaxation to sodium nitroprusside was similar in both strains. In dTGR, serum 8-isoprostaglandin F(2alpha), a vasoconstrictor and antinatriuretic arachidonic acid metabolite produced by oxidative stress, was increased by 100%, and the activity of XOR in the kidney was increased by 40%. Urinary nitrate plus nitrite (NO(x)) excretion, a marker of total body NO generation, was decreased by 85%. Contractile responses of renal arteries to Ang II, endothelin-1 (ET-1), and NA were decreased in dTGR, suggesting hypertension-associated generalized changes in the vascular function rather than a receptor-specific desensitization. Valsartan (30 mg/kg PO for 3 weeks) normalized blood pressure, endothelial dysfunction, and the contractile responses to ET-1 and NA. Valsartan also normalized serum 8-isoprostaglandin F(2alpha) levels, renal XOR activity, and, to a degree, NO(x) excretion. Thus, overproduction of Ang II in dTGR induces pronounced endothelial dysfunction, whereas the sensitivity of vascular smooth muscle cells to nitric oxide is unaltered. Ang II-induced endothelial dysfunction is associated with increased oxidative stress and vascular xanthine oxidase activity.
Hypertension 2001 Feb
PMID:Endothelial dysfunction and xanthine oxidoreductase activity in rats with human renin and angiotensinogen genes. 1123 Mar 10

Endothelial dysfunction is associated with hypertension, hypercholesterolemia, and heart failure. We tested the hypothesis that spontaneously diabetic Goto-Kakizaki (GK) rats, a model for type 2 diabetes, exhibit endothelial dysfunction. Rats also received a high-sodium diet (6% NaCl [wt/wt]) and chronic angiotensin type 1 (AT(1)) receptor blockade (10 mg/kg PO valsartan for 8 weeks). Compared with age-matched nondiabetic Wistar control rats, GK rats had higher blood glucose levels (9.3+/-0.5 versus 6.9+/-0.2 mmol/L for control rats), 2.7-fold higher serum insulin levels, and impaired glucose tolerance (all P<0.05). Telemetry-measured mean blood pressure was 15 mm Hg higher in GK rats (P<0.01) compared with control rats, whereas heart rates were not different. Heart weight- and kidney weight-to-body weight ratios were higher in GK rats (P<0.05), and 24-hour albuminuria was increased 50%. Endothelium-mediated relaxation of noradrenaline-precontracted mesenteric arterial rings by acetylcholine was impaired compared with the control condition (P<0.05), whereas the sodium nitroprusside-induced relaxation was similar. Preincubation of the arterial rings with the NO synthase inhibitor N(G)-nitro-L-arginine methyl ester and the cyclooxygenase inhibitor diclofenac inhibited relaxations to acetylcholine almost completely in GK rats but not in Wistar rats, suggesting that endothelial dysfunction can be in part attributed to reduced relaxation via arterial K(+) channels. Perivascular monocyte/macrophage infiltration and intercellular adhesion molecule-1 overexpression were observed in GK rat kidneys. A high-sodium diet increased blood pressure by 24 mm Hg and 24-hour albuminuria by 350%, induced cardiac hypertrophy, impaired endothelium-dependent relaxation further, and aggravated inflammation (all P<0.05). The serum level of 8-isoprostaglandin F(2alpha), a vasoconstrictor and antinatriuretic arachidonic acid metabolite produced by oxidative stress, was increased 400% in GK rats on a high-sodium diet. Valsartan decreased blood pressure in rats fed a low-sodium diet and prevented the inflammatory response. In rats fed a high-sodium diet, valsartan did not decrease blood pressure or improve endothelial dysfunction but protected against albuminuria, inflammation, and oxidative stress. As measured by quantitative autoradiography, AT(1) receptor expression in the medulla was decreased in GK compared with Wistar rats, whereas cortical AT(1) receptor expression, medullary and cortical angiotensin type 2 (AT(2)) receptor expressions, and adrenal ACE and neutral endopeptidase expressions were unchanged. A high-sodium diet did not influence renal AT(1), AT(2), ACE, or neutral endopeptidase expressions. In valsartan-treated GK rats, the cortical and medullary AT(1) receptor expressions were decreased in the presence and absence of a high-sodium diet. A high-sodium diet increased plasma brain natriuretic peptide concentrations in presence and absence of valsartan treatment. We conclude that hypertension in GK rats is salt sensitive and associated with endothelial dysfunction and perivascular inflammation. AT(1) receptor blockade ameliorates inflammation during a low-sodium diet and partially protects against salt-induced vascular damage by blood pressure-independent mechanisms.
Hypertension 2001 Feb
PMID:Endothelial dysfunction and salt-sensitive hypertension in spontaneously diabetic Goto-Kakizaki rats. 1123 Mar 14

Previous studies have shown that angiotensin II stimulates the synthesis of plasminogen activator inhibitor-1 in cultured vascular cells, which suggests that activation of the renin-angiotensin system may impair fibrinolysis. We have investigated the effects of angiotensin II and of valsartan, a recently developed angiotensin II antagonist that is highly specific and selective for the angiotensin II subtype 1 receptor, on plasminogen activator inhibitor-1 secretion by smooth muscle cells isolated from rat and human vessels. Angiotensin II induced a time- and concentration-dependent increase of plasminogen activator inhibitor activity in supernatants of rat aortic cells, which reached a plateau after 6 hours of incubation with 100 nmol/L angiotensin II (2.4+/-0.6-fold over control value; P:<0.001). The angiotensin II-induced plasminogen activator inhibitor activity was inhibited, in a concentration-dependent manner, by valsartan with an IC(50) value of 21 nmol/L. Valsartan fully prevented the angiotensin II-induced increase in plasminogen activator inhibitor-1 protein and mRNA. Furthermore, angiotensin II doubled the secretion of plasminogen activator inhibitor-1 by smooth muscle cells obtained from human umbilical and internal mammary arteries, and valsartan fully prevented it. Angiotensin II did not affect the secretion of tissue plasminogen activator antigen by any of the cell systems tested. Thus, valsartan effectively inhibits angiotensin II-induced plasminogen activator inhibitor-1 secretion without affecting that of tissue plasminogen activator in arterial rat and human smooth muscle cells.
Hypertension 2001 Mar
PMID:Effect of valsartan on angiotensin II-induced plasminogen activator inhibitor-1 biosynthesis in arterial smooth muscle cells. 1124 25

Valsartan is a highly selective, orally available antagonist of the angiotensin Type 1 (AT1) receptor. It is indicated for treatment of mild to moderate essential hypertension. Experimental studies have confirmed the abolition or attenuation of angiotensin II (AII)-related effects, such as vasoconstriction, cell growth promotion and aldosterone release. In humans, valsartan is rapidly absorbed with maximal plasma concentrations occurring 1-2 h after oral administration. The elimination half-life comes to about 7-8 h, valsartan is metabolised to a negligible extent and most of the drug is excreted via the faeces. There is no dose adjustment required for patients with a creatinine clearance > 10 ml/min. The dose should not exceed 80 mg o.d. in patients with hepatic dysfunction, valsartan is not recommended for patients with severe hepatic dysfunction and/or biliary cirrhosis. At present, no clinically relevant pharmacokinetic drug interactions have been observed. Valsartan produces persistent blood pressure reductions in patients with mild to moderate hypertension, the recommended starting dose is 80 mg o.d. If required, the dose may either be increased to 160 mg o.d. or hydrochlorothiazide may be added. In comparison to other antihypertensive drugs valsartan therapy leads to similar blood pressure reductions, while exhibiting a favourable tolerability profile. Preliminary studies suggest beneficial effects in patients with hypertensive end-organ damage such as renal disease and left ventricular hypertrophy. Furthermore, the drug is evaluated for its efficacy in heart failure and patients post-myocardial infarction.
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PMID:Valsartan: a novel angiotensin type 1 receptor antagonist. 1124 53


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