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

Candesartan is a highly potent, long-acting and selective angiotensin II type 1 (AT1) receptor blocker. It is administered orally as the inactive prodrug candesartan cilexetil which is rapidly and completely converted to candesartan during gastrointestinal absorption. In vitro studies have shown that candesartan acts as an insurmountable angiotensin II receptor antagonist, binding tightly to and dissociating slowly from the AT1 receptor. The above characteristics are thought to contribute to the marked and long-lasting antihypertensive effects of candesartan cilexetil in several animal models of hypertension. These included rodent models of renal hypertension in which candesartan cilexetil also demonstrated efficacy equivalent to or greater than enalapril. In other animal models, candesartan cilexetil reduced the incidence of stroke, renal dysfunction and renal disease while reducing cardiac and vascular hypertrophy. Furthermore, candesartan cilexetil conferred some protection against cerebral and renal damage at a dose that had no blood pressure-lowering effect. In toxicity and general pharmacology studies, candesartan cilexetil was shown to possess a 'clean' profile with a large safety margin. Also it did not potentiate chemical- or autocoid-induced cough or anaphylactoid reactions.
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PMID:Candesartan cilexetil: a review of its preclinical pharmacology. 933 Sep 99

The effects of the nonpeptide angiotensin II AT1 receptor antagonist candesartan on responses to angiotensin II were investigated in the mesenteric vascular bed of the cat. Under constant-flow conditions, injections of angiotensin II caused dose-related increases in perfusion pressure that were reduced by candesartan in doses of 3, 10, and 30 microg/kg i.v.. After administration of the AT1 receptor antagonist in a dose of 3 microg/kg i.v., the dose-response curve for angiotensin II was shifted to the right in a parallel manner, whereas the administration of higher doses resulted in nonparallel rightward shifts of the angiotensin II dose-response curves. The duration of the inhibitory actions of candesartan were dependent on dose, and the AT1 receptor antagonist did not alter responses to norepinephrine, U46619, vasopressin, neuropeptide Y, BAY K8644, endothelin-1, alpha,beta-methylene ATP, adenosine, acetylcholine, and bradykinin. Treatment with the AT2 receptor antagonist PD123,319 or with sodium meclofenamate did not alter the inhibitory effects of candesartan on responses to angiotensin II. Candesartan also decreased pressor responses to angiotensin III and IV with a parallel shift at the low dose and a nonparallel shift to the right of the dose-response curve at the high dose. These results indicate that candesartan is a potent, selective, long-acting AT1 receptor antagonist that, depending on dose, can produce both competitive and noncompetitive blockade of responses to angiotensin II, III, and IV.
Hypertension 1997 Nov
PMID:Analysis of the effects of candesartan in the mesenteric vascular bed of the cat. 936 85

We previously reported a new animal model of progressive glomerulonephritis induced by a single intravenous injection of the anti-Thy-1 monoclonal antibody MoAb 1-22-3 into uninephrectomized rats (Clin Exp Immunol 102: 181-185, 1995). We examined the effects of angiotensin II (Ang II) receptor antagonist (candesartan) on the clinical features and morphological lesions of this new model. By 10 weeks after induction of nephritis, untreated rats had developed hypertension, massive proteinuria, renal dysfunction, and severe glomerular injury, while uninephrectomized control rats had not. There was a significant increase in levels of glomerular protein and cortical mRNA for transforming growth factor-beta (TGF-beta) and type I and type III collagens in untreated nephritic rats. Ten week treatments with candesartan and hydralazine significantly reduced blood pressure (BP) to an equal extent. Candesartan, but not hydralazine, prevented proteinuria, normalized renal function, and ameliorated glomerular injury. Candesartan also reduced levels of glomerular protein and cortical mRNA for TGF-beta and type I and type III collagens, while hydralazine did not. These findings suggest that candesartan prevents progression to end-stage renal failure by modulating the effects of Ang II at least in part on the production of TGF-beta and type I and type III collagens, and not merely on systemic BP.
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PMID:Candesartan prevents the progression of mesangioproliferative nephritis in rats. 940 66

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.
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PMID:Clinical efficacy of a new AT1 blocker. 983 63

The current study was conducted to determine the potential influence of ibuprofen on the renal and systemic response to AT1 receptor blockade in conscious rats developing spontaneous hypertension. Experiments used spontaneously hypertensive rats (SHR) during the early developmental phase of hypertension (6 to 7 wk old). Six groups of rats were given the following during a 2-wk treatment protocol: (1) candesartan cilexetil (AT1 receptor antagonist) at 1 mg/kg body wt per d; (2) candesartan cilexetil at 10 mg/kg per d; (3) ibuprofen at 30 mg/kg per d; (4) a combination of candesartan cilexetil at 1 mg/kg per d + ibuprofen; (5) candesartan cilexetil at 10 mg/kg per d + ibuprofen; and (6) untreated (controls). All compounds were added to the drinking water at concentrations adjusted to maintain the desired dosage. In the young untreated SHR, systolic arterial pressure significantly increased from 134+/-4 to 170+/-11 mmHg. Candesartan at 1 mg/kg per d prevented any increase in arterial pressure (131+/-5 mmHg at week 0 versus 131+/-4 mmHg at week 2). At a dose of 10 mg/kg per d, candesartan lowered arterial pressure from 131+/-2 to 91+/-4 mmHg. Ibuprofen treatment alone had no effect on the increase in arterial pressure observed in young SHR over the study period, and had no effect on the changes produced by candesartan at either dose. In the two groups of rats receiving candesartan at 10 mg/kg per d (with and without ibuprofen), a significant increase in urine volume and water intake was observed; urine volume rose from 9.5+/-1.0 to 22.9+/-1.1 ml/d in rats given only candesartan and from 11.5+/-0.7 to 22.0+/-0.6 ml/d in rats given candesartan + ibuprofen. Urine volume and water intake were unchanged in all other groups. These effects on water handling are consistent with previous findings that chronic angiotensin II inhibition inhibits water reabsorption in the kidney. These results demonstrate that nonsteroidal anti-inflammatory drug treatment has no effect on the antihypertensive efficacy and diuretic effects of AT1 receptor blockade in rats developing hypertension.
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PMID:Combined treatment with ibuprofen and the AT1 receptor antagonist candesartan in young spontaneously hypertensive rats. 989 51

Candesartan, which is the active compound formed during adsorption of candesartan cilexetil, is one of the new generation of angiotensin II AT1 receptor blockers. Candesartan is an insurmountable blocker with a slow dissociation from the AT1 receptor, and it has been shown to effectively reduce BP in humans and in a variety of genetic and experimental models of hypertension. Possible mechanisms for a better effect in BP reduction compared with losartan may be the insurmountable characteristics of binding or more pronounced renal effects, but these need further evaluation. Candesartan has favorable effects on renal function demonstrated in both humans and animals, and has also been shown to protect the kidney in several models of renal injury. The beneficial effects exerted by candesartan could even be demonstrated in experimental models of hypertension in which BP is affected little, if at all. The renoprotective effects have been observed in the regulation of gene expression, as well as in biochemical and histologic evaluations.
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PMID:Candesartan: a new-generation angiotensin II AT1 receptor blocker: pharmacology, antihypertensive efficacy, renal function, and renoprotection. 989 73

-Previous studies have shown that whereas the nonclipped kidney in two-kidney, one clip (2K1C) rats undergoes marked depletion of renin content and renin mRNA, intrarenal angiotensin II (Ang II) levels are not suppressed; however, the distribution and functional consequences of intrarenal Ang II remain unclear. The present study was performed to assess the plasma, kidney, and proximal tubular fluid levels of Ang II and the renal responses to intrarenal Ang II blockade in the nonclipped kidneys of rats clipped for 3 weeks. The Ang II concentrations in proximal tubular fluid averaged 9.19+/-1.06 pmol/mL, whereas plasma Ang II levels averaged 483+/-55 fmol/mL and kidney Ang II content averaged 650+/-66 fmol/g. Thus, as found in kidneys from normal rats with normal renin levels, proximal tubular fluid concentrations of Ang II are in the nanomolar range. To avoid the confounding effects of decreases in mean arterial pressure (MAP), we administered the nonsurmountable AT1 receptor antagonist candesartan directly into the renal artery of nonclipped kidneys (n=10). The dose of candesartan (0.5 microg) did not significantly decrease MAP in 2K1C rats (152+/-3 versus 148+/-3 mm Hg), but effectively prevented the renal vasoconstriction elicited by an intra-arterial bolus of Ang II (2 ng). Candesartan elicited significant increases in glomerular filtration rate (GFR) (0.65+/-0. 06 to 0.83+/-0.11 mL. min-1. g-1) and renal blood flow (6.3+/-0.7 to 7.3+/-0.9 mL. min-1. g-1), and proportionately greater increases in absolute sodium excretion (0.23+/-0.07 to 1.13+/-0.34 micromol. min-1. g-1) and fractional sodium excretion (0.38+/-0.1% to 1.22+/-0. 35%) in 2K1C hypertensive rats. These results show that proximal tubular fluid concentrations of Ang II are in the nanomolar range and are much higher than can be explained on the basis of plasma levels. Further, the data show that the intratubular levels of Ang II in the nonclipped kidneys of 2K1C rats remain at levels found in kidneys with normal renin content and could be exerting effects to suppress renal hemodynamic and glomerular function and to enhance tubular reabsorption rate.
Hypertension 1999 Jan
PMID:Proximal tubular angiotensin II levels and renal functional responses to AT1 receptor blockade in nonclipped kidneys of Goldblatt hypertensive rats. 993 Oct 89

In an in vivo study, spontaneously hypertensive rats (SHR) were treated with an angiotensin II (Ang II) type 1 receptor antagonist of candesartan or hydralazine. Untreated SHR progressively developed severe hypertension, and treatment with candesartan or hydralazine decreased blood pressure. Candesartan reduced left ventricular (LV) weight, LV wall thickness, transverse myocyte diameter, the relative amount of V3 myosin heavy chain, and interstitial fibrosis, while treatment with hydralazine slightly prevented an increase in LV wall thickness, but did not exert a significant reduction on other parameters. In an in vitro study, neonatal rat cardiomyocytes were cultured on deformable silicone dishes. Stretching cardiomyocytes activated second messengers such as protein kinase C, Raf-1 kinase, and mitogen-activated protein (MAP) kinase, increasing protein synthesis, enhancing endothelin (ET)-1 release, activating the Na+/H+ ion exchanger. Moreover, pretreatment with candesartan diminished an increase in phenylalanine incorporation, MAP kinase activity, and c-fos gene expression induced by the stretching of cardiomyocytes. This suggests that the cardiac renin-angiotensin system is linked to the formation of pressure-overload hypertrophy and that Ang II increases the growth of cardiomyocytes by an autocrine mechanism. Finally, we examined the signalling pathways leading to MAP kinase activation both in cardiac myocytes and in cardiac fibroblasts. Ang II-evoked signal transduction pathways differed between cell types. In cardiac fibroblasts, Ang II activated MAP kinase through a pathway including the Gbetagamma subunit of Gi protein, Src, Shc, Grb2, and Ras, while Gq and protein kinase C were important in cardiac myocytes.
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PMID:Role of tissue angiotensin II in myocardial remodelling induced by mechanical stress. 1007 20

The intrarenal renin-angiotensin system plays a critical role in the paracrine regulation of renal function and the pathophysiology of hypertension. Angiotensin II (AngII) is formed intrarenally from systemically delivered angiotensin I (AngI) and intrarenally formed AngI. Intrarenal AngII content, which is greater than can be explained by the circulating AngII concentrations, is compartmentalized such that proximal tubule concentrations of AngI and AngII greatly exceed plasma concentrations. Proximal tubule cells are thought to secrete AngII or precursors of AngII into the tubular fluid to activate luminal AngII receptors. Recent immunohistochemical studies have demonstrated an abundance of AT1 receptors on the luminal surface of proximal and distal tubule cells and on afferent and efferent arteriolar vascular smooth muscle cells and mesangial cells of glomeruli. Activation of luminal AT1 receptors stimulates tubular sodium reabsorption rate. To evaluate the direct effects of AT1 receptor blockade on renal function in AngII-dependent hypertension, experiments were performed on two-kidney, one-clip (2K1C) Goldblatt hypertensive rats. Although the nonclipped kidney is renin-depleted, the intrarenal AngII levels are not suppressed, and AngII concentrations in proximal tubular fluid remain high (10(-8) M). Candesartan was administered into the renal artery of nonclipped kidneys to avoid the confounding consequences of decreases in arterial pressure. Blockade of intrarenal AT1 receptors elicited significant increases in GFR, renal blood flow, sodium excretion, and fractional sodium excretion, suggesting synergistic actions on tubular transport and vascular smooth muscle cells.
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PMID:Intrarenal angiotensin II generation and renal effects of AT1 receptor blockade. 1020 81

The purpose of this study was to compare the angiotensin II type 1 receptor antagonist candesartan cilexitil (candesartan) and the angiotensin-converting enzyme inhibitor cilazapril on cardiac function, assessed by Doppler echocardiography and cardiac gene expression associated with cardiac remodeling, in rats with myocardial infarction. Candesartan or cilazapril was administered after myocardial infarction. At 1 and 4 weeks after myocardial infarction, cardiac function and mRNA expression in noninfarcted myocardium were analyzed. Candesartan and cilazapril equally prevented increases in hypertrophy in noninfarcted myocardium, left ventricular dilatation, and ejection fraction at 4 weeks. The E-wave/A-wave velocity ratio and the rate of E-wave deceleration, measures of diastolic function, increased to 9.2+/-0.6 and 26.3+/-2. 6 m/s2 at 1 week after myocardial infarction. Candesartan and cilazapril, administered at a dose of 1 mg/kg per day, prevented increases in E-wave/A-wave velocity ratio and E-wave deceleration at 1 and 4 weeks. Candesartan and cilazapril significantly suppressed increased mRNA expression of beta-myosin heavy chain, alpha-skeletal actin, and atrial natriuretic peptide in noninfarcted ventricle at 1 and 4 weeks and expression of collagen I and III at 4 weeks to a similar extent. When given at a dose of 10 mg/kg per day, both candesartan and cilazapril prevented cardiac dysfunction and gene expression to the same extent as when given at 1 mg/kg per day. In conclusion, Doppler echocardiography showed that candesartan and cilazapril equally improved systolic and diastolic function and that ventricular remodeling accompanied modulation of cardiac gene expression.
Hypertension 1999 Apr
PMID:Effects of candesartan and cilazapril on rats with myocardial infarction assessed by echocardiography. 1020 31


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