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Nephrol Dial Transplant. 2008 Jul 2;
Satoh M, Fujimoto S, Arakawa S, Yada T, Namikoshi T, Haruna Y, Horike H, Sasaki T, Kashihara N
Background Recent studies showed that angiotensin II type 1 receptor blocker (ARB) slows progression of chronic renal disease in patients with type 2 diabetes, regardless of changes in blood pressure. We showed that the imbalance of nitric oxide (NO) and reactive oxygen species (ROS) due to endothelial NO synthase (eNOS) uncoupling contributed to renal dysfunction in the diabetic nephropathy. The aim of this study was to determine the effects of ARB on uncoupled eNOS in rat diabetic nephropathy. Methods. Diabetes was induced in Sprague-Dawley rats with streptozotocin (65 mg/ kg body weight). After 6 weeks, rats were divided into saline (DM; n = 11) and ARB, losartan groups (DM+Los; n = 11). After 2-week treatment, glomerular ROS production was assessed by 2',7'-dichlorofluorescin diacetate (DCFH-DA)-derived chemiluminescence. Renal NO and ROS production were imaged by confocal laser microscopy after renal perfusion with DCFH-DA and diaminorhodamine-4M acetoxymethyl ester with l-arginine. The dimeric form of eNOS was measured by low-temperature sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Serum tetrahydrobiopterin (BH4) concentrations were determined by high-performance liquid chromatography. Protein and mRNA expression of GTP cyclohydrolase 1 (GTPCH1), key enzyme of BH4 synthesis, were examined. Results Losartan attenuated glomerular ROS production in DM. Accelerated ROS production and diminished bioavailable NO caused by NOS uncoupling were noted in DM glomeruli. Losartan reversed the decreased GTPCH1 and decreased dimeric form of eNOS and glomerular NO production by increased BH4 bioavailability. CONCLUSIONS: ARB improved the NOS uncoupling in diabetic nephropathy by increasing BH4 bioavailability.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 2007 Dec; 29(6): 719-24
Yuan KL, Shi XZ, Lu X, Gao P, Xu GW
OBJECTIVE: To assess the therapeutic effect of losartan on type 2 diabetes mellitus (DM2) with gas chromatography (GC)-based metabonomics. METHODS: DM2 patients were dosed with losartan (100 mg/d) and urines were collected at week 8 and 12. The biochemical criteria (blood pressure, urinary albumen, urinary 8-hydroxy-2'-deoxyguanosine and blood creatinine) were analyzed. Urine samples were derivatived and analyzed by GC. Multivariate metabonomics analysis was performed after peak alignment. RESULTS: After 8-12 weeks, losartan showed little curative effect and no remarked changes of biochemical criteria were observed. However, metabonomics analysis revealed that some biomarkers such as glucitol and inositol changed. CONCLUSION: GC-based metabonomics analysis enables the rapid identification of metabolic differences and provides information concerning therapeutic effect of losartan.
Clin Ter. 2008 May-Jun; 159(3): 151-4
Morano S, Cipriani R, Santangelo C, Fallarino M, Carnovale A, Mandosi E, Gatti A, Sensi M, Di Mario U
Aims. Angiotensin converting enzyme inhibitors (ACEIs) and angiotensin II receptor-1 (AT-1) antagonists are used in the treatment of proteinuria of diabetic nephropathy. One of the major pathogenic events in this condition is represented by the alteration of the extracellular matrix protein synthesis by glomerular epithelial cells. Materials and Methods. We evaluated the effects of the angiotensin converting enzyme inhibitor, Enalaprilat, and the AT-1 receptor antagonist, Losartan, on mRNA fibronectin and laminin synthesis by glomerular epithelial cells, in conditions mimicking hyperglycemia. Results. In high glucose conditions, Enalaprilat reduced significantly the mRNA expression of fibronectin (p 0.03), but not significantly that of laminin. Losartan addition to high glucose incubated cells reduced (-30%) mRNA expression of fibronectin, and significantly (p 0.05) the mRNA expression of laminin.Conclusions. In addition to the known hemodynamic effects, the improvement of renal function in diabetic patients treated with these compounds may also be due to a modulator effect on extracellular matrix content and composition. Clin Ter 2008; 159(3):151-154.
J Cardiovasc Pharmacol Ther. 2008 Jul 1;
Crespo MJ, Cruz N, Altieri PI, Escobales N
To assess the role of the renin-angiotensin (RAS) and adrenergic systems in the development and progression of dilated cardiomyopathy in the Syrian cardiomyopathic hamster (SCH), echocardiographic parameters were evaluated in 6-month-old animals after 5 months of treatment with enalapril (25 mg/kg/day) plus losartan (10 mg/kg/day), or with carvedilol (1 mg/kg/day). Cardiac output indexes (COI) increased by 53% after RAS blockade and by 20% after beta-blockade in SCH. Moreover, LVEDV and LVESV decreased 30% and 62%, respectively (P < .05) during RAS blockade, whereas ejection fraction (EF) increased by 48%. By contrast, carvedilol reduced LVESV by only 28% (P < .05) and increased EF by only 15% (P < .05). These results suggest that RAS activation plays a critical role in the development of cardiac dysfunction in SCH and that suppression of RAS may be more effective than beta-blockade in retarding the development of cardiomyopathy in SCH. Owing to timing (pre-heart failure stage) and to the single dose protocol, the implications of this study for human subjects remain to be clarified.
Biol Pharm Bull. 2008 Jul; 31(7): 1356-61
Yayama K, Miyagi R, Sugiyama K, Sugaya T, Fukamizu A, Okamoto H
Angiotensin II (Ang II) is an important mediator stimulating liver fibrosis after liver injury. However, it is not known whether Ang II plays a role in liver regeneration. Here, we investigate the effects of Ang II type 1 (AT(1)) receptor blocker (ARB), angiotensin-converting enzyme inhibitor (ACEI), systemic infusion of Ang II, and genetic deficiency of the AT(1a) receptor (AT1a-KO) on the hepatic regenerative response to partial hepatectomy (PH) in mice. Administration of ARB (candesartan cilexetil and losartan) or ACEI (enarapril and lisinopril) enhanced 5-bromo-2'-deoxyuridine (BrdU) incorporation into hepatocyte nuclei in remnant liver as well as the restoration of liver weight after PH. Systemic infusion of Ang II (100 ng/kg/min) suppressed the PH-induced BrdU incorporation and the restoration of liver weight. In contrast to Ang II infusion, these hepatic responses to PH were significantly greater in AT1a-KO mice than in wild-type mice. The PH-induced increases in hepatic levels of hepatocyte growth factor (HGF) mRNA and plasma HGF concentrations were greater in candesartan- and enarapril-treated mice or in AT1a-KO mice than in vehicle-treated mice or wild-type mice, respectively, whereas they were less in Ang II-infused mice than in vehicle-infused mice. In contrast to HGF, blockades of the renin-angiotensin system or Ang II infusion produced opposite effects on the PH-induce increases in hepatic transforming growth factor (TGF)-beta 1 mRNA and plasma TGF-beta 1 levels. These studies suggest that Ang II plays a role in the liver regeneration as a suppressor of hepatocyte proliferation via the AT(1) receptor-mediated control of growth factor production.
Exp Physiol. 2008 Jun 27;
Badzyñska B, Sadowski J
While PGE2 is an established renal vasodilator, EP receptor studies suggest it also has vasoconstrictor potential. PGE2 is much more abundant in the medulla than cortex, yet likely differences in effects between zones have not been defined. This study is focused on different vascular effects in the cortex and medulla and interaction with the renin-angiotensin (R-A) system. In anaesthetised rats, the effects of COX blockade and of PGE2 infused into the renal artery or renal interstitium were examined. Total renal blood flow was measured by ultrasonic renal artery probe, and local perfusion, separately, of the superficial cortex, outer- and inner medulla, as laser-Doppler fluxes. Indomethacin, 5 mg kg-1 i.v., increased cortical perfusion (~10%) and decreased medullary perfusion (~20%). Renal artery infusion of PGE2, 15-30 microg kg-1 h-1, increased cortical and medullary perfusion only transiently. Previous inactivation of the R-A system using losartan or captopril, and background infusion of exogenous angiotensin II, prevented the transient increase and enhanced the subsequent stable decrease in perfusion. PGE2 infused into the medullary interstitium (7-22 microg kg-1 h-1) increased medullary perfusion 13% while cortical perfusion decreased 6%. Misoprostol, an agonist of constrictor EP3 receptors decreased perfusion of the cortex and medulla, with both renal artery and medullary interstitial infusion. In conclusion, in rat renal cortex the dominating stable PGE2 effect is vasoconstriction, most probably mediated by EP3 receptors and unrelated to activation of the R-A system. PGE2 applied to the cortical or medullary interstitium, a natural route for paracrine agents, induces medullary vasodilatation.
J Pharm Biomed Anal. 2008 May 21;
Obando MA, Estela JM, Cerdà V
In this paper, a combination of multi-syringe chromatography analysis technique with extraction disks sorbents for the pre-concentration and determination of hydrochlorothiazide and losartan potassium in superficial water, groundwater and wastewater outlet samples has been developed. The system developed was proved for the determination of hydrochlorothiazide and losartan potassium in spiked water samples with recoveries ranging from 95 to 118%. The method involves the on-line enrichment of the targeted analytes from spiked water samples onto a Cation-SR sorbent material. The analytes are subsequently eluted and transported to the monolithic column, Chromolith Flash RP-18e column (25mmx4.6mm i.d.). The mobile phase used was 10mM potassium dihydrogen phosphate (pH 3.0):acetonitrile:methanol (60:30:10 v/v/v), flow-rate 0.8mLmin(-1). UV detection is carried out at 226nm. Under the optimized chemical and physical variables, the detection limit for hydrochlorothiazide and losartan potassium calculated as 3Syx/b was 0.07 and 0.09mgL(-1), respectively, for a sample loading volume of 1.0mL.
J Renin Angiotensin Aldosterone Syst. 2008 Jun; 9(2): 112-8
De Mello WC
The influence of intracellular renin plus angiotensinogen (Ao) as well as angiotensin (Ang) II on cell volume was investigated in myocytes isolated from the heart of four-month-old cardiomyopathic hamsters (TO-2) and normal hamsters (F1B). Measurements of cell width and cell length were performed on quiescent cells using a Px-it imaging and computer system. The cell volume was calculated assuming the cells as elliptical cylinders and taking the cell depth equal to one third of cell width. For measurements of sodium pump current, the cells were voltage clamped (holding potential -40 mV) using the whole cell configuration. Cells were exposed to K-free solution to inhibit the pump and then to normal Krebs solution to reactivate the pump. In other experiments the cells were voltage clamped (holding potential -40 mV) and changes in the background current elicited by renin plus Ao or by Ang II were monitored. The results indicated that: a) intracellular dialysis of renin (128 pmol Ang I/ml) plus Ao (110 pmol Ang I generated by renin by exhaustion) decreased the cell volume concurrently with the activation of the sodium pump; b) intracellular losartan (10-8 M) or extracellular ouabain (10-8 M) abolished the effect of renin plus Ao on cell volume; c) intracellular Ang II (10-8 M), by itself, reduced cell volume and increased the pump current density; d) extracellular administration of renin plus Ao, at the same concentration used intracellularly, increased cell volume and inhibited the sodium pump. This increase of cell volume elicited by extracellular renin plus Ao was related to the activation of the Na-K-2Cl cotransporter; e) intracellular Ang II (10-8 M) reversed cell swelling induced by hypotonic solutions. Conclusions: Intracellular and extracellular renin plus Ao have opposite effects on sodium pump and cell volume regulation in the failing heart. Both effects of renin plus Ao are dependent upon the formation of Ang II. Since intracellular Ang II counteracted the cell swelling induced by hypotonic solution, it is reasonable to think that the activation of the intracrine renin-angiotensin system might play a protective role during myocardial ischaemia by reducing cell volume.
J Renin Angiotensin Aldosterone Syst. 2008 Jun; 9(2): 107-11
Sekuri C, Utuk O, Bayturan O, Bilge A, Kurhan Z, Tavli T
OBJECTIVES: The aim of this study was to assess the effects of losartan treatment on exercise tolerance and echocardiographic parameters in patients with mitral regurgitation (MR) secondary to mitral valve prolapse or rheumatic heart disease. METHODS: Twenty-seven patients (14 males, 13 females, mean age 51+/-11, range 21-76) with moderate MR due to mitral valve prolapse or rheumatic heart disease were examined by means of Doppler echocardiography. The subjects were submitted to treadmill exercise tests using the modified Bruce protocol at baseline, after six hours and after the six-week treatment period to be evaluated based on their exercise tolerance. Mitral Regurgitant Volume (MRV), effective regurgitant orifice diameter, left atrial volume, left ventricle (LV) end-diastolic volume index, LV end-systolic volume index, LV ejection fraction (LVEF), left ventricle mass index were calculated at baseline and after six weeks of treatment with single dose of losartan (50 mg/day). RESULTSs: Total treadmill exercise time increased from 477.7+/-147.9 to 535.7+/-149.0 seconds after six hours (p
[Perindopril and losartan attenuate bleomycin A5-induced pulmonary fibrosis in rats.]
Nan Fang Yi Ke Da Xue Xue Bao. 2008 Jun; 28(6): 919-24
Meng Y, Meng Y, Li X, Cai SX, Tong WC, Cheng YX
OBJECTIVE: To evaluate the effects of angiotensin-converting enzyme inhibitor (ACEI) and angiotensin II type 1 receptor (AT-1 receptor) blocker on the progression of rat pulmonary fibrosis induced by bleomycin A5. METHODS: Twenty-four male Wistar rats were randomized into pulmonary fibrosis model, perindopril treatment, losartan treatment and control groups. In the former 3 groups, pulmonary fibrosis was induced via intratracheal injection of bleomycin A5 (5 mg/kg), after which the rats in the perindopril and losartan groups received intragastric administration of the corresponding agents at the daily dose of 2 mg/kg and 10 m/kg, respectively. The rats in the control group had intratracheal injection of normal saline only. In the 4th week, the histological changes of the lung tissues were examined microscopically with Masson staining. Hydroxyproline content in the lungs was measured, and the protein expressions of AT-1 receptor, TGF-beta1 and IkappaBalpha were examined using Western blotting. DNA binding activity of NF-kappaB was analyzed with electrophoretic gel mobility shift assay (EMSA), and zymography was used to assess the activity of matrix metalloproteinase-2 and 9 (MMP-2, 9). RESULTS: Both perindopril and losartan treatment significantly reduced the pulmonary fibrosis score, content of hydroxyproline, protein expression of TGF-beta1, DNA binding activity of NF-kappaB and MMP-2, 9 activity, and increased cytoplasmic protein expression of IkappaBalpha. Perindopril treatment lowered the protein level of AT-1 receptor. CONCLUSION: Perindopril and losartan may inhibit bleomycin A5-induced pulmonary fibrosis in rats by reducing the protein expression of TGF-beta1 and suppressing the DNA binding activity of NF-kappaB and MMP-2, 9 activity.