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Accumulation of Angiotensin II (Ang II) in the kidneys of hypertensive rats infused chronically with Ang II occurs by AT1
111 363 – 368 . [11]. T. Fischer 2006 Referensi megjegyzés a humán érrendszer részeinek egylényegűségéről Orv. Hetil. 147 1145 (Comment to the human vascular system.). [12]. A. M. Heagerty 2004 Effect of AT1-receptor blockade
.: Effect of AT1-receptor blockade on vascular structure and function. Eur. Heart J., 2004, 6 , H17–H21. Heagerty A. M. Effect of AT1-receptor blockade on vascular structure and
The glomerular filtration barrier is a highly specialized tri-layer structure with unique functional properties. Podocyte dysfunction and cytoskeletal disorganization leads to disruption of the slit diaphragma, and proteinuria. Inflammatory diseases involving the kidney as well as inherited podocytopathies or diabetic nephropathy cause injury of the podocyte network. Focal segmental glomerulosclerosis (FSGS) is a pathologic entity that is a common cause of nephrotic syndrome with severe proteinuria in both adults and children. Several causative genes have been identified in the pathogenesis of FSGS. Mutations of the transient receptor potential canonical-6 (TRPC6), a non-selective cation channel that is directly activated by diacylglycerol (DAG), cause a particularly aggressive form of FSGS. Angiotensin II, acting through its AT1 receptor, plays a critical role in generation of proteinuria and progression of kidney injury in a number of kidney diseases, including FSGS. Mounting evidence suggest the central role of TRPC6 and perhaps other TRPC channels in the pathogenesis of FSGS as well as of acquired forms of proteinuria such as diabetic nephropathy or hypertension. Identification of signaling pathways downstream of TRPC6 may provide novel targets for the treatment of proteinuria and prevent progression of podocyte injury.
Valsartan is a potent and specific competitive antagonist of the angiotensin-II AT 1 -receptor and is used orally for treatment of hypertension. A sensitive, selective, precise, and stability-indicating high-performance thin-layer chromatographic method for analysis of valsartan both as the bulk drug and in formulations has been developed and validated. The method uses aluminum-backed silica gel 60F 254 plates with toluene-ethyl acetate-methanol-formic acid 60.0:20.0:20.0:1.0 ( v/v ) as mobile phase. The system gave compact bands for valsartan ( R F 0.44 ± 0.05). Densitometric analysis of valsartan was performed in absorbance mode at 250 nm. Linear regression analysis data for the calibration plots revealed a good linear relationship with r 2 = 0.9946 ± 0.0013 in the working concentration range 200 to 1600 ng per band. The method was validated for precision, robustness, and recovery. The limits of detection and quantification were 25 and 150 ng per band, respectively. Valsartan was subjected to different stress conditions — acid and alkaline hydrolysis, oxidation, photo degradation, and dry and wet heat treatment — as prescribed by International Conference on Harmonization guidelines. The degradation products were well resolved from the pure drug with significantly different R F values. Since the method could effectively separate the drug from its degradation products, it could be used as a stability-indicating method for analysis of valsartan.
Classical densitometry and videoscanning were compared for a new TLC method of quantitative analysis of two AT1 receptor antagonists, candesartan and losartan, in pharmaceuticals. Chromatography was performed on silica gel with 1,4-dioxane-hexane-99% formic acid 5:5:0.1 (ν/ν) as mobile phase. Classical densitometry was performed at the wavelengths of maximum absorption of candesartan (258 nm) and losartan (243 nm) whereas videoscanning was performed at 254 nm for both drugs. Compact spots were obtained for candesartan (R F 0.47 ± 0.01, mean ± SD) and losartan (R F 0.35 ± 0.01). Calibration plots were constructed in the range 0.2–1.4 μg per band for the both drugs and were linear with good correlation coefficients — 0.9997 and 0.9981 for candesartan, and 0.9986 and 0.9982 for losartan, for densitometry and videoscanning, respectively. The methods were validated for robustness, precision, accuracy, and specificity in relation to excipients present in the respective formulations. Finally, the methods were compared statistically in respect of robustness, precision and accuracy.
The antihypertensive effect of sartans is a result of inhibition of the binding of angiotensin (AT) II to the AT1 receptor in vascular smooth muscle. The aim of current study is to apply the validated thin-layer chromatography (TLC)-densitometric method for simultaneous identification and determination of losartan potassium, telmisartan, and valsartan in tablets, by using the following chromatographic system:stationary phase:TLC plates with silica gel G60 F254, mobile phase: 7.5:1.5:5:5:0.01:0.03 = CHCl3-CH3OH-acetone-toluene-CH3COOH, ultraviolet detection at λ= 254 nm, and densitometer CAMAG. Accuracy is represented by the values of the degree of recovery R (%) and relative standard deviation (RSD). All data for R correspond to the relevant confidence interval $ - \bar X - t.S\bar X \div \bar X + t.S\bar X$: tablet Lorista® 99.43 ÷ 102.59, RSD = 1.15; tablet Losap®: 99.37 ÷ 101.87, RSD = 0.89; tablet Micardis®: 99.19 ÷ 99.97, RSD = 0.36; tablet Valtensin®: 98.74 ÷ 101.1, RSD = 0.85. Precision is estimated by the uncertainty of the result, determined by standard deviation (SD), RSD, and confidence interval. All data for the obtained quantity of sartans (C) suit their respective confidence interval: tablet Lorista®: 49.69 ÷ 51.31 (SD = 0.58; RSD = 1.15); tablet Lozap®: 49.7 ÷ 50.92 (SD = 0.45; RSD = 0.89); tablet Micardis®: 79.35 ÷ 79.97 (SD = 0.29; RSD = 0.36); tablet Valtensin®: 157.99 ÷ 161.77 (SD = 1.36; RSD = 0.85).Conclusion: the applied TLC-densitometric method is appropriate for quality control of sartans in dosage drug products — tablets.
This work aims at studying the possible alteration of renal renin secretion after human ischemic stroke and correlating it to the post stroke neurological and renal function alterations using angiotensin II type 1(AT1) receptor blocker (ARB), candesartan, and β 1 adrenoreceptor blocker atenolol, which inhibits renin secretion, in Wistar rats subjected to middle cerebral artery occlusion. Methods . This study comprised 21 patients with cerebral ischemic stroke. Seventeen normal persons were used for comparison. Recumbent and standing plasma renin activity (PRA), reflex plasma renin sensitivity, plasminogen activator inhibitor and creatinine clearance (Ccr) were estimated at admission and two weeks later. Moreover, 60 male Wistar rats were divided into two groups SHAM and ischemic. Each of the two groups was further subdivided into three subgroups, non-treated, atenolol treated, and candesartan treated. In all rats, mean arterial blood pressure (MAP), systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse pressure (PP), heart rate (HR), neurobehavioral evaluation, Ccr, PRA, and infarct size were measured. Results . Together with the significant deterioration of the neurological score, focal cerebral ischemia in rats resulted in increased PRA and decreased glomerular filtration rate (GFR). In ischemic stroke patients, GFR was significantly decreased at admission and two weeks later, PRA increased at admission and two weeks later while plasma renin reflex secretion sensitivity had decreased significantly at admission relative to controls, but it increased significantly 2 weeks later. Atenolol caused significant improvement of the neurobehavioral score and renal function and decrease infarct size of rats subjected to focal cerebral ischemia whereas candesartan caused significant improvement of the neurobehavioral score and decreased infarct size with no significant change in GFR. Neither atenolol nor candesartan caused significant change in MAP, SBP, DBP, PP and HR Conclusion . (1) Ischemic stroke seems to be associated with a postischemic increase of the plasma renin secretion, which may increase the infarct size in the brain and may induce acute renal insufficiency. (2) This study confirms that Atenolol and ARBs could benefit ischemic stroke patients without altering blood pressure.
Prieto-Carrasquero, M. C., Kobori, H., Ozawa, Y., et al.: AT1 receptor-mediated enhancement of collecting duct renin in angiotensin II-dependent hypertensive rats. Am. J. Physiol. Renal. Physiol., 2005, 289 , F632–F637
