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Query: UMLS:C0004135 (ATM)
 13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent evidence indicates that transforming growth factor-beta 1 (TGF-beta 1) plays an important role in renal fibrosis via stimulation of extracellular matrix synthesis. The present study was undertaken to investigate the role of angiotensin II type I receptor (AT1 receptor) in hypertension-induced renal injury. Twenty-two-week-old stroke-prone spontaneously hypertensive rats (SHRSP), which had established hypertension and moderate renal damage, were orally given TCV-116, a selective non-peptide AT1 receptor antagonist (0.1, 1 or 10 mg/kg/day), enalapril (10 mg/kg/day) or vehicle once a day for 10 weeks. At the end point of the treatment, we examined renal function, the gene expressions of TGF-beta 1 and extracellular matrix components in the interstitium [collagen types I (COI) and III (COIII), fibronectin (FN)] and the basement membrane (COIV and laminin), and renal microscopic morphology in rats aged 32 weeks. In vehicle-treated 32 week-old SHRSP with renal dysfunction and nephrosclerosis, renal mRNA levels for TGF-beta 1, COI, COIII, FN, COIV were all several-fold higher than in WKY. Thus, renal TGF-beta 1 gene expression was enhanced in SHRSP, which may contribute to the increased renal expressions of COI, COIII, FN, COIV in SHRSP. Treatment with TCV-116 (0.1 mg/kg/day) in SHRSP, in spite of no reduction of blood pressure, decreased renal mRNA levels for TGF-beta 1, COI, COIII, FN, COIV, being accompanied by the significant decrease in urinary protein and albumin excretion, blood urea nitrogen and plasma creatinine. Treatment with TCV-116 (10 mg/kg/day) in SHRSP decreased mRNAs for TGF-beta 1, COI, COIII, FN and COIV to almost the same levels as WKY, being associated with normalization of urinary protein and albumin excretion and the prevention of nephrosclerosis, as judged by microscopic histological observations. On the other hand, the effects of enalapril (10 mg/kg/day) on the above mentioned mRNA levels, renal function and renal morphology were weaker than those of TCV-116 (10 mg/kg/day) and were as much as TCV-116 (1 mg/kg/day). These results suggest that independently of hypotensive action, AT1 receptor antagonist has a potent renal protective effect by inhibiting the gene expression of renal TGF-beta 1 and extracellular matrix components.
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PMID:Contribution of renal angiotensin II type I receptor to gene expressions in hypertension-induced renal injury. 785 93

Selective antagonists were used to determine the presence of angiotensin II (Ang II) receptor subtypes (AT1 and AT2) in normal human renal cortex and renal cell carcinoma. Normal and tumor tissues were obtained from fresh radical nephrectomy specimens in 7 patients. All patients had a patent renal artery, and the mean preoperative serum creatinine level was 1.1 mg./dl. Tissues were snap frozen and sectioned (14 microns.) for in vitro autoradiography, then incubated in 125I-Ang II (0.3 nM.), with or without unlabeled Ang II or subtype selective antagonists (1 nM. to 1 microM.), rinsed, air dried and apposed to SB-5 X-ray film for 3 to 21 days. In normal renal tissue, low densities of diffuse 125I-Ang II binding sites were observed in cortical areas containing tubules. Higher densities of binding sites occurred over glomeruli and large cortical vessels. Specific binding ranged between 60 and 90% depending on the area as determined by displacement with excess unlabeled Ang II. Specific binding in large cortical vessels was displaced by the two AT2 selective antagonists PD123177 (1 microM.) or CGP 42112A (0.01 microM.), whereas these antagonists were less effective competitors for 125I-Ang II binding in glomeruli. In contrast, the AT1 selective antagonists, DuP 753 and L-158,809 (0.1 and .01 microM., respectively), were potent competitors for glomerular, but not extraglomerular, cortical vessel binding. In the normal cortical tubulointerstitium, both AT1 and AT2 antagonists caused partial displacement of specific binding (55 +/- 12% AT1, 39 +/- 12% AT2). Low density 125I-Ang II binding was present in all tumors. Specific binding averaged 59 +/- 10% as defined by displacement with unlabeled Ang II (1 microM.). As in the normal tubulointerstitial area, each of the selective antagonists produced partial displacement of the specific binding (60 +/- 12% AT1, 31 +/- 8% AT2). In conclusion, AT1 receptors predominate in glomeruli, while AT2 binding sites predominate in large preglomerular vessels of the human renal cortex. In the normal tubulointerstitium and renal cell carcinoma, a 60%/40% mixture of AT1 to AT2 receptors exists. These findings provide a pharmacologic framework for the differential effects of Ang II receptor-mediated function in the human kidney.
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PMID:Angiotensin II receptor subtypes in the human renal cortex and renal cell carcinoma. 825 15

1. The interaction of losartan, a non-peptide specific AT1 receptor antagonist with the renal handling of lithium was analysed in conscious normotensive Wistar rats and compared with the known increase in renal tubular lithium reabsorption induced by the non-steroidal anti-inflammatory drug, indomethacin. 2. The rats were treated for five days with losartan (10 mg kg-1 day-1, orally), indomethacin (2.5 mg kg-1 day-1, intramuscularly) or their solvents. Lithium chloride (16.7 mg kg-1, i.p.) was given as a single dose on the fifth day; renal functions were then measured. 3. Indomethacin, in the absence of any effect on creatinine clearance, increased renal fractional lithium reabsorption and led to an increase in plasma lithium levels. 4. Losartan did not modify renal lithium handling and its plasma level. No change was observed in renal lithium clearance, the quantity of filtered lithium or the fractional reabsorption of the metal. As expected, losartan had no effect on systolic blood pressure in normotensive rats. 5. In conclusion, our results indicate that losartan, when given orally in the rat at a dose of 10 mg kg-1 day-1 over five days, does not modify renal lithium handling. They suggest that blockade of the angiotensin II receptors does not interfere with renal lithium reabsorption, which occurs mainly at a proximal tubular site.
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PMID:Absence of a losartan interaction with renal lithium excretion in the rat. 856 44

Angiotensin receptor antagonists represent a new class of drugs for the treatment of patients with hypertension. Reduction of blood pressure in patients with essential hypertension requires increased activity of the renin-angiotensin system. Losartan, the first orally active, nonpeptide angiotensin antagonist, specifically competes with angiotensin II (Ang II) for the AT1 receptor and reversibly alters the receptor. Maximum blood pressure reductions occur after doses of approximately 50 mg, although some patients will require 100 mg; the parent compound and a metabolite are responsible for a smooth 24-hour effect on blood pressure. Once-daily dosing with losartan has been documented to be safe. The drug's safety has been evaluated in 4,058 patients; of these patients, more than 1,200 were treated for longer than 6 months and more than 800 were treated for longer than 1 year with doses of 10 mg to 150 mg. Overall, no hypertensive patients were withdrawn from treatment because of elevated serum creatinine or potassium levels, and there were no reports of angioedema. In addition, some reductions in plasma uric acid levels were noted. Cough occurred significantly less often in patients treated with losartan than in those treated with hydrochlorothiazide or lisinopril. In contrast to angiotensin-converting enzyme (ACE) inhibitors, losartan does not activate bradykinin-nitric oxide-prostanoid vasodilation.
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PMID:Losartan: first of a new class of angiotensin antagonists for the management of hypertension. 893 38

Since angiotensin II (ANGII) AT1-receptor antagonists have been shown to possess a beneficial effect on the course of ablation nephropathy, and since the possibility that AT2-receptors are also involved could not be ruled out, the effect of the AT1 antagonist, losartan (L), on the course of ablation nephropathy was compared wit that of PD123319 (PD), an AT2 antagonist. Wistar rats underwent surgical ablation of 5/6 of their renal parenchyma (5/6NX) and for the next 8 weeks were treated with either L alone (5 mg/kg/day), or with L + PD (10 mg/kg/day) or with PD alone. The drugs were administered in drinking water and rats drinking pure water served as controls. Whereas in both groups drinking L the survival rate was 100%, it was only 60% in controls and 66.6% in PD (no significant difference). The rats drinking L have a lower blood pressure, proteinuria and glomerulosclerosis score, and higher creatinine clearance than control and PD rats, again with no difference between these two. Cardiac and kidney remnant hypertrophy was completely abolished in both L groups, whereas it was distinctly present in the other 2 groups without a difference between them. Plasma renin activity was elevated only in both L groups. In conclusion, the beneficial effect of the AT1-receptor blocker L was again confirmed. AT2 receptors are obviously not involved in the detrimental effect of ANGII on the course of ablation nephropathy.
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PMID:Lack of a beneficial effect of PD123319, an AT2-angiotensin receptor antagonist, on the course of ablation nephropathy in the rat. 895 35

Normalization of blood pressure--and use of an ACE inhibitor or AT1-receptor blocker for patients with abnormal albumin or creatinine levels--can prevent or significantly slow the rate of progression toward end-stage renal disease.
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PMID:Prevention of diabetic nephropathy. 904 Apr 25

The effect of blockade of the renin-angiotensin system on kidney function using non-peptide angiotensin AT1 receptor antagonists was investigated in renovascular hypertensive rats. An angiotensin converting enzyme inhibitor, captopril and two angiotensin AT1 receptor antagonists, losartan and GR138950 (1-([3-bromo-2[2-[[(trifluoro-methyl)sulphonyl]amino]phenyl]-5 benzofuranyl]methyl)-4-cyclopropyl-2-ethyl-1H-imidazole-5-carboxamide) were administered in Na+-deplete two-kidney, two-clip Goldblatt hypertensive rats over a 3-day period. Captopril, losartan (30 mg/kg body weight) and GR138950 (5 mg/kg body weight) significantly (P < 0.001) lowered the systolic blood pressure in the hypertensive rats from 290 +/- 5, 252 +/- 9 and 238 +/- 13 mmHg to 152 +/- 17, 148 +/- 9 and 123 +/- 6 mmHg, respectively. The magnitude of reduction in blood pressure in these three groups of rats was similar and occurred with comparable marked increases in plasma levels of urea and creatinine indicative of acute renal failure. These findings demonstrate an important role for angiotensin II in the maintenance of renal function during blood pressure reduction in renovascular hypertensive states during restriction of dietary Na+ intake.
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PMID:The effect of angiotensin II receptor antagonists on kidney function in two-kidney, two-clip Goldblatt hypertensive rats. 927 78

The purpose of the present investigation was to examine the effects of KW-3902 [8-(noradamantan-3-yl)-1,3-dipropyl-xanthine], a selective and potent adenosine A1 receptor antagonist, in order to clarify the role of adenosine in the control of renal hemodynamics and urine formation in anesthetized dogs. KW-3902 was directly infused into the renal artery to eliminate the systemic effects of the drug. KW-3902 (10 micrograms/kg/min) almost completely inhibited the renal vasoconstriction induced by adenosine via A1 receptors. Intrarenal infusion of KW-3902 did not affect mean arterial pressure, renal blood flow, creatinine clearance, or arterial plasma renin activity, but drastically increased urine flow, urinary excretion of sodium, and osmolar clearance. Inhibition of the renin-angiotensin system using CV-11974 [2-ethoxy-1-((2'-(1-H-tetrazole-5-yl)biphenyl-4-yl) methyl)-1-H-benzimidazole-7-carboxylic acid], a selective AT1 antagonist, did not affect the diuretic action of KW-3902. These data suggest that endogenous adenosine does not play a significant role in the control of renal hemodynamics in whole kidney, but that it plays an important role in preserving body fluid via the A1 receptor independent of the renin-angiotensin system in anesthetized dogs.
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PMID:Effects of KW-3902, a selective and potent adenosine A1 receptor antagonist, on renal hemodynamics and urine formation in anesthetized dogs. 939 79

The present studies determined the effect of renal ischemia/reperfusion on components of the intrarenal renin-angiotensin system in rats and evaluated the effect of AT1 angiotensin (ANG) II receptor blockade on functional recovery. After bilateral renal pedicle occlusion for 60 min, serum creatinine increased, peaking at 72 h, and returned to sham levels after 120 h. ANG II levels in ischemic kidneys were significantly increased 24 h after reperfusion but did not differ from levels in sham kidneys after 120 h. Both renal cortical angiotensinogen mRNA and proximal tubular AT1 receptor mRNA were significantly reduced early after reperfusion, returning to sham levels by 120 and 72 h, respectively. AT2 ANG II receptor mRNA was undetectable in proximal tubules from sham rats but was consistently present in ischemic rats at 120 h. By histoautoradiography, we found that binding of 125I-labeled ANG II was preserved in glomeruli but was decreased in whole cortex and outer medulla early after reperfusion and was completely blocked by the AT1 antagonist losartan. Treatment of rats with losartan (25 mg/kg s.c. daily), starting at the time of reperfusion, had no effect on expression of proliferating cell nuclear antigen in cortical tubules but caused a significant decrease in serum creatinine at 72 h (ischemia: 334 +/- 69 microM vs. ischemia + losartan: 135 +/- 28 microM; P < 0.025, n = 6). These data indicate that renal ischemic injury causes an early increase in intrarenal ANG II levels, associated with reduction of mRNA for angiotensinogen and proximal tubular AT1 receptors, and maintenance of glomerular ANG II binding. Losartan accelerates recovery of renal function, suggesting that activation of AT1 receptors impairs glomerular filtration in the postischemic kidney.
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PMID:Role of AT1 angiotensin II receptors in renal ischemic injury. 945 26

It is well-known that cardiac hypertrophy and arterial and renal dysfunction are serious complications of hypertension. Therefore, we investigated the chronic effects of 606A (2-propyl-3-[2'(1H-tetrazole-5-yl)biphenyl-4-yl]methyl-5-acetyl-4,5,6,7- tetrahydro imidazo [4,5-c]pyridine-4-carboxylic acid disodium salt), a novel AT1-receptor antagonist, on these complications of hypertension in stroke-prone spontaneously hypertensive rats (SHRSP) using Wistar Kyoto rats (WKY) as the control. After 8 weeks treatment from 16 weeks of age with 606A by a subcutaneously implanted osmotic pump, cardiac function, cardiac weight, acetylcholine-induced endothelium-dependent relaxation in the isolated aorta and renal function were estimated. Furthermore, wall thickness of the left ventricle was studied morphologically. We found that 606A (0.3 mg, 1 mg and 3 mg/head/day) dose-dependently lowered blood pressure without any effects on heart rate in SHRSP. Long-term treatments with 606A significantly reduced cardiac weight, left ventricular wall thickness and left ventricular end diastolic pressure, whereas it did not affect cardiac contractility. Endothelium-dependent relaxation of the aorta was recovered, and total protein excretion as well as total protein excretion/creatinine excretion ratio was reduced to the level of WKY by the treatment. These results suggest that 606A not only has a hypotensive effect but also protects cardiac, renal and vascular tissues from complications of hypertension. Thus, 606A could be an useful drug for treatment of hypertension.
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PMID:A novel angiotensin II-receptor antagonist, 606A, induces regression of cardiac hypertrophy, augments endothelium-dependent relaxation and improves renal function in stroke-prone spontaneously hypertensive rats. 954 Dec 81


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