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

Flow cytometry DNA analysis has been used to measure the percentage of aortic vascular smooth muscle cells in G2 + M phase of the cell cycle in mature stroke-prone spontaneously hypertensive rats (SHRSP). The effects of three different pharmacological interventions on the cell cycle parameters have also been studied. Vascular smooth muscle cells isolated from SHRSP have significantly elevated G2 + M phase of the cell cycle compared with cells from the normotensive reference strain, Wistar-Kyoto (WKY). This observation reflects an increased tetraploid and octaploid cell populations in vivo. Treatment with a combination of hydralazine and hydrochlorothiazide had no effect on the percentage of cells in G2 + M phase of the cell cycle. Treatments with angiotensin converting enzyme inhibitor, perindopril or AT1 receptor antagonist, losartan, resulted in an equivalent blood pressure-lowering effect to that obtained with hydralazine/hydrochlorothiazide. In contrast to hydralazine/hydrochlorothiazide, these two treatments resulted in a highly significant regression of vascular smooth muscle polyploidy in the SHRSP. We hypothesise that angiotensin II plays an important role in cell cycle regulation in that, alone or in conjunction with one of the inhibitory proteins, it is able to stop the cell cycle progression after endoduplication but before the cytoplasmic division. Pharmacological interventions which remove an excess of angiotensin II may allow the cells to re-enter the cell cycle thus resulting in the regression of vascular smooth muscle polyploidy and improved arterial compliance.
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PMID:Vascular smooth muscle polyploidy in genetic hypertension: the role of angiotensin II. 747 34

In renal hypertensive rats with pressure overload left ventricular hypertrophy the angiotensin converting enzyme inhibitor ramipril, given in a high blood pressure lowering dose as well as in a low, non-antihypertensive dose, prevented and regressed left ventricular hypertrophy. These beneficial effects were abolished by coadministration of the specific bradykinin receptor antagonist (HOE 140) in the prevention--but not in the regression studies. Vascular function of rats with pressure overload left ventricular hypertrophy was impaired, whereas treated animals showed a reversal to normal. The angiotensin II subtype AT1 receptor antagonist, losartan, was barely active in the prevention, however markedly active in the regression of left ventricular hypertrophy. From these experimental studies in rats with pressure overload left ventricular hypertrophy and vascular dysfunction we conclude that inhibition of bradykinin degradation induced by ramipril may contribute to the antihypertrophic action during the prevention phase, whereas attenuation of angiotensin II formation may be more important during the regression period. In another model, the spontaneously hypertensive rat (SHR and stroke prone SHR)--a non-renal hypertensive model--cardiac left ventricular hypertrophy could be reduced by chronic high-dose ramipril treatment in prevention and regression studies, whereas the low dose regimen only reduced left ventricular hypertrophy in the regression experiments. In addition, both doses improved the myocardial capillary supply to the heart leading to improved function and metabolism. In comparison, vascular hypertrophy of the mesenteric artery could only be prevented by early-onset high dose treatment with the angiotensin converting enzyme inhibitor but not once hypertrophy has been established.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Experimental evidence for effects of ramipril on cardiac and vascular hypertrophy beyond blood pressure reduction. 764 9

The effects of long-term oral administration of losartan on the occurrence of stroke and on mortality were investigated in young salt-loaded stroke-prone spontaneously hypertensive rats (SHR-SPs) during the treatment period (5-20 weeks of age) and up to 8 weeks thereafter. Two doses of losartan, 1 and 10 mg/kg/day, were investigated, which afforded no and only moderate antihypertensive effects, respectively. During the treatment period, losartan at both doses completely suppressed stroke and mortality and strongly opposed (low dose) or abolished (high dose) the increases in saline intake, diuresis, and proteinuria observed in controls. It markedly limited (low dose) or abolished (high dose) vascular fibrinoid necrosis formation in the brain, kidneys, and heart. Finally, losartan, especially at the high dose, reduced arterial thickening and glomerular and tubulo-interstitial lesions in the kidneys, as well as arterial thickening, infarction, and fibrosis in the heart. Eight weeks after treatment discontinuation, all animals but one (low dose) were still alive. Vascular fibrinoid necrosis development remained strongly prevented (low dose) or fully suppressed (high dose) in all investigated organs. Finally, cardiac and renal lesions tended to worsen, and proteinuria was noted only in the low-dose group. We conclude that in SHR-SPs, angiotensin II, through AT1 receptor stimulation, most likely plays a major role in fibrinoid necrosis formation, vascular proliferative changes, and stroke occurrence and that losartan, most likely independently of its effect on blood pressure, affords a full and long-lasting protection against stroke and mortality both during and after the treatment period.
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PMID:Losartan's protective effects in stroke-prone spontaneously hypertensive rats persist durably after treatment withdrawal. 769 74

TCV-116 [(+/-)-(cyclohexyloxycarbony-loxy)ethyl2-ethoxy-1-[[2' -(1H- tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylate ], a nonpeptide selective angiotensin II type I receptor (AT1 receptor) antagonist, at the dose of 0.1, 1 or 10 mg kg-1 day-1, was orally given to 22-week-old stroke-prone spontaneously hypertensive rats (SHRSP) for 10 weeks (from the age of 22-32 weeks) to examine the effects on gene expression of transforming growth factor-beta 1 (TGF-beta 1) and extracellular matrix proteins in the heart and blood vessels. Tissue messenger RNA (mRNA) was measured by northern blot analysis, with a specific complementary DNA probe. In the heart, left ventricular mRNA levels for fibronectin; types I, III and IV collagen; and laminin were significantly higher in SHRSP than control Wistar-Kyoto rats. In the mesenteric artery and aorta of SHRSP, TGF-beta 1 mRNA and the mentioned extracellular matrix protein mRNAs were increased compared with Wistar-Kyoto rats. Thus, the expression of various genes was up-regulated in cardiovascular tissues of SHRSP. Treatment of SHRSP with TCV-116 suppressed the gene expression of the mentioned extracellular matrix proteins and TGF-beta 1 in both heart and blood vessels in a dose-dependent fashion. Furthermore, TCV-116 regressed cardiac hypertrophy and lessened the medial hypertrophy of the aorta in SHRSP. These results show that angiotensin AT1 receptor antagonist in vivo can inhibit the gene expression of TGF-beta 1 and extracellular matrix proteins in hypertensive cardiovascular tissues. These effects may contribute to the beneficial effects of AT1 receptor antagonist on hypertensive cardiac hypertrophy and vascular thickening.
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PMID:Angiotensin II type I receptor antagonist inhibits the gene expression of transforming growth factor-beta 1 and extracellular matrix in cardiac and vascular tissues of hypertensive rats. 771 6

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

We examined the effects of TCV-116, a non-peptide selective AT1 receptor antagonist, on cellular phenotype and on the expression of the transforming growth factor-beta 1 (TGF-beta 1) and extracellular matrix genes in the kidneys of stroke-prone spontaneously hypertensive rats (SHRSP). SHRSP were given vehicle or TCV-116 (10 mg/kg/day) by gastric gavage for 10 weeks (from the age of 22 to 32 weeks). Renal mRNA levels were measured by Northern blot analysis. In vehicle-treated 32-week-old SHRSP, urinary albumin excretion per 24 h was about 26-fold greater than that in age-matched Wistar-Kyoto (WKY) rats, and the mRNA levels of renal TGF-beta 1, fibronectin and collagen types I and III in SHRSP were all several-fold higher than those in WKY. Immunohistochemical studies showed the prominent presence of alpha-smooth muscle actin-expressing glomerular cells in SHRSP, in contrast to their absence in WKY. Treatment of SHRSP with TCV-116 decreased urinary albumin excretion and renal mRNA levels for TGF-beta 1 and for the above-mentioned extracellular matrix components. TCV-116 prevented the phenotypic modulation of glomerular cells in SHRSP. These results suggest that AT1 receptor antagonists may have powerful renal protective effects.
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PMID:Renal protective effect of TCV-116 in stroke-prone spontaneously hypertensive rats. 788 1

Previous studies showed that angiotensin II (AII) infusion increased survival in gerbils subjected to abrupt unilateral carotid ligation. Recently, stimulation of the AII AT2 receptor, reportedly effectively extended the blood pressure (BP) range of cerebral blood flow (CBF) autoregulation. We evaluated the survival of gerbils treated with PD-123319, a ligand of AT2 receptors, to test the hypothesis that restoration of BF to ischemic cerebral tissue produced by AII is mediated through AT2 receptors. Abrupt unilateral carotid ligation was performed on 300 gerbils. In five experimental groups, animals received no drug pretreatment: (a) saline; (b)-(d) PD-123319 1.0, 3.0, and 10 mg/kg; and (e) losartan 10 mg/kg. In three additional experimental groups, animals were pretreated with enalaprilat: (f) saline; (g) PD-123319, 10 mg/kg, and (h) losartan, 10 mg/kg. Survival for 48 h was significantly improved by PD-123319 (10 mg/kg) (p < 0.05) and by losartan (10 mg/kg) (p < 0.05) as compared with animals injected with saline. Pretreatment with enalaprilat neutralized the protective effect of losartan. PD-123319 is an AT2 agonist and improved survival in this animal model of stroke. Losartan, an AT1 antagonist, also improved survival, possibly through renin release and AT2 stimulation by endogenous AII. This effect was neutralized by enalaprilat.
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PMID:Angiotensin AT2 receptor stimulation increases survival in gerbils with abrupt unilateral carotid ligation. 789 77

Through the multiple actions of angiotensin II (AII), the renin-angiotensin system (RAS) participates in cardiovascular homeostasis. Angiotensin II acts by binding to specific membrane-bound receptors, which are coupled to one of several signal transduction pathways. These AII receptors exhibit heterogeneity, represented by AT1 and AT2 receptor subtypes. The AT1 receptor mediates the major cardiovascular action of the RAS. This receptor has been cloned from multiple species, disclosing features consistent with a transmembrane, G-protein-linked receptor. Further AII receptor heterogeneity is evident by the cloning of isotypes of the AT1 receptor. Blocking the interaction of AII with its receptor is the most direct site to inhibit the actions of the RAS. Many AII receptor antagonists, including peptide analogs of AII and antibodies directed against AII, possess unfavorable properties that have limited their clinical utility. The discovery and further development of imidazole compounds with AII antagonist properties and favorable characteristics, however, has promise for clinical utility. The leader in this field is a selective AT1 receptor antagonist losartan (previously known as DuP 753 or MK-954). Losartan was demonstrated to be an effective antagonist of many AII-induced actions and an effective antihypertensive agent in many animal models of hypertension (HTN). Losartan also demonstrated secondary benefits in preventing stroke, treating congestive heart failure (CHF), and delaying the progression of renal disease in animal models. Clinical studies confirm the AII antagonist action of losartan and suggest that losartan will be effective in the treatment of essential HTN. AII antagonism is likely to provide useful treatment in essential HTN and CHF, conditions in which the RAS is known to play a major role. The utility of AII antagonism may extend beyond that of HTN and CHF, as suggested by the potential usefulness of angiotensin-converting enzyme (ACE) inhibition in the treatment or prevention of many other diseases. The key advantage AII antagonists provide over ACE inhibitors is that they may avoid unwanted side effects, related to bradykinin potentiation with the latter drugs. The AII antagonists will help determine the role of the RAS in physiologic regulation and in the pathophysiology of various disease states.
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PMID:Angiotensin II receptor blockade: an innovative approach to cardiovascular pharmacotherapy. 830 Aug 85

The 'discovery' of losartan represents three separate discoveries: (1) losartan as the unique biphenyltetrazole molecule and the first of a new chemical class; (2) losartan as a tool to identify AT1-subtype receptors; and (3) losartan as a specific probe for exploring the multiple roles of angiotensin II (Ang II) in normal physiology and pathologic states. Losartan is the first nonpeptide orally active Ang II receptor antagonist to reach clinical trials. Losartan was selected for its affinity for Ang II receptors, functional antagonism of Ang II, lack of agonist properties, and oral anti-hypertensive effects. Losartan has been widely used to define the distribution and function of AT receptor subtypes. Although possible roles of the AT2 subtype have been reported, virtually all of the known effects of Ang II are blocked by losartan. Specific AT1 receptor blockade has been broadly compared with ACE inhibition. Possible differences on the basis of AT1 selectivity, bradykinin potentiating effects and Ang II formed by non-ACE pathways are discussed. Losartan blocks the vascular constrictor effect of Ang II, the Ang II-induced aldosterone synthesis and/or release, and the Ang II-induced cardiovascular 'growth' in vitro and in vivo. In various models of experimental hypertension, losartan prevents or reverses the elevated blood pressure and the associated cardiovascular hypertrophy similar to ACE inhibitors. Likewise, in models of renal failure (for example reduced renal mass, puromycin, ochratoxin), losartan, like ACE inhibition, markedly reduced the elevation in blood pressure, proteinuria or sclerosis. In aortocaval shunt, coronary ligation and ventricular pacing models of heart failure, losartan demonstrated a pathological role for Ang II by reversing the associated haemodynamic findings. In SHR-stroke prone, losartan dramatically increased survival while having a limited effect on blood pressure, suggesting a non-pressure dependent effect of Ang II. These collective data show that Ang II exerts complex pathological effects in experimental models of vascular, cardiac, renal and cerebral disease. The effectiveness of losartan in experimental models of heart failure supports its evaluation in clinical trials with patients with heart failure.
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PMID:Discovery of losartan, the first angiotensin II receptor antagonist. 858 79

Biological actions of natriuretic peptide (NP) are determined by the condition of the receptor as well as that of the hormone. Although we previously demonstrated in hypertensive rats the up-regulation of NP-A receptor that mediates various biological actions of NPs, the pathophysiologic significance of NP-C receptor, another subtype thought to be related to clearance of NPs and possibly to biological actions, remains unknown. In the present study, we determined NP-C receptor messenger RNA (mRNA) level in the aortic tissue of stroke-prone spontaneously hypertensive rats (SHR-SP/Izm) and in cultured aortic smooth muscle cells by ribonuclease protection assay. The aortic NP-C receptor mRNA level in SHR-SP/Izm was significantly lower than that in the control WKY/Izm. Oral administration of an angiotensin (Ang) II receptor (AT1) antagonist, TCV-116, but not a calcium channel blocker, manidipine, reversed the down-regulated NP-C receptor mRNA in SHR-SP/Izm to the level in WKY/Izm, whereas the latter was more potent in decreasing the blood pressure. In cultured aortic smooth muscle cells, the NP-C receptor was the predominant subtype. Ang II decreased the NP-C receptor mRNA level in a dose-dependent manner, but this effect was reversed by an AT1 antagonist, CV-11974. Neither the NP-A nor NP-B receptor mRNA level was altered by Ang II. These findings indicate that vascular NP-C receptor is down- regulated via Ang-II-mediated mechanism in SHR-SP/Izm. The phenomenon, together with the up-regulation of the NP-A receptor, may play an important role in counteracting hypertension by enhancing the action of NPs.
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PMID:Angiotensin II-dependent down-regulation of vascular natriuretic peptide type C receptor gene expression in hypertensive rats. 860 80


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