UMLS:C0038454 - FACTA Search

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Query: UMLS:C0038454 (stroke)
147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The renin-angiotensin system (RAS) has been implicated in the development of hypertensive glomerulosclerosis. However, there are no experimental findings clearly demonstrating activation of glomerular RAS in hypertensive nephropathy. Using the stroke-prone spontaneously hypertensive rat (SHRSP) as an animal model of hypertensive glomerulosclerosis, we examined the relationship between the sequential changes in urinary albumin excretion (UAE), renal morphology, and glomerular mRNA expression for transforming growth factor-beta (TGF-beta) and fibronectin (FN) and glomerular mRNA levels for RAS components, and determined the effects of the angiotensin II (Ang II) type 1 (AT-1) receptor antagonist (candesartan) and equihypotensive hydralazine on these parameters. In SHRSP, UAE was normal at nine weeks of age and increased by 12 weeks. Plasma renin activity, plasma Ang II concentration, and angiotensin converting enzyme (ACE) activity were not higher in 9- and 12-week-old SHRSP than in WKY. RNase protection assay revealed higher glomerular mRNA levels for angiotensinogen, ACE, and AT-1a and AT-1b receptors in 9-, 12-, and 14-week-old SHRSP than in WKY. The glomerular mRNA levels for TGF-beta and FN in SHRSP were increased from nine weeks of age. SHRSP had a greater glomerulosclerosis index (GSI) at 24 weeks of age than did WKY. Administration of candesartan for two weeks, but not of hydralazine, markedly reduced UAE and normalized mRNA levels for TGF-beta, FN, and RAS components. Candesartan administration for 12 weeks virtually prevented the progression of glomerulosclerosis in rats. We conclude that in SHRSP, RAS activation and increased sensitivity to Ang II in glomeruli play important roles in the progression of glomerulosclerosis.
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PMID:Candesartan prevents the progression of glomerulosclerosis in genetic hypertensive rats. 940 67

Chronic treatment of saline-drinking stroke-prone spontaneously hypertensive rats (SHRSP) with agents that interfere with the formation or actions of angiotensin II (Ang II) prevents the development of stroke and renal vascular damage. Ang II, in addition to its direct vascular effects, stimulates the synthesis and release of aldosterone. To assess the role of aldosterone in the development of pathologic changes in these rats, we implanted time-release pellets containing 200 mg of the mineralocorticoid receptor antagonist, spironolactone, into 14 SHRSP at 7.5 weeks of age. Eight SHRSP littermates received placebo pellets. Over the period of study (3 to 4 weeks), systolic blood pressure (SBP) was not different between the groups. Spironolactone did not enhance water and electrolyte excretion. All placebo-treated SHRSP developed marked proteinuria (150+/-6 mg/d) whereas in spironolactone-treated SHRSP, urinary protein excretion (UPE) averaged 39+/-9 mg/d (P<.0001). In a second study to assess effects on survival, 6 SHRSP received spironolactone (10 mg/kg/d) and 6 received vehicle. All but one of the control rats displayed signs of stroke and died by 16 weeks of age, while the spironolactone-treated SHRSP remained asymptomatic through 19 weeks of age (P<.03). At 16 weeks of age, spironolactone-treated SHRSP were severely hypertensive (247+/-3 mm Hg), yet UPE remained at baseline levels. In contrast, preterminal UPE averaged 136+/-13 mg/d in control rats (P<.0001). In both studies, histopathologic examination revealed a marked protective effect of spironolactone against the development of malignant nephrosclerotic and cerebrovascular lesions. These observations indicate a vascular and end organ protective effect of spironolactone in the absence of lowered blood pressure in saline-drinking SHRSP and are consistent with a major role for mineralocorticoids as hormonal mediators of vascular injury.
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PMID:Mineralocorticoid blockade reduces vascular injury in stroke-prone hypertensive rats. 945 44

The aim of the study was to assess the effects of chronic angiotensin I receptor blockade on blood pressure, the renin-angiotensin system in plasma and kidney and the extent of renal damage in spontaneously hypertensive rats of the stroke prone strain (SHRsp). Four months old male SHRsp rats were orally treated with a high (10 mg/kg b.w. per day) or a low dose (1 mg/kg b.w. per day) of the AT1 receptor antagonist Telmisartan and compared to Losartan- (20 mg/kg b.w. per day), Captopril-treated (50 mg/kg b.w. per day) or untreated control groups for 38 days. Despite a similar extent of blood pressure reduction in all groups (except low dose Telmisartan), high dose Telmisartan but not Losartan or Captopril significantly reduced left ventricular weight by 24% compared to controls (p<0.05). Renal damage as assessed by urinary albumin or glomerulosclerosis index was significantly reduced in all treatment groups (p<0.02). Plasma renin concentration was significantly elevated (p<0.02) and plasma angiotensinogen significantly lowered (p<0.05) in all pharmacologically treated group compared to controls. In the kidney, renin-mRNA as well as AT1 receptor gene expression were elevated in all treatment groups, but no significant changes were found for renal angiotensinogen-mRNA. Chronic oral treatment of genetically hypertensive rats by the AT1 receptor antagonist Telmisartan reveals a blood pressure lowering and reno-protective effect of this drug comparable to other AT1 receptor antagonists or converting enzyme inhibitors, and demonstrates a marked reduction of cardiac hypertrophy by Telmisartan in this model.
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PMID:Effects of AT1 receptor blockade on blood pressure and the renin-angiotensin system in spontaneously hypertensive rats of the stroke prone strain. 953 14

Most antihypertensives have advantages and disadvantages. The ideal antihypertensive drug should be effective in lowering blood pressure, well tolerated, safe in the long term, and easy to use. Ideally, it should be relatively inexpensive. Most importantly it should reduce the risk of the adverse effects of high blood pressure, such as myocardial infarction, sudden death, stroke, heart failure, renal damage, and retinal changes. Most antihypertensive drugs effectively reduce blood pressure, are available as once daily preparations, and are safe long-term. Unfortunately, most antihypertensive drugs cause adverse effects in some patients and for few drugs is there good evidence that they protect the heart, the brain, the kidney, and the eye? Reducing the effects of Angiotensin II (using an ACE inhibitor) has been shown to reduce the incidence of coronary events, sudden death, heart failure, renal damage, and fundal changes. AT1 blocking drugs offer the same pharmacological advantages but also very good tolerability, in particular no cough. Therefore, they have the potential to meet all the criteria for an ideal antihypertensive drug.
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PMID:Therapeutic advantages of AT1 blockers in hypertension. 983 62

To determine the contribution of plasma catecholamines to the cardiovascular effects of elevated levels of angiotensin II (Ang II) in trout, this study investigated (1) the stimulatory effects of [Asn1-Val5]-Ang II on plasma catecholamine levels, (2) the cardiovascular effects of Ang II with and without alpha-adrenoceptor blockade and (3) the relationship between plasma adrenaline concentrations and their cardiovascular effects. Bolus intravascular injections of Ang II (25-1200 pmol kg-1) elicited dose-dependent (between 75 and 1200 pmol kg-1) increases in plasma adrenaline levels; mean plasma noradrenaline levels only increased in response to a dose of 1200 pmol kg-1. Ang-II-elicited increases in plasma adrenaline levels ranged from 3.3+/-0.3 nmol l-1 for 75 pmol kg-1 Ang II to 125.1+/-40.0 nmol l-1 for 1200 pmol kg-1 Ang II. Injections of Ang II (25-1200 pmol kg-1) also elicited dose-dependent increases in dorsal aortic pressure (PDA), systemic resistance (RS), cardiac output (Q) and stroke volume (Vs). In fish first treated with the alpha -adrenoceptor blocker phenoxybenzamine, Ang II injections elicited a decrease in q_dot and Vs, and the increases in PDA and RS following administration of the 600 and 1200 pmol kg-1 Ang II doses were significantly reduced. Bolus injections of adrenaline (1.8x10(-10) to 1.4x10(-8) mol kg-1) elicited dose-dependent increases in PDA at a plasma adrenaline concentration of 16.5 nmol l-1 and in RS at a plasma adrenaline concentration of 50.5 nmol l-1. Adrenaline injections also elicited increases in Q and Vs at plasma adrenaline concentrations of 50.5 nmol l-1; however, higher plasma adrenaline concentrations were not associated with further increases in either Q or Vs. These results demonstrate that, in vivo, Ang II can act as a potent non-cholinergic secretagogue of humoral adrenaline in trout and that some of the cardiovascular effects of exogenous Ang II can be attributed to increased levels of plasma adrenaline. Our data also indicate that the cardiovascular effects of Ang-II-mediated humoral catecholamines are recruited in a dose-dependent manner and, as such, may require an acute stimulation of the renin-angiotensin system to contribute significantly to the pressor activity of endogenous angiotensins.
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PMID:Cardiovascular effects of angiotensin-II-mediated adrenaline release in rainbow trout Oncorhynchus mykiss. 984 95

The influence of endogenous bradykinin(BK) on the control of arterial pressure and the development of cardiac hypertrophy was assessed in chronically angiotensin II(Ang II)-infused rats (200 ng. kg-1. min-1) through the effects of concomitant infusion of 3 doses of BK (15 ng. kg-1. d-1, 100 ng. kg-1. d-1 and 100 ng. kg-1. min-1 ie, 144 000 ng. kg-1. d-1) or BK-blockade by Hoe140 (300 microg. kg-1. d-1) for 10 days. In Ang II-infused rats, tail-cuff pressure increased from 124+/-3 to 174+/-6 mm Hg (P<0.001). The pressor effect of Ang II was not affected by simultaneous infusion of BK or Hoe140. At the end of the experiments, cardiac mass was higher in rats infused with Ang II alone (3.56+/-0.10 versus 2.89+/-0.05 mg/g in untreated controls, P<0.01) and the development of cardiac hypertrophy was not modified by administration of the 3 doses of BK or Hoe140. In addition, the fall in cardiac output associated with Ang II was prevented only by the moderate and high doses of BK, mainly through an increase in stroke volume and a decrease in total peripheral resistance. In the same way, the renal vasoconstrictor effect of Ang II was abolished by the medium and high dose of BK. Hoe140 did not affect cardiac output or renal blood flow in this model. No influence of BK or Hoe140 on the increase in albuminuria induced by Ang II was detected. In conclusion, exogenous BK may oppose the effect of Ang II on vascular tone, but it cannot prevent hypertension and target-organ damage associated with this experimental model of hypertension, even at a very high dose.
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PMID:Chronic bradykinin infusion and receptor blockade in angiotensin II hypertension in rats. 1008 95

Angiotensin II (AII) acts by 2 types of receptors: the ATI receptor which mediates its actions on vasoconstriction, renin (inhibition) and aldosterone (stimulation) secretions, cellular proliferation and angiogenesis and the non-AT1 (often called AT2) receptors. Mainly expressed in the embryon these latter may favor cellular differentiation and recruitment of collateral circulation. Angiotensin converting enzyme inhibitors (ACEI) decrease the synthesis of All and therefore the stimulation of both receptor types whereas AT1-receptor antagonists (AT1RA) block only the stimulation of these latter and increase the stimulation of AT2 receptor since they increase the production of All secondarily to the inhibition of the feedback of renin secretion by All. Experimentally ACEI and AT1RA decrease angiogenesis and cellular proliferation and favor cellular differentiation which could explain the protective effect of ACEI against cancer suggested recently in a Scotish study. Despite of their common suppressive effect on angiogenesis AT1RA may better than ACEI protect against ischemic events specially the cerebral ones because they favor the rapid recruitment of collateral circulation. This has been demonstrated for losartan in case of abrupt ligation of the carotid in the gerbil since its previous administration protects against fatal cerebral ischemia whereas its previous administration with enalapril abolishes this protection. These data may explain why, in the CAPP trial, captopril which has prevented more effectively diabetes occurrence could not be proved superior to diuretics and/or betablocker in the prevention of myocardial infarction and specially of strokes for which exist on the contrary a suspicion of a lower protection. Therefore a comparative trial between AT1RA and ACEI in the prevention of stroke recurrence should appear as a priority for Public Health and Pharmaceutical Industry Authorities.
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PMID:[Duality of angiotensin II receptors and risk for stroke and cancer: what is the connection?]. 1036 Jan 91

The vascular structural remodeling function may be altered in genetically hypertensive animals, spontaneously hypertensive rats (SHR). To examine this possibility, we measured the activity of mitogen-activated protein (MAP) kinases, enzymes believed to be involved in the pathway for cell proliferation, in rat aorta strips, and examined whether the endothelium removal-induced MAP kinase activation function is altered in SHR and whether vascular angiotensin and endothelin systems are responsible for the alteration of MAP kinase activation in SHR. Male 4-week-old SHR and age-matched Wistar Kyoto rats (WKY) supplied by Charles River Japan were used. Endothelium-denuded aorta strips were incubated at 37 degrees C in medium. MAP kinase activity after incubation was time-dependently increased in strips from SHR and WKY. MAP kinase activation was greater in SHR than in WKY aorta strips. Similarly, MAP kinase activation was enhanced in aorta strips from 4-week-old SHR and stroke prone SHR supplied by the Diseases Model Cooperative Research Association (Kyoto, Japan). In aorta strips from SHR and WKY, the angiotensin receptor antagonist, losartan, and the endothelin receptor antagonist, cyclo (D-alpha-aspartyl-L-prolyl-D-valyl-L-leucyl-D-tryptophyl)(BQ123), caused concentration-dependent inhibition of MAP kinase activation. The losartan-induced but not BQ123-induced inhibition of MAP kinase activation was greater in SHR than in WKY aorta strips. Angiotensin II caused a concentration-dependent increase in MAP kinase activity and the angiotensin II-induced MAP kinase activation was greater in SHR than in WKY aorta strips. These results indicate that endothelium removal-induced MAP kinase activation is enhanced in aorta strips from young SHR, suggesting that vascular structural remodeling function may be enhanced in SHR. It appears that the enhancement of MAP kinase activation results, at least in part, from enhanced function of vascular angiotensin system in SHR.
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PMID:Vascular mitogen-activated protein kinase activity is enhanced via angiotensin system in spontaneously hypertensive rats. 1039 23

We have previously demonstrated that angiotensin II (Ang II) contributes to the increase in aortic transforming growth factor-beta(1) (TGF-beta(1)) mRNA levels in hypertensive rats. However, the molecular mechanism whereby Ang II promotes TGF-beta(1) expression in vascular smooth muscle cells (VSMCs) is poorly understood. In this study, we examined the role of extracellular signal-regulated kinase (ERK) in Ang II-mediated TGF-beta(1) expression in VSMCs and the role of Ang II in aortic ERK activity of stroke-prone spontaneously hypertensive rats. Treatment of quiescent VSMCs with 100 nmol/L Ang II induced rapid phosphorylation and activation of ERK1 and ERK2 with a peak at 5 minutes followed by an increase in activator protein-1 (AP-1) DNA binding activity, as shown by gel mobility shift assay. An increase in TGF-beta(1) mRNA was shown by Northern blot analysis. Treatment of VSMCs with PD98059, a specific inhibitor of the ERK pathway, attenuated both the activation of AP-1 and the increase in TGF-beta(1) mRNA induced by Ang II. Inhibition of Ang II-induced AP-1 activation with c-fos antisense oligodeoxynucleotide led to a significant reduction of TGF-beta(1) mRNA in VSMCs. Furthermore, in vivo treatment of stroke-prone spontaneously hypertensive rats with losartan, an Ang II type 1 receptor antagonist, decreased aortic ERK activity. Thus, we show that ERK, through AP-1 activation, is involved in Ang II-induced TGF-beta(1) mRNA expression in VSMCs and suggest that ERK may participate in vascular remodeling of hypertension. However, it remains to be determined whether the increase in TGF-beta(1) mRNA leads to the increase in its active protein.
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PMID:Contribution of extracellular signal-regulated kinase to angiotensin II-induced transforming growth factor-beta1 expression in vascular smooth muscle cells. 1040 35

Hepatocyte growth factor (HGF) is a unique growth factor that has many protective functions against renal damage. Our previous study demonstrated that HGF stimulated the growth of endothelial and epithelial cells without the replication of mesangial cells. Moreover, angiotensin (Ang) II significantly decreased local HGF production in mesangial cells. Therefore, we examined the effects of Ang II blockade on renal HGF expression and renal damage in experimental hypertensive rats. An angiotensin-converting enzyme inhibitor (cilazapril; 10 mg. kg(-1). d(-1)), an Ang II type 1 receptor antagonist (E-4177; 30 mg. kg(-1). d(-1)), hydralazine (8 mg. kg(-1). d(-1)), and vehicle were administered to 16-week-old stroke-prone spontaneously hypertensive rats (SHR-SP) for 3 weeks. Renal damage was evaluated with a computer analysis system, and renal HGF mRNA was measured by Northern blot analysis. Blood pressure of SHR-SP was significantly decreased by all drug treatments compared with vehicle. Moreover, cilazapril, E-4177, and hydralazine significantly decreased the thickening and necrosis of blood vessels compared with vehicle. Similarly, degeneration and necrosis of glomeruli were also markedly improved by cilazapril and E-4177 (P<0.01). We next examined the effects of Ang II blockade on renal HGF expression in SHR-SP. Renal HGF mRNA was markedly decreased in SHR-SP compared with Wistar-Kyoto rats, although Ang II blockade by cilazapril and E-4177 but not hydralazine significantly increased renal HGF mRNA in SHR-SP. Ang II blockade significantly increased renal HGF (a protective growth factor for tubular epithelial cells); thus, we examined tubular histological appearance. Degeneration and necrosis of tubules were significantly improved by cilazapril and E-4177 treatment (P<0.01). In addition, cell infiltration into the glomeruli and hemorrhage were also significantly reduced in SHR-SP treated with cilazapril or E-4177. The present data demonstrated the prevention of renal damage by Ang II blockade in SHR-SP, which was accompanied by a significant increase in renal HGF mRNA. Given the strong mitogenic activity and antiapoptotic actions of HGF on endothelial and epithelial cells, we believe that increased local HGF production by the blockade of Ang II may improve renal function in hypertension.
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PMID:Prevention of renal damage by angiotensin II blockade, accompanied by increased renal hepatocyte growth factor in experimental hypertensive rats. 1045 54

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