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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The renin-angiotensin system plays a critical role in sodium and fluid homeostasis. Genetic or acquired alterations in the expression of components of this system are strongly implicated in the pathogenesis of hypertension. To specifically examine the physiological and genetic functions of the type 1A receptor for angiotensin II, we have disrupted the mouse gene encoding this receptor in embryonic stem cells by gene targeting. Agtr1A(-/-) mice were born in expected numbers, and the histomorphology of their kidneys, heart, and vasculature was normal. AT1 receptor-specific angiotensin II binding was not detected in the kidneys of homozygous Agtr1A(-/-) mutant animals, and Agtr1A(+/-) heterozygotes exhibited a reduction in renal AT1 receptor-specific binding to approximately 50% of wild-type [Agtr1A(+/+)] levels. Pressor responses to infused angiotensin II were virtually absent in Agtr1A(-/-) mice and were qualitatively altered in Agtr1A(+/-) heterozygotes. Compared with wild-type controls, systolic blood pressure measured by tail cuff sphygmomanometer was reduced by 12 mmHg (1 mmHg = 133 Pa) in Agtr1A(+/-) mice and by 24 mmHg in Agtr1A(-/-) mice. Similar differences in blood pressure between the groups were seen when intraarterial pressures were measured by carotid cannulation. These studies demonstrate that type 1A angiotensin II receptor function is required for vascular and hemodynamic responses to angiotensin II and that altered expression of the Agtr1A gene has marked effects on blood pressures.
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PMID:Regulation of blood pressure by the type 1A angiotensin II receptor gene. 772 93

Recent developments in angiotensin II receptor research are discussed in the context of our knowledge in preceding years. Cloning of non-mammalian angiotensin II receptors without high affinity for non-peptide antagonists has permitted a new approach to the delineation of ligand-binding domains. Cloning of the second major isoform of angiotensin II receptor, AT2, and identification as a seven transmembrane domain receptor with only 32% sequence homology with the first isoform, AT1, provide the first concrete step toward our understanding of the roles of AT2. The discovery of phospholipase C-mediated pathway for AT1 in vascular smooth muscle cell signaling introduces an entirely unexpected angle to future research. New aspects of AT1 gene regulation and receptor desensitization and internalization are evolving. Molecular mechanisms and physiological implications of the differential expression of AT1A and AT1B are being clarified. The recent discovery of human AT1B may make studies on animal models interesting and more meaningful. The first paper on the genetic role of the AT1 gene in human hypertension has just been published. A promising future is expected in the further development of angiotensin-receptor research in relation to cardiac, renal, and vascular function by employing techniques of molecular biology.
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PMID:Recent progress in molecular and cell biological studies of angiotensin receptors. 774 57

Angiotensin converting-enzyme inhibitors (alacepril and imidapril) or an AT1-receptor antagonist (SC-52458) was administered to 10-week-old spontaneously hypertensive rats (SHR) for 7 days, and cardiac mRNA levels for contractile proteins and atrial natriuretic polypeptide (ANP) were comprehensively measured. The expression of skeletal alpha-actin and ANP was selectively enhanced in the heart of vehicle-treated SHR compared with Wistar-Kyoto rats (WKY), thereby suggesting that the phenotypic modulation of myocytes occurred at the early stage of hypertension. The above-mentioned three drugs similarly suppressed these enhanced gene expressions, nearly to the control levels. In contrast, although the treatment with hydralazine lowered the blood pressure of SHR similarly, hydralazine did not suppress ANP expression at all and only partially suppressed skeletal alpha-actin. Moreover, alacepril did not affect these gene expressions in WKY. Thus, AT1 receptor may be crucial for phenotypic modulation in the heart of SHR.
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PMID:Cardiac hypertrophy-related gene expression in spontaneously hypertensive rats: crucial role of angiotensin AT1 receptor. 774 53

Circulating angiotensin II (ANG II) has several physiological effects that result from interaction of the peptide with AT1 receptors in the brain. Our purpose was to determine if selective pharmacological blockade of brain AT1 receptors would reverse chronic low-dose ANG II-induced hypertension. Male Sprague-Dawley rats were instrumented with chronic indwelling arterial and venous catheters and a lateral intracerebroventricular (i.c.v.) cannula. All rats received ANG II i.v. for 15 days at a dose of 4 ng.min-1. On days 2, 7 and 12 of the ANG II infusion a bolus of an AT1 receptor antagonist, the active metabolite of losartan, EXP 3174 (1 microgram in 2 microliters of saline, i.c.v.; n = 5) or vehicle (2 microliters of saline; n = 2) was administered into the cerebrospinal fluid. Mean arterial pressure and heart rate were measured at numerous time points after this injection. Although the dose of EXP 3174 used in preliminary experiments was shown to block the responses to i.c.v. ANG II this treatment did not lower MAP in chronic ANG II-hypertension. These results suggested that either ANG II-hypertension does not involve brain AT1 receptors, or that i.c.v. EXP 3174 may not gain access to brain sites at which circulating ANG II acts to produce hypertension. To test this latter possibility ANG II was microinjected into the area postrema of anesthetized rats. The area postrema is one of several circumventricular organs at which circulating ANG II may act to influence arterial pressure regulation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cerebroventricular injection of angiotensin II antagonist: effects on blood pressure responses to central and systemic angiotensin II. 775 62

Angiotensin II (Ang II) is an essential component of the renin-angiotensin system and is partially responsible for the maintenance of hypertension. Two major receptor subtypes have been defined for Ang II and have been detected in the heart of various species. Most of the known functions of Ang II are mediated via the AT1 subtype, whereas the function of the AT2 receptor remains ill defined. In this study we aimed to localize both receptor subtypes in the rabbit heart using film and light microscope autoradiography as well as radioligand binding assays on membranes. Total receptor densities in the atrium and nervous tissue were respectively four and nine times greater than in the ventricle. Conductive tissue shows a density between that of atrial and nervous tissue. In the ventricle, approximately 20% of the Ang II receptors were AT2. This receptor subtype was almost totally absent from nervous, conductive and atrial tissue. The limited resolution of the microscope autoradiography method did not allow us to specify the exact cell-type at this stage.
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PMID:Localization of angiotensin II receptor subtypes in the rabbit heart. 776 Mar 66

We have previously shown that the human adrenocortical H295R cell line expresses the type 1 angiotensin II receptor (AT1-R) and that expression of this receptor is downregulated at the level of mRNA by forskolin or dibutyryl-cAMP as well as by angiotensin II (Ang II). In this study we examine the effects of K+ on both AT1-R mRNA and receptors, as monitored through 125I-Ang II binding in the presence of PD 123319. After treatment with a maximal stimulatory steroidogenic dose of K+ (14 mmol/L), H295R cells showed an increase in cytosolic free Ca2+ from 113 to 212 nmol/L. Unlike the effects of Ang II, this increase could be abolished by pretreatment with the Ca2+ channel antagonist nifedipine (1 mumol/L). AT1-R mRNA levels also fell in response to elevated extracellular K+ in a dose-dependent (Kd, 9 mmol/L; maximal fall in message at 12 mmol/L) and time-dependent (maximum 50% at 12 hours) manner. The change in AT1-R mRNA level was less rapid than that in response to activation of phosphoinositidase C by Ang II or adenylyl cyclase by forskolin or by dibutyryl-cAMP. Unlike the action of Ang II but similar to the action of forskolin or dibutyryl-cAMP, the action of K+ was sustained. Changes in mRNA level in response to treatment with K+, Ang II, or dibutyryl-cAMP were also paralleled by changes in 125I-Ang II binding in each case.(ABSTRACT TRUNCATED AT 250 WORDS)
Hypertension 1995 Jun
PMID:Potassium negatively regulates angiotensin II type 1 receptor expression in human adrenocortical H295R cells. 776 52

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

It has been proposed that the suppression of endogenous levels of angiotensin II by angiotensin converting enzyme inhibition, may result in up-regulation of vascular AT1 receptors. This study evaluated the effects of orally administered enalapril on angiotensin II induced vasoconstriction in the human forearm of patients with mild-moderate hypertension. Patients received in random order, enalapril (20 mg) or matched placebo daily for 2 weeks. Forearm blood flow response to increasing doses of angiotensin II was measured using venous occlusion plethysmography at the beginning of the study and at the end of each 2 week treatment period. Treatment with enalapril significantly reduced plasma angiotensin II levels and supine blood pressure compared to placebo. The percentage reductions in forearm blood flow in the infused arm, in response to the maximum dose of angiotensin II (50 pmol.min-1) were 53.2% at baseline, 51.4% on placebo and 59.5% on enalapril. The differences were not significantly different. This study demonstrates that suppression of plasma angiotensin II does not enhance the response to exogenous intra-arterial angiotensin II in the human forearm of mild-moderately hypertensive patients.
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PMID:Angiotensin converting enzyme inhibition does not affect response to exogenous angiotensin II in the forearm of mild-moderate hypertensive patients. 785 1

1. Angiotensin II (AII) plays a major role in cardiovascular function via direct actions on the vasculature, kidney, adrenal, heart, brain and sympathetic nerves. The cellular effects of AII are extensive and encompass hypertrophy, hyperplasia and the deposition of extracellular matrix. 2. The actions of AII are mediated by the AT1 and AT2 membrane receptor subtypes, and additional forms of each subtype. Evidence is emerging that selective changes in AII receptor subtypes occur in cardiovascular diseases. 3. Thyroid dysfunction increased cardiac, liver and kidney AII receptor density but decreased adrenal gland receptor density. In the heart, there was a selective increase in AT2 receptor density. 4. Diabetes increased cardiac, liver and adrenal gland AII receptor densities but decreased kidney receptor density. 5. Hypertension increased AII receptor density in the heart and kidney. A corresponding increase in receptor mRNA was prevented by selective AT1 receptor antagonists. 6. The human heart contained AII receptors in all chambers; right atrial receptor density was increased in coronary artery bypass graft patients. 7. The presence of AII receptor changes in these models of cardiac hypertrophy and hypertension raises the possibility of using orally active, subtype-selective agonists and antagonists to treat particular forms of cardiovascular diseases.
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PMID:Angiotensin receptors in cardiovascular diseases. 786 32

Angiotensin II (Ang II) receptors were labelled by in vitro autoradiography using 125I-[Sar1,Ile8]Ang II as a ligand in the kidney, adrenal gland, thoracic aorta, and hindbrain of adult spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY). Ang II receptors were differentiated into subtypes by susceptibility to subtype 1 (AT1) and subtype 2 (AT2) antagonists. In both rat strains, the adrenal cortex contained predominantly AT1 receptors, while AT2 receptors predominated in the adrenal medulla. The kidney contained exclusively AT1 receptors in glomeruli, proximal tubules, and the outer medulla. AT1 receptors were predominant in the thoracic aorta. The nucleus of the solitary tract (NTS), dorsal motor nucleus of the vagus (DM10), area postrema, and spinal trigeminal nucleus (Sp5) contained exclusively AT1 receptors, whereas the nucleus of the inferior olive contained AT2 receptors predominantly. Significant differences in receptor density were observed between SHR and WKY. The adrenal cortex, renal outer medulla, NTS, DM10, and Sp5 displayed higher AT1 receptor density in SHR than in WKY. These results indicate that expression of AT1 receptors is regulated differently in important targets of Ang II in SHR, and suggest that altered regulation of AT1 receptor expression may be relevant to the pathogenesis of hypertension in SHR.
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PMID:Quantitative localization of angiotensin II receptor subtypes in spontaneously hypertensive rats. 788 97


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