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

This study examines the effects of angiotensin II on hypertrophy and proliferation of aortic smooth muscle cells from spontaneously hypertensive and Wistar-Kyoto rats and the receptor subtypes mediating these effects. In quiescent confluent cells, angiotensin II induced a dose-dependent increase in thymidine and leucine incorporation without stimulating cell proliferation. In nonconfluent cells, angiotensin II stimulated cell proliferation only in combination with a submaximal concentration of fetal calf serum. These effects were enhanced in cells from spontaneously hypertensive rats compared with Wistar-Kyoto rats. The effects of angiotensin II could be blocked by the AT1 receptor antagonist DuP 753 but not by the AT2 receptor ligand PD 123177. In receptor binding studies with cells derived from both rat strains, AT1-typical binding was observed. These data show that the angiotensin II receptors present in vascular smooth muscle cells in culture from both rat strains are of the AT1 receptor subtype. This receptor subtype appears to mediate vascular smooth muscle cell hypertrophy and proliferation as well as vasoconstriction. Although no difference in the receptor profile was detectable between the two rat strains, the affinity for the ligands to the receptor and the receptor density tended to be greater in cells from spontaneously hypertensive rats than in cells from Wistar-Kyoto rats. These results may partly explain the greater hypotensive response to angiotensin II receptor blockade in spontaneously hypertensive rats than in Wistar-Kyoto rats, although both rat strains have the same plasma concentrations of angiotensin II.
Hypertension 1992 Dec
PMID:Receptor-mediated effects of angiotensin II on growth of vascular smooth muscle cells from spontaneously hypertensive rats. 145 90

Angiotensin II is a potent pressor hormone and a primary regulator of aldosterone secretion. It acts through at least two types of receptors termed AT1 and AT2. We analyzed cDNA and genomic clones encoding the human angiotensin II type-1 receptor, AT1. The human AT1 gene was mapped to chromosome 3q by polymerase chain reaction analysis of DNA from a panel of human-hamster somatic cell hybrids. The predicted amino acid sequence is 95% identical to the corresponding rat and bovine receptors and 25% and 22% identical, respectively, to the receptors encoded by the RTA and MAS genes. Characterization of several human cDNA clones demonstrated the existence of two alternate 5'-untranslated regions (UTRs) that contain a common initial sequence but differ by the presence or absence of an insertion of 84 base pairs. In the genomic sequence, the coding sequences are contained in a single exon, with an intron occurring in the 5'-UTR at the position of insertion of the 84-base pair sequence. The exons encoding the alternate 5'-UTRs are located at least 3.8 kilobases away from the exon encoding the protein. Reverse transcription-polymerase chain reaction analysis showed that both forms of 5'-UTR are present in approximately equal abundance in a range of tissues expressing AT1. The reagents developed in this work may be useful in testing the hypothesis that genetic variations in angiotensin II receptor function are associated with a tendency to develop hypertension.
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PMID:Genetic analysis of the human type-1 angiotensin II receptor. 150 24

The purpose of this study was to examine in vivo the importance of angiotensin subtype 1 (AT1) versus subtype 2 (AT2) receptors in spontaneously hypertensive (hypertensive) versus normotensive Wistar-Kyoto (control) rats. Intravenous infusions of DuP 753, a selective AT1 receptor antagonist, abolished the pressor responses to intravenous infusions of angiotensin II in both strains, and the potency of DuP 753 in this regard was similar in the two strains. DuP 753 also abolished angiotensin II-induced aldosterone release in both strains; however, with respect to inhibiting angiotensin II-induced aldosterone release, DuP 753 was more potent in hypertensive compared with control rats. In hypertensive but not control rats, DuP 753 inhibited angiotensin II-induced aldosterone release at doses lower than required to inhibit angiotensin II-induced pressor responses. Intramesenteric infusions of DuP 753 abolished mesenteric vascular responses to intramesenteric infusions of angiotensin II with a similar potency in both strains. In control but not hypertensive rats, angiotensin II consistently potentiated noradrenergic neurotransmission in the mesenteric vascular bed, and this effect of angiotensin II was abolished by DuP 753. High doses of PD123177, a selective AT2 antagonist, did not influence any of the aforementioned effects of angiotensin II in either strain.(ABSTRACT TRUNCATED AT 250 WORDS)
Hypertension 1991 Dec
PMID:Effects of angiotensin subtype 1 and subtype 2 receptor antagonists in normotensive versus hypertensive rats. 174 58

Angiotensin II is an important effector molecule controlling blood pressure and volume in the cardiovascular system. Its importance is manifested by the efficacy of angiotensin-converting enzyme inhibitors in the treatment of hypertension and congestive heart failure. Angiotensin II interacts with two pharmacologically distinct subtypes of cell-surface receptors, AT1 and AT2. AT1 receptors seem to mediate the major cardiovascular effects of angiotensin II. Here we report the isolation by expression cloning of a complementary DNA encoding a unique protein with the pharmacological specificity of a vascular AT1 receptor. Hydropathic modelling of the deduced protein suggests that it shares the seven-transmembrane-region motif with the G protein-coupled receptor superfamily. Knowledge of the AT1 receptor primary sequence should now permit structural analysis, definition of the angiotensin II receptor gene family and delineation of the contribution of AT receptors to the genetic component of hypertension.
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PMID:Isolation of a cDNA encoding the vascular type-1 angiotensin II receptor. 204 70

Recent studies have revealed that angiotensin II (Ang II) interacts with two pharmacologically different types of seven-transmembrane domain receptors, hence named Ang II type 1 and type 2 (AT1 and AT2) receptors. cDNAs for the AT1 receptor have been cloned, and the existence of two receptor subtypes, AT1A and AT1B, has been revealed in rat and mouse. This study presents a new approach for the specific quantification of AT1A and AT1B receptor mRNAs by reverse transcription and polymerase chain reaction amplification in the presence of an AT1 receptor mutant cRNA as internal standard. Absolute quantities of mRNA are then determined by extrapolation using the standard curve generated with the internal standard. Moreover, addition of this internal standard to each tube controls for both reverse transcription and polymerase chain reaction amplification in each sample. In male Wistar rats, the highest absolute AT1A receptor mRNA levels were found in liver and kidney and those for AT1B receptor mRNA in the pituitary. Expressed as a percentage of total AT1A+AT1B receptor mRNA content, AT1A receptor mRNA content was 100% in liver, 85% in lung, 73% in kidney, 65% in aorta, 48% in adrenals, and 15% in the hypophysis. Since this approach can determine absolute AT1A and AT1B receptor mRNA quantities in different organs, it allows the study of the regulation of their expression under different pathophysiological conditions. After sodium depletion, known to induce hyperactivity of the renin-angiotensin system, adrenal AT1A and AT1B receptor mRNA levels were increased by 60% and 110%, respectively. In contrast, in renovascular hypertension (two-kidney, one clip), also associated with elevated circulating plasma renin activity, adrenal AT1B receptor mRNA levels decreased by 50%, whereas there was no change in those of AT1A. Therefore, the differential distribution and regulation of these two receptor subtypes suggest that each of them might be involved in the mediation of different biological effects of Ang II.
Hypertension 1994 Nov
PMID:Tissular expression and regulation of type 1 angiotensin II receptor subtypes by quantitative reverse transcriptase-polymerase chain reaction analysis. 752 76

ACE inhibitors are superior to other vasodilators in the treatment of congestive heart failure and may be advantageous in patients with myocardial infarction and hypertension. The mechanisms mediating these beneficial effects are not clear. The present article discusses the mechanisms leading to augmented release of endothelium-derived nitric oxide during ACE inhibition. Acute potentiation of bradykinin (Bk)-induced vasodilation was studied in rings of bovine and human coronary arteries mounted in organ chambers for recording of isometric force. The ACE inhibitors captopril, enalaprilat, fosinoprilat, lisinopril, or ramiprilat alone did not affect vascular tone in isolated coronary tone in isolated coronary artery preparations with intact endothelium. However, in the presence of exogenous Bk, kallidin, or one of the slowly degradable Bk2-receptor agonists D-Arg(Hyp3)-Bk or [Hyp3-Tyr(Me)8]-Bk they elicited potent concentration-dependent relaxations. Relaxations in response to lisinopril were not observed in the presence of other vasodilators. They were prevented by mechanical removal of the endothelium, inhibition of nitric oxide synthase or Bk2-receptor blockade. The data indicate that ACE inhibitors potentiate the effects of Bk on endothelial cells by a local mechanism, probably independent of the degradation of bradykinin. The chronic effects of ACE inhibitors on endothelial function were compared with those of selective angiotensin(AT)1-receptor blockade in cyclosporin A (CsA) treated rats. Chronic AT blockade alone does not affect endothelium-dependent relaxation and increases contractions to ATII in the rot aorta. Combination of CsA with either an ACE-Inhibitor or an AT2 receptor antagonist prevented the endothelial dysfunction in the rat arta observed after CsA alone.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Endothelium-mediated vasodilation during ACE inhibition. 755 74

Angiotensin II (Ang II) is the primary mediator of the renin-angiotensin system (RAS). Inappropriate control of the RAS is critically involved in the development and maintenance of hypertension and congestive heart failure. The actions of Ang II are thought to be mediated by specific surface receptors on the various target organs. At present, two receptors for Ang II have been firmly established in mammals, including man. According to current nomenclature, losartan represents the prototype antagonist of the Ang II type 1 (AT1) receptor and does not possess significant affinity for the so-called AT2 receptor. Losartan is the first of a new class of orally active, nonpeptide Ang II receptor antagonists able to very specifically and selectively inhibit the RAS while lacking the agonistic effects of the peptide receptor antagonists, e.g. sarlasin, or the bradykinin potentiating effects of the angiotensin converting enzyme (ACE) inhibitors. Virtually all of the known actions of Ang II, e.g. those defined by Ang II itself, saralasin, ACE or renin-inhibitors are blocked by losartan, emphasizing the major role of this distinct Ang II receptor subtype in mediating the responses of Ang II. The functional correlate of the AT2 receptor remains poorly understood. In several models of experimental and genetic hypertension, AT1 receptor antagonists are effective antihypertensive agents with similar efficacy to that of ACE and renin-inhibitors. In animal models of renal disease, AT1 receptor antagonists significantly decrease proteinuria, protect against diabetic glomerulopathy and increase survival in stroke-prone spontaneously hypertensive rats.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:A new class of therapeutic agents: the angiotensin II receptor antagonists. 763 3

The renin-angiotensin system is critical for regulating extracellular fluid volume and blood pressure. Angiotensin II, the active peptide hormone produced by the renin enzymatic cascade, sustains vascular volume and blood pressure by constricting vessels, stimulating adrenal aldosterone secretion, increasing renal tubular sodium absorption, activating the sympathetic nervous system, and increasing cardiac contractility. These actions are a disability in the pathophysiologic states of hypertension and congestive heart failure (CHF), however, since reactive increases in renal renin and angiotensin II stimulate sympathetic activity and renal sodium retention, leading consequently to circulatory volume over-load. The actions of angiotensin II are mediated by its interactions with specific cell-surface angiotensin II receptors, namely, AT1 and AT2; most cardiovascular actions of angiotensin II come from its interaction with the AT1 receptor. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin-II-receptor blockers antagonize the actions of the renin-angiotensin axis, neutralizing its effects on hypertension and heart failure. Losartan is the first oral, nonpeptide, selective AT1-receptor blocker to be approved. Clinical trials show it to be effective and well tolerated as therapy for hypertension and CHF. Data obtained thus far suggest ACE inhibitors and AT1-receptor blockers have similar efficacy for treating these conditions, but the receptor blockers appear to produce fewer adverse effects. Whether the sustained increase in angiotensin II concentrations after AT1-receptor antagonism produces deleterious effects is not known. The concern is that these high levels may stimulate unblocked AT2 receptor; the effect of that stimulation may not be important, however.
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PMID:Angiotensin receptors: physiology and pharmacology. 763 61

Angiotensinogen is a glycoprotein with intriguing structural similarities to the serine proteinase inhibitors but with only one known function: to act as a substrate in the enzymatic generation of angiotensin peptides. It is expressed as a constitutive protein by the liver and various other tissues, including the brain. It is in this tissue that the expression of angiotensinogen attains its most complex and controversial manifestations. In late gestation, an unfolding of cellular expression occurs, starting at an epicentre in the eppendymal and astroglia cells of the hypothalamus, which rapidly and sequentially spreads to sub-cortical and then cortical regions, concentrating at sites of electrolyte, fluid and pressure regulation. This initial burgeoning of astroglial angiotensinogen is trailed by a wave of neuronal expression in various limbic and sensorimotor regions of the brain. The predominance of AT2 receptors in these regions suggests that the RAS actions are mediated by AT2 receptors. The angiotensinogen found in the CSF and secreted by cultures of glia and neurones is similar to the two major molecular sizes found in plasma. However, by electrophoretic separation on the basis of charge imparted by differential glycosylation, it can be shown that glia and neurones secrete distinct forms. The expression of different forms is under hormonal regulation. If these structural forms are shown to affect function, then the resulting ramifications may extend to pathological conditions, such as hypertension. Primary cell cultures of astrocytes secrete angiotensinogen constitutively and in a region-specific manner related to the size of the sub-population of secretory cells. Neurone cultures secrete angiotensinogen at about 25% the rate of hypothalamic astrocytes. The use of RT-PCR shows that both cell types express angiotensinogen mRNA. There is still an unresolved mismatch between these data and in situ hybridization histochemistry which shows expression limited to astrocytes but it is suggested that changes to more appropriate techniques will resolve any outstanding discrepancies.
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PMID:Location and secretion of brain angiotensinogen. 764

With the development of subtype specific angiotensin II (Ang II) receptor antagonists and their introduction into the treatment of heart failure and hypertension, the regulation of the Ang II receptor with its subtypes AT1 and Ang T2 gains clinical importance. In cell cultures, the number of surface AT1 is clearly down-regulated by Ang II exposure. Down-regulation can be due to reversible internalization, to phosphorylation and to reduced synthesis and involves protein kinase C and phospholipase C mediated pathways. In this respect, the AT1 behaves as a typical G-protein coupled receptor. Aldosterone, cAMP, norepinephrine and extracellular glucose concentrations can contribute to AT1 regulation. There are very few data regarding the regulation of the subtype AT2, indicating modulation by a number of growth factors and by Ang II. In whole animal models receptor regulation deviates partially from cell cultures. In the rat, the two subtypes AT1A and AT1B are differentially regulated and the expression of subtypes is organ specific. In most experiments, including our own experiences, the AT1, in the adrenals was up-regulated by Ang II infusion and down-regulated by angiotensin converting enzyme inhibitors (ACEI) or Ang II receptor antagonists. Differing effects were observed in other organs. In humans, a number of studies seeking an association between Ang II levels, Ang II receptor regulation and physiological events have been conducted in platelets. In pregnant women, a negative correlation between plasma Ang II levels and Ang II binding and an association between receptor regulation and pregnancy-induced hypertension has been described.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Regulation of the angiotensin receptor subtypes in cell cultures, animal models and human diseases. 771 21


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