Gene/Protein Disease Symptom Drug Enzyme Compound
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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 present study examines the effects of prolonged angiotensin II antagonism in spontaneously hypertensive rats by using an angiotensin II receptor antagonist (DuP 753) that is devoid of agonistic properties and selective for the subtype 1 of the angiotensin II (AT1) receptor. The antihypertensive effects of DuP 753 and its effects on circulating parameters of the renin-angiotensin system were compared with those of a converting enzyme inhibitor (benazeprilat). To minimize any influence of differences in the pharmacokinetic properties of the two blockers, administration was by continuous intravenous infusion. The experiments were performed in conscious, freely moving rats with continuous 24-hour monitoring of blood pressure. DuP 753 (10 or 30 mg/kg/day) lowered mean arterial pressure to the same extent as benazeprilat (3 or 10 mg/kg/day) during a 48-hour period. The antihypertensive effect was sustained when the treatment was extended to 7 days (DuP 753, 10 mg/kg/day; benazeprilat, 3 mg/kg/day). Neither of the compounds affected the baseline or diurnal rhythm of heart rate. Plasma concentrations of renin and angiotensin II were increased sevenfold and 10-fold, respectively, in the rats treated with DuP 753. In rats treated with benazeprilat, plasma renin concentration increased threefold, whereas angiotensin II was unchanged. Heart weights were significantly reduced to a similar extent by DuP 753 and benazeprilat. Both compounds also induced a smaller but significant decrease in blood pressure in Wistar-Kyoto rats. Our results indicate that the antihypertensive effects of converting enzyme inhibitors in spontaneously hypertensive rats are mainly due to the blockade of the renin-angiotensin system. In this rat model, angiotensin II appears to play an important role in the maintenance of hypertension that is mediated via the AT1 receptor.
Hypertension 1991 Sep
PMID:Prolonged angiotensin II antagonism in spontaneously hypertensive rats. Hemodynamic and biochemical consequences. 188 42

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

DuP 532 is a novel nonpeptide angiotensin II (AII) receptor antagonist under development for the treatment of hypertension. DuP 532 is a more potent antihypertensive agent in renal hypertensive rats (ED30 = 0.042 mg/kg, i.v.) and displays a similar or longer duration of action than the previously described AII antagonist, DuP 753. DuP 532, in contrast to DuP 753, is a noncompetitive antagonist of AII-induced contractions of rabbit aortic strips (KB = 1.1 x 10(-10) M). However, the inhibition of AII binding by DuP 532 in rat adrenal cortex does not correlate with either the aortic contractile response or with the hypotensive response. Assay conditions were evaluated and the presence or absence of BSA was shown to markedly affect the apparent binding affinity of DuP 532 and other 5-carboxylic acid derivatives. DuP 753 and other compounds were much less affected. The IC50 for DuP 532 was 4.7 x 10(-6) M with and 3 x 10(-9) M without BSA. The IC50s for DuP 753 were 1.7 x 10(-8) M with and 5 x -9 M without BSA. Both compounds with or without BSA did not completely inhibit AII binding which is characteristic of AT1 selectivity. BSA also reduced the effect of DuP 532 on the AII-induced contractions of rat main pulmonary artery preparations and the AII-induced Ca2+ mobilization in rat aortic smooth muscle cells. DuP 532 was very specific for AT1 receptors and did not interfere with receptors associated with neurotensin, prazosin, bradykinin, nitrendipine, or vasopressin. It is concluded that DuP 532 represents a new class of specific, but noncompetitive. AII receptor antagonists whose binding characteristics may provide new insight into AII receptor function.
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PMID:DuP 532: a second generation of nonpeptide angiotensin II receptor antagonists. 204 7

A novel series of nonpeptide angiotensin II (A II) antagonists containing a pyrimidinone ring which carries a C-linked biphenyltetrazole moiety and a carboxyheteroaryl group on the 3-position have been prepared. Their affinity for the AT1 receptor was determined in a binding assay on rat adrenal cortical membranes. The in vivo antihypertensive properties were tested by evaluating the inhibition of the pressor response to A II followed by iv and id administration. Extensive molecular modeling studies, including comparison of molecular electrostatic potential distributions, conformational analysis, and overlays on a computational pharmacophore model of A II, were used to evaluate structural parameters of the new compounds, in comparison to other known A II antagonists (e.g., DUP-753 and SK&F 108566). According to the modeling studies, the introduction of a (carboxyheteroaryl)methyl moiety at the 3-position of the pyrimidinone ring led to derivatives with increased potency. Methyl 2-[[4-butyl-2-methyl-6-oxo-5-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl ]- 4-yl]methyl]-1-(6H)-pyrimidinyl]methyl]-3-thiophenecarboxylate (3k, LR-B/081), one of the most potent compounds in the series (Ki = 1.4 nM), exhibited a marked antihypertensive activity on oral administration to conscious renal hypertensive rats, with long duration of action. It was selected for clinical evaluation in the treatment of hypertension in man.
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PMID:N-3-substituted pyrimidinones as potent, orally active, AT1 selective angiotensin II receptor antagonists. 749 Jul 30

Fructose feeding induces a moderate increase in blood pressure levels in normal rats that is associated with insulin resistance, hyperinsulinemia, and hypertriglyceridemia. The sympathetic nervous system seems to participate in the alterations of this model. To further explore the mechanisms underlying fructose-induced hypertension, the effects of the AT1 receptor antagonist losartan on blood pressure, insulin resistance, renal function, and vascular reactivity in mesenteric vascular beds were studied. Sprague-Dawley rats were fed for 4 weeks with diets containing 60% fructose or 60% starch (control), and half of each group received losartan (1 mg/kg per day) in the drinking water. Fructose-fed rats showed higher (P < .05) blood pressure levels and plasma concentrations of triglycerides and insulin than those of controls. Losartan treatment prevented both blood pressure elevation and hyperinsulinemia in fructose-fed rats but not elevation of plasma triglycerides. Plasma glucose and insulin levels in response to an oral glucose load were higher (P < .05) in fructose-fed rats than in controls. These exaggerated responses were prevented by losartan treatment. No differences in the constrictor responses of mesenteric vascular beds to KCl (60 mumol), angiotensin II (1 nmol), phenylephrine (10(-5) mol/L), or endothelin-1 (10 pmol) were found between the two groups. Relaxing responses to acetylcholine or sodium nitroprusside in phenylephrine-precontracted mesenteric vascular beds and constrictor response to the nitric oxide synthesis inhibitor NG-nitro-L-arginine methyl ester (100 nmol) were comparable in both groups. Losartan blunted angiotensin II constriction and reduced (P < .05) responses to phenylephrine in all groups.(ABSTRACT TRUNCATED AT 250 WORDS)
Hypertension 1995 Dec
PMID:Effects of losartan on blood pressure, metabolic alterations, and vascular reactivity in the fructose-induced hypertensive rat. 749 71

The renin angiotensin system is a major contributor to the pathophysiology of cardiovascular diseases such as congestive heart failure and hypertension. For this reason, attempts to specifically block this system have been a pharmacological goal for over 25 years. Blockade of the renin system has been attempted at 3 pivotal sites: the rate limiting angiotensinogen-renin step, conversion of angiotensin I to angiotensin II, and the active receptor sites for the terminal products of angiotensin II and aldosterone. Converting enzyme inhibitors have been successfully studied and utilised in clinical cardiovascular disorders, but questions persist regarding the specificity of their action. Thus, other more specific approaches remain under evaluation. Inhibition of the action of renin on angiotensinogen was demonstrated with early inhibitory peptides and in experimental studies with specific antibodies. Most currently available renin inhibitors are nonpeptides, which nonetheless require intravenous administration. An oral renin inhibitor with clinical effects has been evaluated in early human trials. Like renin inhibitors and converting enzyme inhibitors, specific angiotensin antagonists were studied early in the course of renin system pharmacological blockade. Early angiotensin antagonists were limited, due to the requirement for intravenous administration and because of their short half-lives. They also had the potential for mixed agonist/antagonist physiological and pharmacological effects, which could result in a pressor, rather than a depressor, response. The angiotensin receptor antagonists have the appeal of blocking the specific receptor at its target tissue site, analogous to other well described systems. Newer angiotensin antagonists do not have the limitations of the precursor peptides. Losartan (DUP753) is a specific angiotensin II AT1 receptor antagonist. It is orally effective without agonist activity, and has high receptor binding characteristics. Early studies indicate that it is a specific probe of the renin system, and is providing newer insights into the role of the renin system in cardiovascular disorders. Emerging clinical studies indicate that it is effective for blood pressure reduction and as a vasodilator. Aldosterone antagonists such as spironolactone have been available for decades. Spironolactone is being used in an ongoing trial to assess the impact of combined converting enzyme and aldosterone inhibition. Newer aldosterone antagonists could add to targeted blockade of aldosterone without the adverse effects of the precursor compound, and the potential for combined specific renin system blockade.
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PMID:The clinical potential of renin inhibitors and angiotensin antagonists. 751 58

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

On the basis of recent advances in molecular biology and statistical genetics, it has become possible to search for chromosome regions that contain genes predisposing to hypertension and to directly link specific mutations on candidate genes to hypertension. As the human genome has been extensively mapped, highly informative, polymorphic markers are available, which can be used to detect genes in their proximity with 'hypertensinogenic' alleles. Some of these markers have been shown to be tightly linked to the genes of the renin-angiotensin system. Furthermore, the coding and regulatory regions of the genes encoding for renin, ACE, angiotensinogen and the AT1 receptor have been partially characterized. This provides a basis for further definition of specific polymorphisms within these genes that are of functional importance and that can be used to examine their contribution to the inheritance of primary hypertension. The first studies of these links have already emerged and have been reviewed in this article. Several problems arise in performing such linkage studies in human primary hypertension, however. It is difficult to define the genetic background of heterogeneous, multigenetic and multifactorial diseases such as human hypertension. Extensive studies of population genetics, including the analysis of large numbers of generations and controlled breeding experiments, cannot be performed, for obvious reasons. Blood pressure is not a convenient study trait, because it exhibits great intraindividual variance and also because of the relatively low reliability of just a few indirect measurements obtained under loosely controlled environmental conditions. Twenty-four-hour ambulatory blood pressure measurements may improve such investigations in the near future. Ravogli et al (1990) reported that the 24-hour ambulatory systolic blood pressure is higher in normotensive subjects of hypertensive parents than in normotensive subjects of normotensive parents--a finding that had not been previously reported using the conventional method of measurement. Hypertension as a trait per se is also problematic: its classification (above 140/90 mmHg) is purely artefactual, and its aetiology is highly heterogeneous. Thus, we have to keep in mind that even strong gene effects, if present in only a small subgroup of hypertensives, may not be detected in these studies. Attempts are being made to strengthen the analysis by characterizing physiologically distinct subgroups. In addition, the investigation of intermediate phenotypes, such as plasma parameters, which are more reliable and less subject to variations, may be helpful.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Molecular basis of human hypertension: the role of angiotensin. 757 36


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