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

Although the angiotensin II subtype 2 receptor (AT2-R) is expressed abundantly in the adrenal medulla, its physiological significance has not yet been determined. To obtain fundamental knowledge of the regulation of AT2-R expression in the adrenal medulla, we investigated the effects of modulating several ion channels on AT2-R expression in PC12W cells. Experiments were performed after 24 hours of serum depletion under subconfluent conditions. After 48 hours of treatment with various agonists or antagonists, the receptor density and mRNA level of AT2-Rs were quantified by 125I-[Sar1, Ile8]angiotensin II binding and Northern blot analysis. Ouabain (10 to 100 nmol/L) and insulin (10 to 100 nmol/L) dose-dependently increased receptor density and mRNA level. Analysis of the binding characteristics revealed that the ouabain-dependent increase in AT2-R levels was due to an increase in binding capacity without a change in the Kd value. These increases were blocked by lowering the Na+ concentration in the medium. A low concentration of the sodium ionophore monensin (10 nmol/L), the K+-channel blocker quinidine (10 micromol/L), and the ATP-sensitive K+-channel blockers tolbutamide (100 micromol/L) and glybenclamide (10 micromol/L) also significantly increased receptor density, but the ATP-sensitive K+-channel agonist cromakalim (100 micromol/L) decreased receptor density significantly (P<0.01). Nifedipine (10 micromol/L) decreased basal receptor density and completely blocked the increase in receptor density caused by these agents. The increase in receptor density caused by an increase in intracellular Na+ was accompanied by an increase in mRNA level, whereas the ATP-sensitive K+-channel blockers did not change mRNA level. Nifedipine slightly decreased mRNA level. These results suggest that AT2-R expression is sensitively regulated by intracellular cation levels. The change in intracellular Na+ level transcriptionally regulates AT2-R expression, whereas the K+-channel blocker-dependent upregulation appears to be at least in part posttranslational.
Hypertension 1999 Feb
PMID:Intracellular sodium modulates the expression of angiotensin II subtype 2 receptor in PC12W cells. 1002 18

The renin-angiotensin system (RAS) plays an important role in blood pressure control and in water and salt homeostasis. It is involved in the pathophysiology of hypertension and structural alterations of the vasculature, kidney, and heart, including neointima formation, nephrosclerosis, postinfarction remodeling, and cardiac left ventricular hypertrophy (LVH). Recently, an increased knowledge of the effector peptides of the RAS, their receptors, and their respective functions has led to a new principle of treatment for hypertension: the inhibition of angiotensin (Ang) II via angiotensin-converting enzyme inhibitors or Ang II-receptor antagonists. In this review, the Ang receptors AT1 and AT2 and the potential roles of shorter angiotensin fragments, including Ang III(2-8), Ang IV(3-8), and Ang(1-7), are discussed.
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PMID:The renin-angiotensin system and its receptors. 1002 50

Pharmacologic interruption of the renin-angiotensin system (RAS) with angiotensin-converting enzyme inhibitors (ACEI) is considered a standard therapeutic intervention for patients with chronic renal disease, regardless of whether systemic hypertension is present. The advent of orally active angiotensin receptor blockers (ARB) increases the number of therapeutic options for inhibiting the RAS in patients with chronic renal diseases. Clinical studies of ARB that can be compared with large-scale ACEI clinical trials have yet to be completed. More than a dozen experimental studies comparing ARB with ACEI suggest that the two classes of drugs share similar renoprotective properties. Like ACEI, ARB are effective antihypertensive and antiproteinuric agents, which greatly reduce glomerular and tubulointerstitial scarring. Although both reduce stimulation of the AT1 receptor, ARB lack the kinin-potentiating effects of ACEI. ARB may exert antifibrotic actions via the AT2 receptor, through increased levels of angiotensin II resulting from AT1 receptor blockade. Despite these pharmacologic distinctions, recent studies have not detected differences in renoprotection between ARB and ACEI. In the context of RAS inhibition, the magnitude of antihypertensive and antiproteinuric effects achieved appears to be the major determinant of renoprotection, not the class of drug used. Thus, experimental data suggest that ARB will fulfill their promise as effective agents to be used as mainstays in multifaceted clinical strategies designed to slow or arrest the progression of chronic renal disease. Confirmation of this view awaits the results of clinical trials.
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PMID:Angiotensin receptor blockers in chronic renal disease: the promise of a bright clinical future. 1020 84

NCI-H295, a human adrenocarcinoma cell line, has been proposed as a model system to define the role of the renin-angiotensin system in the regulation of aldosterone production in humans. Because the precise cellular localization of the components of the renin-angiotensin system in human adrenal cortical cells remains unclear, we investigated their localization in this defined cell system. NCI-H295 cells expressed both angiotensinogen and renin as shown by reverse transcriptase polymerase chain reaction and immunohistochemistry. Human angiotensin-converting enzyme (ACE) was not detectable by immunocytochemistry, ACE binding, or reverse transcriptase polymerase chain reaction. However, 3.5 mmol/L K+ stimulated the formation of both angiotensin I and angiotensin II 1. 9- and 2.5-fold, respectively, and increased aldosterone release 3. 0-fold. The K+-induced stimulation of aldosterone release was decreased by captopril and enalaprilat (24% and 26%, respectively) and by the angiotensin type 1 (AT1)-receptor antagonist losartan (28%). Angiotensin II-induced stimulation of aldosterone release was abolished by losartan treatment. Specific [125I]Sar1-angiotensin II binding was detected by receptor autoradiography. The binding of [125I]Sar1-angiotensin II was completely displaced by the AT1 antagonist losartan but not by the AT2 receptor ligand PD 123319, confirming the expression of angiotensin II AT1 receptors in NCI-H295 cells. Our results demonstrate that NCI-H295 cells express most of the components of the renin-angiotensin system. Our failure to detect ACE, however, suggests that the production of angiotensin II in NCI-H295 cells may be ACE independent. NCI-H295 cells are able to produce angiotensin II, and K+ increases aldosterone secretion in part through an angiotensin-mediated pathway. The production of angiotensin II in NCI-H295 cells demonstrates that this human cell line can be useful to characterize the role of locally produced angiotensin II in the regulation of aldosterone release.
Hypertension 1999 Apr
PMID:Local renin-angiotensin system is involved in K+-induced aldosterone secretion from human adrenocortical NCI-H295 cells. 1020 42

A review of the drug class of angiotensin receptor blockers (ARBs) as well as the ARBs currently available by prescription in the United States is presented. The importance of angiotensin II production by non-angiotensin-converting enzyme (non-ACE) pathways, particularly human chymase, is discussed. Emphasis is placed on the mechanism of action of ARBs and the different binding kinetics of these agents. Although all ARBs, as a group, block the AT1 receptor, they may differ in the pharmacological characteristics of their binding and be classified as either surmountable or insurmountable antagonists. Mechanisms of surmountable and insurmountable antagonism as well as possible benefits of these blocking characteristics are discussed in relation to the various ARBs. The cardiovascular effects of activation of the two main subtypes of angiotensin receptors (AT1 and AT2) are presented. In addition to their treatment of hypertension, ACE inhibitors are recognized as being effective in the management of heart failure, left ventricular hypertrophy, recurrent myocardial infarctions, and renal disease. ARBs are currently indicated only for the treatment of hypertension; however, in vitro and in vivo pharmacological studies as well as preliminary clinical data suggest that ARBs, like ACE inhibitors, may also provide effective protection against end-organ damage in these conditions.
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PMID:Practical considerations of the pharmacology of angiotensin receptor blockers. 1035 58

Angiotensin (A) II is a potent constrictor as well as growth stimulant of vascular smooth muscle cell caused by activation of AT1 receptor signal transduction systems. There are two major signal systems of AT1 receptor: one leads to an increase in cytosolic free calcium levels causing smooth muscle contraction which may result in high blood pressure, and the other leads to smooth muscle proliferation and inflammation which may result in atherosclerosis. AT1 receptor activation induces phosphinositide hydrolysis by phospholipase C and creates an inositol phosphate, which release calcium from cytosolic calcium pools. Cytosolic calcium can also be elevated by activation of calcium channel via a link between AT1 receptor and a G protein. Protein phosphorylation triggered by AT1 receptor is important for cell growth, in which tyrosine kinase, serine/threonine kinase and protein kinase C are involved. Free radicals are generated by NADH/NADPH oxidase in response to AT1 receptor activation, causing expression of genes leading to atherosclerosis. On the other hand, activation of AT2 receptor is shown to play a role of lowering blood pressure. Some phosphatases and NO/cyclic GMP would be involved in the mechanism. In renal vasculature, endothelium dependent epoxygenase products are synthesized by AT2 receptor stimulation causing vasorelaxation. In summary, AT1 receptor signals are vasopressive and evoke atherosclerosis, whereas AT2 receptor signals may possibly be vasodilatory.
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PMID:[Signal transduction systems of angiotensin II receptors]. 1036 37

Angiotensin II (Ang II) acts at the cellular level on two receptor subtypes: the AT1 receptor which can be blocked by losartan and its analogues (the 'sartan family'), and the AT2 receptor that does not react with the above antagonists but which can be blocked by different compounds, such as PD123319. AT1 receptor blockade has proven to be a highly effective means of interference with the renin-angiotensin system (RAS) and hence of reducing high blood pressure. As a result of the terminal blockade of the RAS cascade, circulating Ang II levels tend to rise two- to threefold. The free access of such enhanced levels to uninhibited AT2 receptors may be clinically relevant, as argued in the present review. The most extensive experimental and clinical experience with AT1 receptor blockade so far has been obtained with the pioneer drug losartan, although major contributions have also been made on candesartan cilexetil, irbesartan and valsartan. All of these four drugs have been instrumental in substantial clinical trials, serving as sources of information in the clinically oriented part of this review. AT1 receptor blocking drugs generally provide a relatively gradual decrease in blood pressure, which is comparable to that obtained with conventional anti-hypertensive drugs. Clinical trials reveal an astounding lack of drug-related adverse effects, scoring even better than placebo in terms of frequencies and sometimes patterns. The trough/peak ratio on single dosages seems to have been mastered, particularly with the second generation of AT1 receptor blockers, as is evident from 24 h ambulatory blood pressure monitoring. Combination with low-dose thiazide regimens is well established. Intermediate endpoints (micro-albuminuria and left ventricular hypertrophy) appear to be controllable. Morbid cardiovascular sequelae are currently under study in comparison with beta- and calcium channel blockade.
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PMID:Non-peptide angiotensin type 1 receptor antagonists in the treatment of hypertension. 1041 59

Systolic hypertension is a major risk factor for cardiovascular disease. The determinants of systolic blood pressure are peripheral resistance and arterial compliance. Arterial vasoconstriction, vascular growth and fluid retention, induced by the renin-angiotensin system directly or indirectly by enhancing sympathetic nervous system activity, are important factors in increasing peripheral resistance, decreasing arterial compliance and, consequently, elevating systolic blood pressure. Selective blockade of the angiotensin II type 1 (AT1) receptor represents a novel mechanism for interrupting the renin-angiotensin system. This provides the additional benefit of blocking angiotensin II generated by non-angiotensin-converting-enzyme pathways without altering either bradykinin metabolism or the potential beneficial effects of AT2 receptor stimulation. Eprosartan is a potent (1.4 nmol/l) AT1 receptor antagonist that inhibits angiotensin-II-induced vascular contraction in a competitive manner. Eprosartan is effective in reducing disease progression in animal models of hypertension, heart failure, renal disease and stroke. Furthermore, eprosartan causes a large increase in arterial compliance in hypertensive rats fed high-salt and high-fat diets. Eprosartan also possesses sympathoinhibitory activity as demonstrated by an inhibition of the pressor responses induced by activation of sympathetic outflow through spinal cord stimulation in pithed rats. In contrast, other angiotensin II receptor antagonists, such as losartan, used at equivalent angiotensin II blocking activity, do not appear to alter sympathetic nervous system activity. Angiotensin II receptor antagonists, such as eprosartan, that have the ability to block both the direct effects of angiotensin II and the indirect effects mediated by enhanced sympathetic neurotransmission, may represent an important advance in the treatment of elevated systolic blood pressure.
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PMID:Pharmacological mechanism of angiotensin II receptor antagonists: implications for the treatment of elevated systolic blood pressure. 1046 64

Selective blockade of the angiotensin II AT1 receptor represents a novel mechanism for interrupting the renin-angiotensin system without altering the potential benefits of AT2 receptor stimulation. This selective inhibition produces none of the disadvantages associated with reduced bradykinin metabolism and angiotensin II generated by non-angiotensin-converting enzyme pathways. Eprosartan is a potent (1.4 nmol/L) AT1 receptor antagonist that competitively blocks angiotensin II-induced vascular contraction. In various animal models of disease, including hypertension and stroke, eprosartan is effective in reducing disease progression. Eprosartan also has sympathoinhibitory activity, as demonstrated by an inhibition of the pressor responses induced by activation of sympathetic outflow through spinal cord stimulation in pithed rats. In contrast, some of the other angiotensin II receptor antagonists, such as losartan, at equivalent angiotensin II blocking doses, have no effect on sympathetic nervous system activity. Because eprosartan can inhibit both the direct effects of angiotensin II as well as the indirect effects that are mediated by enhanced sympathetic neurotransmission, this may represent an important advance in the treatment of elevated systolic blood pressure.
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PMID:Pharmacology of eprosartan, an angiotensin II receptor antagonist: exploring hypotheses from clinical data. 1046 20

Recent developments in molecular biological techniques allowed us to examine the genetic risk factors responsible for essential hypertension. The candidate gene approach revealed that several gene polymorphisms increase the relative risk for hypertension. Most genetic studies, however, examined only young subjects but not elderly ones. To examine the importance of gene polymorphisms in elderly hypertension, we carried out a case-control study and compared the odds ratio for hypertension between young (< 60) and elderly (> or = 60) subjects. The participants of this study were recruited from the outpatients of Osaka University Medical School with informed consent. We examined the following polymorphisms as candidates: the angiotensinogen (AGT/M235T), angiotensin converting enzyme (ACE I/D), angiotensin II type 1 (AT1/A1166C) and type 2 (AT2/C3123A) receptors, alpha-adducin (adducin/Gly460Trp), methylenetetrahydrofolate reductase (MTHHR/C677T), and apolipoprotein (apoE/epsilon 4, apoE/T-491A). In young subjects, the AGT/T235 allele significantly increased the odds ratio for hypertension but not in elderly subjects. In young males, the AT2/A3123 allele was also associated with hypertension but not in females or in elderly subjects. Other associations between polymorphism and hypertension did not reach a significant level. To sum up, it was revealed that some polymorphisms increase the susceptibility for hypertension but others do not, which suggests that there is heterogeneity in the genetic involvement of polymorphism due to aging.
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PMID:[Genetic analysis of candidate gene polymorphisms in elderly hypertension]. 1055 62


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