Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004135 (ATM)
 13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Through the multiple actions of angiotensin II (AII), the renin-angiotensin system (RAS) participates in cardiovascular homeostasis. Angiotensin II acts by binding to specific membrane-bound receptors, which are coupled to one of several signal transduction pathways. These AII receptors exhibit heterogeneity, represented by AT1 and AT2 receptor subtypes. The AT1 receptor mediates the major cardiovascular action of the RAS. This receptor has been cloned from multiple species, disclosing features consistent with a transmembrane, G-protein-linked receptor. Further AII receptor heterogeneity is evident by the cloning of isotypes of the AT1 receptor. Blocking the interaction of AII with its receptor is the most direct site to inhibit the actions of the RAS. Many AII receptor antagonists, including peptide analogs of AII and antibodies directed against AII, possess unfavorable properties that have limited their clinical utility. The discovery and further development of imidazole compounds with AII antagonist properties and favorable characteristics, however, has promise for clinical utility. The leader in this field is a selective AT1 receptor antagonist losartan (previously known as DuP 753 or MK-954). Losartan was demonstrated to be an effective antagonist of many AII-induced actions and an effective antihypertensive agent in many animal models of hypertension (HTN). Losartan also demonstrated secondary benefits in preventing stroke, treating congestive heart failure (CHF), and delaying the progression of renal disease in animal models. Clinical studies confirm the AII antagonist action of losartan and suggest that losartan will be effective in the treatment of essential HTN. AII antagonism is likely to provide useful treatment in essential HTN and CHF, conditions in which the RAS is known to play a major role. The utility of AII antagonism may extend beyond that of HTN and CHF, as suggested by the potential usefulness of angiotensin-converting enzyme (ACE) inhibition in the treatment or prevention of many other diseases. The key advantage AII antagonists provide over ACE inhibitors is that they may avoid unwanted side effects, related to bradykinin potentiation with the latter drugs. The AII antagonists will help determine the role of the RAS in physiologic regulation and in the pathophysiology of various disease states.
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PMID:Angiotensin II receptor blockade: an innovative approach to cardiovascular pharmacotherapy. 830 Aug 85

We evaluated the role of endogenous angiotensin II and III (ANG II and ANG III) at the rostral nucleus reticularis ventrolateralis (NRVL) in the modulation of baroreceptor reflex (BRR) response and the subtype of angiotensin receptors involved in this process. Adult male Sprague-Dawley rats anesthetized and maintained with pentobarbital sodium were used. Exogenous application of ANG II or ANG III (10, 20, or 40 pmol) by bilateral microinjection into the NRVL significantly suppressed the BRR response to transient hypertension induced by phenylephrine (5 micrograms/kg i.v.). The suppressive effect of ANG II (20 pmol) was reversed by an equimolar dose (1.6 nmol) of its peptide antagonist, [Sar1, Ile8]ANG II, and the nonpeptide antagonists for AT1 and AT2 receptors, losartan and PD-123319, respectively. On the other hand, the inhibitory action of ANG III (20 pmol) was blunted by its peptide antagonist. [Ile7]ANG III or PD-123319, but not by losartan. Blocking the endogenous activity of the angiotensins by microinjection into the bilateral NRVL of [Sar1, Ile8]ANG II, [Ile7]ANG III, or PD-123319 elicited an appreciable enhancement of the BRR response, whereas losartan produced minimal effect. These results suggest that, under physiological conditions, both endogenous ANG II and ANG III may exert a tonic inhibitory modulation on the BRR response by acting selectively on the AT2 receptors at the NRVL.
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PMID:Involvement of AT2 receptors at NRVL in tonic baroreflex suppression by endogenous angiotensins. 917 87

Diabetic nephropathy is the most common cause of end-stage renal disease (ESRD) in the United States, and accounts for 35% of all the patients with ESRD entering a dialysis program; 63% of patients with diabetic nephropathy have type II diabetes mellitus. Hypertension is a major risk factor for renal disease and is common in people with diabetes mellitus. Strategies for preventing the progression of renal failure in patients with diabetes mellitus include glycemic control, and control of blood pressure. Blocking the renin-angiotensin system (RAS) slows the progression of established diabetic nephropathy in type I diabetes mellitus, and inhibiting angiotensin II formation retards or impedes the progression from microalbuminuria to established diabetic nephropathy (macroproteinuria) in people with type I diabetes mellitus. The situation could be the same for people with type II diabetes mellitus. The ability of RAS blockade using irbesartan, an AT1 angiotensin II receptor antagonist, to slow the progression in renal failure has been compared with that of the calcium channel blocker amlodipine and placebo in a pilot study. The results suggest that blockade of the RAS, in this case with irbesartan, is at least equivalent to calcium channel blockers with respect to antihypertensive efficacy, but provides better renoprotective benefits.
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PMID:Renoprotection and renin-angiotensin system blockade in diabetes mellitus. 943 77

We evaluated the endogenous action of angiotensin II (AII) and its active metabolite, angiotensin III (AIII), at the nucleus tractus solitarii (NTS) in the modulation of baroreceptor reflex (BRR) response, and the subtype(s) of angiotensin receptors involved in this process. Adult, male Sprague-Dawley rats that were anesthetized and maintained with pentobarbital sodium were used. Bilateral microinjection of AII or AIII (10, 20 or 40 pmol) into the NTS significantly and dose-dependently suppressed the BRR response, which was evoked by transient hypertension induced by phenylephrine (5 micrograms/kg, i.v.). The suppressive effect of AII (40 pmol) was reversed by co-administration of the non-peptide AT1 receptor antagonist, losartan (1.6 nmol), but only partially by the non-peptide AT2 receptor antagonist, PD-123319. On the other hand, both angiotensin receptor antagonists appreciably reversed the depressive action of AIII (40 pmol). Blocking the endogenous activity of the angiotensins by microinjection into the bilateral NTS of losartan (1.6 nmol) or PD-123319 (1.6 nmol) elicited a significant enhancement of the BRR response. An interruption of the conversion of AII to AIII with the aminopeptidase A inhibitor, amastatin (3.3 nmol), attenuated, but did not eliminate, the AII-induced inhibition of the BRR response. We conclude that whereas the endogenous AIII may exert a tonic inhibitory modulation on the BRR response by acting on both the AT1 and AT2 receptor subtypes, the same action of the endogenous AII engaged only the AT1 receptor subtype at the NTS. Furthermore, at least part of the suppressive action of AII may result from its metabolic conversion to AIII.
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PMID:Participation of AT1 and AT2 receptor subtypes in the tonic inhibitory modulation of baroreceptor reflex response by endogenous angiotensins at the nucleus tractus solitarii in the rat. 951 51

To date established treatment of transplant arteriosclerosis is basically missing and there is a need for new therapeutic approaches. Angiotensin II (Ang II) and Ang II receptor type 1 (AT) are present in the vascular wall. Blocking of the AT1 receptor by pharmacological agents may inhibit damaging effects of Ang II on endothelial and smooth muscle cells. The purpose of the study was to evaluate the effect of the AT1 receptor blocker Candesartan cilexetil on the development of graft arteriosclerosis in a rat aortic transplant model. Two strain combinations were used for aortic transplantation: DA to PVG; and PVG to PVG. The animals received Candesartan cilexetil treatment (9.5 + 1.4 mg/kg/day) for 8 weeks. Candesartan cilexetil treatment reduced neointimal formation both in allografts (Qint 30.2 +/- 8.8% vs. 22.1 +/- 8.7%, P < 0.05) and in isografts (Qint 15.5 +/- 4.4% vs. 6.7 +/- 3.3%, P = 0.0001). Blocking of the AT1 receptor signalling by Candesartan cilexetil was also associated with a reduced expression of TGF-beta1. Macrophage infiltration was not affected by the treatment. Candesartan cilexetil treatment leads to reduced neointimal formation in aortic transplant. The positive effect of the drug might be partly explained by a reduction of TGF-beta1 expression in the grafts. Candesartan treatment may provide another possibility for prevention of transplant arteriosclerosis and chronic rejection.
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PMID:Candesartan cilexetil reduces graft arteriosclerosis in aortic transplantation model in rat. 1131 67

Blocking aldosterone action has been of clinical interest in the treatment of hypertension and related target organ damage. Although we have previously demonstrated aldosterone escape during long term administration of AT1 antagonist, pathological significance of aldosterone remains unknown. We investigated the effects of co-administration of spironolactone(SPRL) on the cardioprotective effects of AT1A in SHR-SP. Administration of AT1A alone resulted in a significant decrease in cardiac weight, cardiac transverse section area, cardiac fibrosis, and mRNA expression of BNP, type I and type III collagen, while cardiac ET-1 mRNA showed a significant increase. Co-administration of AT1A with SPRL resulted in a significant decrease in all the parameters including ET-1 mRNA expression. These results provide theoretical rationale for combination therapy of AT1A and SPRL in hypertension.
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PMID:[Significance of combining spironolactone during long-term administration of ARB]. 1239 93

We examined whether interactions between angiotensin II (Ang II), endothelin (ET), nitric oxide (NO), and prostaglandins (PGs) differentially regulate perfusion to distinct vascular beds. For this, we blocked either angiotensin AT1 or ET receptors or both and then sequentially inhibited NO and PG synthesis in anesthetized dogs. Blocking Ang II or ET had similar effects on systemic hemodynamics: Mean arterial pressure fell slightly without altering cardiac output. Blocking both caused a synergistic fall in mean arterial pressure and increased cardiac output. Pulmonary vascular resistance was not altered by blocking Ang II, ET, or both but progressively increased during NO and PG blockade in group 2 (which had unblocked ET receptors), suggesting that endogenous ET exerts pulmonary vasoconstriction that is tempered by NO and PGs. In the kidney, blocking Ang II increased regional blood flow (RBF), glomerular filtration rate (GFR), and fractional excretion of sodium (FENa). In contrast, blocking ET did not alter RBF, and it decreased GFR and FENa. Combined Ang II and ET blockade markedly increased RBF without altering GFR, and FENa was maintained at the levels as when only ET was blocked. Sequentially inhibiting NO and PGs decreased RBF when Ang II or ET were blocked but had little effect when both were blocked. Finally, Ang II or ET blockade did not alter iliac blood flow. Inhibiting NO and PGs decreased iliac blood flow when Ang II or ET but not both were blocked. These results suggest that regional differences in the interactions between endogenous Ang II, ET, NO, and PGs are important determinants in systemic, pulmonary, and regional hemodynamics.
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PMID:Interactions between vasoconstrictors and vasodilators in regulating hemodynamics of distinct vascular beds. 1292 63

We compared the phenotype of two common mouse models, C-57BL/6J (C57), which carries only the Ren-1c gene, and 129/SvJ (Sv-129), with both Ren 1d and Ren-2. We hypothesized two renin gene Sv-129 would have increased blood pressure and the renin-angiotensin system would be more influential in regulating renal function compared with one renin gene mice. Sv-129 consistently had higher blood pressure than C-57, whether conscious (128 versus 108 mm Hg, P<0.001) or anesthetized (102 versus 88 mm Hg, P<0.001). Plasma renin concentration in both conscious and anesthetized C-57 mice was 3- to 4-fold higher than in Sv-129 (P<0.05), whereas renal cortical renin content was 2.5-fold higher (P<0.005). Renal blood flow and renal vascular resistance were the same in C-57 and Sv-129. Exogenous angiotensinogen produced identical pressor and renal vasoconstrictor responses in both strains. Blocking AT1 receptors with losartan reduced blood pressure by 19 mm Hg in both strains. Nitric oxide synthase inhibition by l-NAME increased blood pressure by 29 mm Hg in C-57 and 35 mm Hg in Sv-129 mice, but the decrease in renal blood flow was 30% less in C-57 (P<0.025). We conclude that Sv-129 mice with two renin genes have higher blood pressure but lower plasma and renal renin than C-57 mice with one renin gene. Renin substrate may limit angiotensin II production in the mouse. In Sv-129, the influence of nitric oxide on renal but not systemic resistance may be exaggerated. Renin from Ren-2 may act independently of normal renin control mechanisms.
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PMID:Cardiovascular and renal phenotype in mice with one or two renin genes. 1466 50

Atherosclerosis is the leading cause of death in the United States, and human cytomegalovirus (HCMV), a member of the herpes virus family, may play a role in the development of the disease. We previously showed that HCMV regulated endothelial apoptosis. In this study, we investigated the induction of apoptosis and signal transduction pathways regulating this process in HCMV-infected endothelial cells. As observed previously, HCMV induced a typical cytopathic effect in human aortic endothelial cells (HAECs), ie, the formation of single nucleated or multinucleated giant cells. Although infected HAECs were resistant to apoptosis at earlier stages of infection, they became apoptotic with prolonged infection as demonstrated by positive staining using terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL). This apoptotic process was mediated by the caspase-dependent mitochondrial apoptotic pathway as indicated by increased expression and cleavage of caspases 3 and 9 as well as increased expressions of pro-apoptotic molecules Bax and Bak. Blocking caspases 3 or 9 significantly inhibited the HCMV-induced apoptosis. Further exploration of the upstream pathway demonstrated upregulation of the tumor suppressor p53 gene and activation of the ataxia telangiectasia mutant (ATM) pathway in the infected cells. Blocking p53 inhibited HCMV-stimulated Bax and Bak expression as well as caspase-3 activation and blocking the ATM pathway inhibited HCMV-stimulated p53 activation. Although early infection may render cells antiapoptotic, prolonged infection, however, induced endothelial apoptosis through ATM and p53-dependent activation of the mitochondrial death pathway. This proapoptotic effect may be relevant to endothelial dysfunction and HCMV-associated vascular diseases.
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PMID:Human cytomegalovirus causes endothelial injury through the ataxia telangiectasia mutant and p53 DNA damage signaling pathways. 1510 95

The ability to inappropriately progress through S phase during drug treatment is a key determinant of tumor cell sensitivity to thymidylate synthase inhibitors such as 5-fluoro-2'-deoxyuridine (FdUrd). Previous studies suggest that SW620 cells, which are relatively resistant to FdUrd, have an intact early S-phase checkpoint that protects against FdUrd-induced DNA damage and cytotoxicity and that this checkpoint is defective in the relatively sensitive HT29 cells, which continue to progress through S phase during drug treatment. To test this hypothesis, we examined the expression and activation of known S-phase checkpoint mediators in FdUrd-treated SW620 and HT29 cells. FdUrd induced degradation of cdc25A in SW620, but not HT29 cells, in a manner that correlated with the previously described drug-induced S-phase arrest. This difference, however, could not be attributed to differences in either chk1 activation, which was similar in both cell lines, or chk2 activation, which only occurred in HT29 cells and correlated with uracil misincorporation/misrepair-induced DNA double-stranded breaks. These observations suggest that although FdUrd-induced S-phase arrest and associated cdc25A degradation are impaired in HT29 cells, signaling by ATM/ATR is intact upstream of chk1 and chk2. Finally, FdUrd induced premature mitotic entry, a phenomenon associated with deregulated cdc25A expression, in HT29 but not SW620 cells. Blocking cdc25A expression in HT29 cells with small interfering RNA attenuated FdUrd-induced premature mitotic entry, suggesting that progression of HT29 cells through S phase during drug treatment results in part from the inability of these cells to degrade cdc25A in response to FdUrd-induced DNA damage.
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PMID:5-fluoro-2'-deoxyuridine-induced cdc25A accumulation correlates with premature mitotic entry and clonogenic death in human colon cancer cells. 1537 72


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