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)

The aim of this study was to evaluate the acute effects of E-3174, a human active metabolite of the AT1 receptor antagonist, losartan, on hemodynamic functions in dogs with severe heart failure (HF). In dogs, insignificant plasma levels of E-3174 are present following administration of losartan, and therefore, the effects of these two drugs can be studied independently in the dog. HF was established by rapid pacing of the right ventricle (250-270 beats/min) for 4 weeks. We examined changes in cardiovascular functions after acute intravenous administration of losartan (1 mg/kg) and E-3174 (0.3 and 1 mg/kg), as well as an ACE inhibitor, enalapril (0.3 and 1 mg/kg), under condition of HF. The HF before treatment was characterized by increases in pre- and after-load of the left ventricle (LV), consequent low cardiac output, and LV dilatation. E-3174 at 0.3 and 1 mg/kg reduced pulmonary artery pressure (-13+/-6% and -22+/-3% from baseline, respectively, p<0.05), pulmonary capillary wedge pressure (-18+/-4% and -36+/-10%, p<0.05) and mean arterial pressure (-24+/-2% and -36+/-7%, p<0.05), increased stroke volume (SV: +12+/-7% p>0.05; +36 +/-19%, p<0.05), and reduced peripheral resistance (-23+/-5% and -41+/-9%, p<0.05), but had no effect on the first derivative of left ventricular pressure (dP/dt/P) or the time constant for relaxation. Effects of losartan at 1 mg/kg were similar to those of 0.3 mg/kg of E-3174. Enalapril at 1 mg/kg caused changes comparable to those seen after E-3174 administration (1 mg/kg), except that the increase in SV (+16+/-8%, p<0.05) with enalapril was not as great as that with E-3174. Both losartan at 1 mg/kg and E-3174 at 0.3 and 1 mg/kg increased fractional shortening to a similar extent (FS: +52+/-12%, +47+/-8% and +56+/-8%), while enalapril at 0.3 and 1 mg/kg had no significant effects on FS. Reflex elevation of plasma renin activity induced by 1 mg/kg of E-3174 was similar to that caused by 1 mg/kg of enalapril, suggesting that the two drugs achieved similar inhibition of the endogenous renin angiotensin system. Our study demonstrated that acute blockade of the AT1 receptor with E-3174 reduced elevated pre- and after-load and consequently increased stroke volume in a canine HF model. With the exception of changes in stroke volume, these effects of E-3174 were comparable to those produced by enalapril, and were 3 times stronger than those by losartan.
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PMID:Acute effects of E-3174, a human active metabolite of losartan, on the cardiovascular system in tachycardia-induced canine heart failure. 1121 32

Multiple factors are involved in thrombus formation and require complex and highly therapeutic strategies. Platelet activation plays a critical role in the genesis of acute coronary syndromes involving not only platelets but also endothelial cells, leucocytes and erythrocytes. Angiotensin II (Ang II) is a vasoconstrictor that could participate in the thrombotic process. Platelets also express Ang II AT1 type receptors on their surface. Losartan is a non-peptidic inhibitor of AT1 receptors. It has been demonstrated that losartan reduced platelet aggregation induced by the thromboxane A2 (TXA2) analogue U46619. This effect was not observed with the losartan metabolite EXP 3174. The effect of losartan was assessed in binding studies in which losartan competitively inhibited the binding of [3H]U46619 to platelets in a dose-dependent manner. Irbesartan also inhibits the TXA2 receptor in platelets, an effect that was not obtained with the active form of candesartan, CV11974, and with valsartan. These results suggest that the structural requirements necessary to antagonize the TXA2/PGH2 platelet receptor may be different from those involved in AT1 receptor antagonism. The in vivo relevance of the in vitro findings has been confirmed by the fact that in vivo administration of losartan decreases P-selectin expression in platelets obtained from stroke-prone spontaneously hypertensive rats.
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PMID:Angiotensin II AT(1) receptor antagonists and platelet activation. 1136 20

Poly(ADP-ribose) polymerase (PARP) is responsible for post-translational modification of proteins in the response to numerous endogenous and environmental genotoxic agents. PARP and poly(ADP-ribosyl)ation are proposed to be important for the regulation of many cellular processes such as DNA repair, cell death, chromatin functions and genomic stability. Activation of PARP is one of the early DNA damage responses, among other DNA sensing molecules, such as DNA-PK, ATM and p53. The generation and characterization of PARP deficient mouse models have been instrumental in defining the biological role of the molecule and its involvement in the pathogenesis of various diseases including diabetes, stroke, Parkinson disease, general inflammation as well as tumorigenesis, and have, therefore, provided information for the development of pharmaceutical strategies for the treatment of diseases.
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PMID:Functions of poly(ADP-ribose) polymerase (PARP) in DNA repair, genomic integrity and cell death. 1137 91

In order to investigate the role of Angiotensin II (AII) for the vasogenic cerebral edema, the AT1 receptor antagonist (TCV-116) was administered to 19-week-old stroke-prone spontaneously hypertensive rats (SHRSP) for 2 weeks at a dosage which did not decrease the blood pressure. Although no remarkable changes were found in blood pressure after treatment, the average brain weight of the treated group was relatively lower as compared to that of control SHRSP and no edematous changes were found in any brains. The immunohistochemical expression of intercellular adhesion molecule-1 (ICAM-1) was less and the glucose transporter-1 (GLUT-1) expression was much more intense in the endothelial cells of the micro vessels in the cerebral cortex of the treated group. Fibrinogen expression around micro-vessels was also remarkably reduced in the treated group. A decreased expression of ICAM-1 in the treated group was confirmed by RT-PCR analysis. These results indicate that the AT1 receptor blockade ameliorates hypertensive cerebral injury in a blood pressure-independent manner and suggest that AII may have an important role for endothelial injury in severe hypertension.
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PMID:AT1 receptor antagonist prevents brain edema without lowering blood pressure. 1144 94

Measurement of vascular compliance has assumed increasing importance as a marker of early disease of the vascular wall, a predictor of future vascular disease, and a way to monitor the effects of vasoactive agents on arterial wall stiffness. Vascular compliance can be estimated by several methods: measurement of the pulse pressure, or pulse pressure-stroke volume ratio; analysis of the systolic pulse wave augmentation index and the diastolic pulse wave contour; ultrasonic echo-tracking; and MRI. Because few comparative studies have been done, the physiologic significance of the measures of compliance obtained by each method is uncertain. Antihypertensive drugs may improve vascular compliance by reducing blood pressure, relaxing vascular smooth muscle, or promoting long-term effects on vascular smooth muscle and cardiomyocyte growth and remodeling. Angiotensin converting enzyme (ACE) inhibitors have been reported to improve vascular compliance in nearly all studies, suggesting a beneficial class effect independent of blood pressure reduction. Favorable changes in the vascular wall-lumen ratio of small vessels from subcutaneous gluteal biopsy specimens after treatment with ACE inhibitors and the persistence of improved vascular compliance after withdrawal of therapy indicate that these agents may produce long-term vascular remodeling. Although few studies have been done, angiotensin II receptor antagonists improve vascular compliance, possibly by blocking angiotensin II-mediated cell proliferation and increasing apoptosis via unopposed AT1 receptor stimulation. In contrast, calcium antagonists and beta-blockers have variable effects on vascular compliance, although beta-blockers with intrinsic sympathomimetic activity improve vascular compliance. Diuretics have little effect on vascular compliance beyond their blood pressure-lowering actions, except for spironolactone, which by improving vascular compliance may have contributed to the reduction in heart failure mortality seen in the Randomized Aldactone Evaluation Study.
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PMID:The effect of antihypertensive drugs on vascular compliance. 1147 12

Since pharmacological interactions of the renin-angiotensin system appear to alter the neurological outcome of stroke patients significantly, we examined the effect of elevated levels of angiotensin II and the role of its receptor subtype AT1 in brain infarction in transgenic mice after focal cerebral ischemia. Angiotensinogen-overexpressing and angiotensin receptor AT1 knockout mice underwent 1 h or 24 h permanent middle cerebral artery occlusion (MCAO). The current study revealed a much smaller penumbra size, i.e., brain tissue at risk, in angiotensinogen-overexpressing animals compared with their wild-type subgroup after 1 h MCAO, but an enlarged infarct size after 24 h. In contrast, a smaller lesion area of energy failure and a much larger penumbral area were found in AT1 knockout mice compared with wild-type littermates. Lower perfusion thresholds for ATP depletion and protein synthesis inhibition after MCAO in AT1-deficient mice and reduced cell damage in an in vitro model using embryonic neurons of AT1 knockout mice suggest injury mechanisms independent of arterial blood pressure. Our data, therefore, demonstrate a direct correlation between brain angiotensin II and the severity of ischemic injury in experimental stroke.
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PMID:Ischemic injury in experimental stroke depends on angiotensin II. 1181 64

Activation of the RAAS has been linked with an increased risk of myocardial infarction and stroke,(1,2,37,38) and recently these beneficial effects have, in part, been attributed to the effects of the RAAS on the fibrinolytic system. Indeed, ACE seems to occupy a central position in modulating the fibrinolytic balance, where an angiotensin II-mediated increase of PAI-1 plays a major role. By contrast, the effect on bradykinin stimulated t-PA release may be of lesser importance, although the data are conflicting. Importantly, the impact of the RAAS on the fibrinolytic balance may also contribute to the favourable effects of ACE inhibition and AT1-receptor antagonists on cardiovascular events, particularly when considering the activation of the RAAS in hypertension and heart failure. More work is clearly required in this area to elucidate potential therapeutic targets.
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PMID:The renin-angiotensin-aldosterone system and fibrinolysis. 1188 Oct 31

Angiotensin II type 2 (AT2) receptor is developmentally regulated and exerts antiproliferative and proapoptotic actions. Genetic ablation of this receptor in mice affects regulation of blood pressure, but the involvement of the AT2 receptor in the pathogenesis of hypertension remains unknown. In the present study, we examined developmental changes of angiotensin receptor subtypes in the kidney of stroke-prone spontaneously hypertensive rats (SHRSP), and compared them with those in normotensive Wistar-Kyoto rats (WKY). We also investigated the regulation and functional role of the AT2 receptor in cultured mesangial cells. Receptor binding and Northern blot analyses revealed that AT2 receptor expression is significantly lower in the SHRSP kidney than in the WKY kidney during the perinatal period, while AT1 receptor expression is not different between them. In WKY mesangial cells, AT2 receptor stimulation exerted a potent antiproliferative effect; this effect was not observed in SHRSP cells lacking the AT2 receptor expression. The expression of interferon regulatory factor (IRF)-1 paralleled the growth-dependent induction of AT2 receptor in WKY mesangial cells, and transfection of IRF-1 antisense oligonucleotide significantly suppressed AT2 receptor expression, indicating IRF-1-dependent regulation of AT2 receptor expression in mesangial cells. However, this induction was inefficient in SHRSP cells. Thus, we found impaired AT2 receptor expression in the SHRSP kidney in vivo and in mesangial cells in vitro. The unbalanced expression of renal angiotensin receptor subtypes with exaggerated AT1 receptor signaling during early life in SHRSP may play a role in the programming for hypertension and related renal injury.
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PMID:Expression and role of angiotensin II type 2 receptor in the kidney and mesangial cells of spontaneously hypertensive rats. 1192 18

The LIFE study ("Losartan Intervention For Endpoint reduction in hypertension study") demonstrated a significant cardiovascular protection by an angiotensin AT1 receptor antagonist, losartan, in hypertensive patients with left ventricular hypertrophy. At similar blood pressure control, losartan, as compared to atenolol, reduced the relative risk of primary cardiovascular event (death, myocardial infarction, or stroke) by 13% (p = 0.021) in the whole cohort of 9.193 patients after a mean follow-up of 4.7 years. In a subgroup of 1.195 diabetic patients, the protection was even more marked with a reduction of the combined risk of 24% (p = 0.031) and a fall of the mortality of 39% (p = 0.002). In conclusion, losartan prevents cardiovascular morbidity and death more effectively than atenolol, and seems to confer benefits beyond reduction in blood pressure.
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PMID:[Clinical study of the month. The LIFE study: cardiovascular protection of hypertensive patients by losartan]. 1207 99

Recently, we have shown that treatment of stroke-prone spontaneously hypertensive rats with angiotensin inhibitors for a limited time-window before puberty results in an attenuation of hypertensive nephrosclerosis in later life. The aim of this study was to examine the applicability of this therapeutic paradigm to a low-renin model. Dahl salt-sensitive (Dahl-S) rats were fed a high-salt diet from age 6 weeks. Some rats were treated with the angiotensin receptor blocker (ARB) candesartan cilexetil (2 mg/kg/d) from weaning to puberty (age 3-10 weeks), whereas other rats were treated continuously until overt renal damage was seen (age 3-16 weeks). Dahl-S rats on a high salt diet had increased blood pressure (207 +/- 3 vs. 125 +/- 2 mm Hg), proteinuria, and glomerular/vascular histological changes. The prepubertal treatment with ARB resulted in a continued suppression of blood pressure (153 +/- 2 mm Hg) at 16 weeks. Both proteinuria and renal histological changes were significantly (p < 0.05) attenuated, but not completely prevented by the treatment. No significant differences in plasma renin activity, renin mRNA, or AT1/AT2 mRNA were seen between groups. These results suggest that prepubertal treatment affords sustained renoprotection, even in an animal model with a suppressed renin-angiotensin system, and support the notion that appropriate prepubertal intervention may lead to a partial attenuation in the susceptibility to inherited renal diseases.
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PMID:Prepubertal treatment with angiotensin receptor blocker causes partial attenuation of hypertension and renal damage in adult Dahl salt-sensitive rats. 1213 77


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