Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.15.1 (ACE)
18,300 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Angiotensin II (ANG II) receptors were present in the thymus of newborn rats (179 +/- 34 fmol/mg protein). In newborns, binding was predominantly localized in the trabecula, and was selectively displaced by the AT2 ligand CGP 42112A (83-85%) and to a lower extent by the AT1 antagonist losartan (15-17%), indicating a marked predominance of AT2 receptors. Angiotensin II binding was very low in the cortical and medullary areas in the thymus of newborn rats and was no longer detected in the thymus of 4- and 8-week-old rats. No detectable binding for the ACE inhibitor [125I]351A was observed in the thymus of the rat, regardless of the age studied. Our results indicate a possible role for circulating ANG II during development of the thymus with no clear correlation to lymphocyte maturation.
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PMID:Autoradiographic localization and characterization of angiotensin II receptor subtypes in the rat thymus. 798

Angiotensin II (ANG II) receptor subtypes (AT1, displaced by losartan, and AT2, displaced by CGP 42112A) were characterized by quantitative autoradiography after incubation with the ANG II agonist [125I]Sar1-ANG II, in specific brain nuclei of 19-day-old rat embryos. Binding to AT1 receptors, located in the subfornical organ, paraventricular nucleus, nucleus of the solitary tract and choroid plexus, was sensitive to incubation with GTP gamma S. The sensitivity of AT2 receptors to GTP gamma S was heterogeneous. In the ventral thalamic, rostral hypoglossal and medial geniculate nuclei, and in the locus coeruleus, binding to AT2 receptors was sensitive to GTP gamma S and these areas belong to the AT2A subgroup. Conversely, in the inferior olive, medial (fastigial) cerebellar nucleus and caudal part of the hypoglossal nucleus, areas belonging to the AT2B subgroup, binding was insensitive to GTP gamma S. AT2 receptors were also present in cerebral arteries. In the fetal anterior pituitary, AT1 receptors predominated. The angiotensin-converting enzyme (ACE; EC 3.4.15.1) was studied by autoradiography with the selective inhibitor [125I]351A. In 19-day-old embryos, ACE was highly expressed in choroid plexus, with high concentrations in subfornical organ, posterior pituitary and cerebral arteries. No ACE binding was detected in extrapyramidal structures or anterior pituitary in 19-day-old embryos.
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PMID:Angiotensin II receptor subtypes and angiotensin-converting enzyme in the fetal rat brain. 813 Oct 49

In experiments designed to analyze cardiovascular structure in response to antihypertensive therapy with an ACE inhibitor, we decided to start very early in life with the aim to prevent blood pressure increases and the development of vascular structural changes. In these treated groups of rats we unexpectedly observed that after they were weaned, their water consumption and urine volume, respectively, increased substantially. The present study was designed to determine if inhibition of the renin-angiotensin system produced similar effects in different strains of rats, and focused on characterizing the abnormal fluid balance occurring as a consequence to neonatal treatment with ACE inhibitors or angiotensin II blockers. Three-day-old Wistar Kyoto (WKY), Wistar (WR) and spontaneously hypertensive rats (SHR) were given either saline, enalapril, captopril, losartan and the AT2 blocker, PD123319, in the same amount of volume for 20 days. Treatment was stopped and rats were examined with regard to renal morphology at 4, 14 and 30 weeks of age. In addition, water consumption, urine volume, urine electrolytes and osmolality were analyzed at 14 weeks of age, that is, 10 weeks off treatment. Early treatment with the ACE inhibitors, enalapril and captopril, and the AT1 blocker, losartan, but not the AT2 blocker, PD 123319, in the SHR and in the normotensive strains WKY and WR produced persistent, irreversible histopathological renal abnormalities in adult life, long after the rats had been taken off treatment. These abnormalities consisted of mainly cortical tubulointerstitial inflammation, various degrees of papillary atrophy and pelvic dilation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Renin-angiotensin system in neonatal rats: induction of a renal abnormality in response to ACE inhibition or angiotensin II antagonism. 816 37

A-II exerts its activity on various target tissues by binding to its receptors. The discovery of local RASs and A-II receptors within various tissues has generated interest in the clinical usefulness of RAS inhibition by directly blocking the action of A-II at the receptor level. Different A-II receptor subtypes have been identified and subsequently termed AT1 and AT2. AT1-receptor subtypes are the predominant receptor subtypes existing in most organs and, by coupling to a transmembrane G protein, seem to be the main subtypes participating in the vasoactive responses of A-II. Saralasin, a peptide with specific A-II receptor-antagonistic activity, had limited practical long-term usefulness as a result of its short half-life, significant agonistic properties, and lack of oral bioavailability. The discovery of simple benzyl-substituted imidazoles, which possess weak but highly selective A-II receptor antagonistic properties, led to the development of losartan (DuP 753). Losartan is a potent, orally active, specific, competitive nonpeptide A-II receptor antagonist that appears to be an effective antihypertensive agent both in animal studies and in preliminary clinical trials. The therapeutic usefulness of losartan, however, is not limited to its antihypertensive effects. The potential benefits of A-II receptor antagonists include roles in postmyocardial infarction therapy, slowing A-II-induced cardiac hypertrophy, 154, 155 slowing the progression of heart failure, preventing postangioplasty restenosis, and in slowing the progression of renal disease. Furthermore, losartan, a selective A-II type 1 (AT1) receptor antagonist, has also been a valuable pharmacologic probe for studying the mechanism of A-II stimulation of its receptors. A-II receptor antagonism appears to be as effective as ACE inhibition in the treatment of hypertension and other pathologic processes that involve the RAS and may offer an alternative to those patients who cannot tolerate ACE inhibitors because of their side effects.
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PMID:Angiotensin II receptor antagonists: a new approach to blockade of the renin-angiotensin system. 817 70

Angiotensin receptors are present in many tissue types, including adrenal cortex, renal glomeruli, heart, hypothalamus, liver, pancreas, pituitary, platelets, renal tubules, uterus and vascular smooth muscle. Two high-affinity receptor subtypes have been identified by radioligand binding with antagonists: losartan (DuP 753/MK954) identifies AT1 receptors; PD123177 and CGP42112A are markers for AT2 receptors. Angiotensin II may be produced locally in tissues outside the humoral system. For example, it is found in the brain, kidney and heart. Within the brain, the heptapeptide angiotensin(1-7) mimics some effects of angiotensin II, but may be formed directly from angiotensin I. Evidence for non-ACE-mediated angiotensin II production has been reported in the heart. Intravascular angiotensin II receptors are implicated in the central release of vasopressin and other hypophyseal hormones, in increasing sympathetic outflow, in the thirst response and, possibly, in cognitive function; in the inotropic and chronotropic effects of angiotensin II on the heart as well as in growth/hypertrophy; in the control of aldosterone release and in the balance between cortisol and aldosterone secretion; and in modulating sodium, chloride and bicarbonate transport within the kidney. Effects on the reproductive system, liver and pancreas have not been established. The pharmacological effects of angiotensin II antagonists will depend on their distribution characteristics as well as affinity for specific receptor subtypes. At present, however, the physiological role of AT2 receptors has not been defined.
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PMID:Role of angiotensin in the extravascular system. 823 88

Results of a previous study showed that angiotensin II (AII) inhibited the induction of long-term potentiation (LTP) in hippocampal granule cells in response to dorsomedial perforant path stimulation in urethane-anesthetized rats. The results of present experiments demonstrate a dose-dependent inhibition of LTP induction under the same conditions due to ethanol (EtOH) administered by stomach tube and diazepam (DZ) injected IP. The inhibition of LTP induction by EtOH and DZ can be blocked by saralasin (SAR) applied directly to the dorsal hippocampus and by lorsartan (DuP 753) administered IP. Lorsartan or a metabolite crosses the blood-brain barrier because it also blocks the inhibition of LTP induction due to AII administration directly into the dorsal hippocampus. Lorsartan is a competitive antagonist of the AT1 subtype AII receptor. Therefore, the AII and the EtOH and DZ inhibition of LTP induction are mediated by the AII subtype receptor AT1. AIII and the AT2 antagonist PD123319 did not produce any significant effects. These in vivo effects can be reproduced in brain slices and therefore cannot be attributed to other factors, such as the urethane. In addition, electrical stimulation of the lateral hypothalamus (LH) inhibits LTP induction, and the inhibition can be blocked by SAR. These data on LH stimulation indicate that LH AII-containing neurons send axons into the hippocampus that inhibit the induction of LTP. These results not only provide new information on a neurotransmitter involved in the amnesic effects of benzodiazepines and ethanol-induced memory blackouts, but also testable hypotheses concerning recent observations that angiotensin converting enzyme (ACE) inhibitors elevate mood and improve certain cognitive processes in the elderly.
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PMID:Role of angiotensin II and AT1 receptors in hippocampal LTP. 832 52

Angiotensin II receptors of the AT1 subtype were very highly expressed in medroxyprogesterone-induced ductal adenocarcinomas of the mammary gland in BALB/c mice. AT1 receptors are associated only to neoplastic epithelial cells. Lobular adenocarcinomas expressed very few AT1 receptors and expressed AT2 receptors only in areas corresponding to peritumoral connective tissue. Binding to angiotensin converting enzyme was present in all adenocarcinomas studied and was higher in ductal than in lobular adenocarcinomas. Normal mammary gland did not express either angiotensin II receptors or angiotensin converting enzyme. The present results are the first demonstration of angiotensin receptor subtypes and converting enzyme in mammary adenocarcinomas differentially expressed in tumors of ductal and lobular origin. Localization of receptor subtypes could be useful to study the differentiation of mammary cells during experimental mammary carcinogenesis in mice.
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PMID:Enhanced expression of angiotensin II receptor subtypes and angiotensin converting enzyme in medroxyprogesterone-induced mouse mammary adenocarcinomas. 838 52

In this article, we have discussed the localization of components of the renal renin-angiotensin system, as well as the existing information on the regulation of this axis and the effects of Ang II on renal function. All the components of the renin-angiotensin system are present in both fetal and adult kidney. In the adult kidney, renin is principally localized to jg cells of the distal afferent arteriole, where release is stimulated by increases in intracellular cAMP and inhibited by increases in cytosolic calcium. Four distinct stimuli mediating renin release are (1) NaCl sensed at the macula densa, (2) the sympathetic nervous system, (3) humoral factors, with Ang II, vasopressin, endothelin, and adenosine inhibiting renin release, and (4) changes in intrarenal blood pressure. Alterations in renal renin gene expression have been reported in pathophysiological states, such as salt depletion, diabetes mellitus, ureteral obstruction, Bartter's syndrome, and with high protein feeding. The highest renal concentrations of mRNA for the renin substrate angiotensinogen are found in the PT, where the protein is localized to subapical granules. Both salt depletion and androgens upregulate renal angiotensinogen mRNA. Of interest, renal angiotensinogen mRNA levels are lower in SHR than in normotensive WKY rats. As with angiotensinogen, renal ACE is mainly localized to the PT, with highest concentration on the brush border. The mechanisms of regulation of both renal angiotensinogen and ACE require further study. Using recently developed specific nonpeptide Ang II receptor antagonists, it appears that adult renal Ang II receptors are principally of the AT1 class, whereas fetal kidney Ang II receptors are of the AT2 subtype. By binding to AT1 receptors, Ang II exerts constrictive effects on both afferent and efferent arterioles, with increased effect reported on efferent arterioles. Glomerular Ang II receptors are localized to mesangial cells, mediating contractile responses resulting in changes in glomerular surface area and Kf, and potentially regulating mesangial sieving and phagocytosis. These receptors are reduced with salt restriction or in experimental diabetes. The highest concentrations of tubular Ang II receptors are found in PT, on both brush border and basolateral membranes.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The intrarenal renin-angiotensin system. 843 83

The 'discovery' of losartan represents three separate discoveries: (1) losartan as the unique biphenyltetrazole molecule and the first of a new chemical class; (2) losartan as a tool to identify AT1-subtype receptors; and (3) losartan as a specific probe for exploring the multiple roles of angiotensin II (Ang II) in normal physiology and pathologic states. Losartan is the first nonpeptide orally active Ang II receptor antagonist to reach clinical trials. Losartan was selected for its affinity for Ang II receptors, functional antagonism of Ang II, lack of agonist properties, and oral anti-hypertensive effects. Losartan has been widely used to define the distribution and function of AT receptor subtypes. Although possible roles of the AT2 subtype have been reported, virtually all of the known effects of Ang II are blocked by losartan. Specific AT1 receptor blockade has been broadly compared with ACE inhibition. Possible differences on the basis of AT1 selectivity, bradykinin potentiating effects and Ang II formed by non-ACE pathways are discussed. Losartan blocks the vascular constrictor effect of Ang II, the Ang II-induced aldosterone synthesis and/or release, and the Ang II-induced cardiovascular 'growth' in vitro and in vivo. In various models of experimental hypertension, losartan prevents or reverses the elevated blood pressure and the associated cardiovascular hypertrophy similar to ACE inhibitors. Likewise, in models of renal failure (for example reduced renal mass, puromycin, ochratoxin), losartan, like ACE inhibition, markedly reduced the elevation in blood pressure, proteinuria or sclerosis. In aortocaval shunt, coronary ligation and ventricular pacing models of heart failure, losartan demonstrated a pathological role for Ang II by reversing the associated haemodynamic findings. In SHR-stroke prone, losartan dramatically increased survival while having a limited effect on blood pressure, suggesting a non-pressure dependent effect of Ang II. These collective data show that Ang II exerts complex pathological effects in experimental models of vascular, cardiac, renal and cerebral disease. The effectiveness of losartan in experimental models of heart failure supports its evaluation in clinical trials with patients with heart failure.
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PMID:Discovery of losartan, the first angiotensin II receptor antagonist. 858 79

Angiotensin had a dual action on the epididymal half of rat vas deferens. It potentiated electrical stimulated contraction and exerted a direct contractile effect on the muscle. The potentiation of electrically stimulated response may be mediated by presynaptic facilitation of neurotransmitter release. Muscular contractile response to angiotensin is concentration dependent. Angiotensin II was found to be much more potent than angiotensin III, and the order of potencies was angiotensin II > angiotensin I > angiotensin III. The presence of a mixture of protease inhibitors (10 microM chymostatin, 50 microM bacitracin, 10 microM leupeptin and 10 microM pepstatin) did not alter the contractile activity of angiotensin II. In contrast, angiotensin I (10 nM)-induced contraction was significantly reduced in the presence of ACE inhibitor SQ 20881 (500 nM). The angiotensin II induced contraction was not reduced by CGP 42112, a specific AT2 receptor antagonist, but was significantly inhibited by losartan, a specific AT1 receptor antagonist. Losartan shifted the dose-response curve of angiotensin II to the right with a pA2 value of 8.68. In addition, p-aminophenylalanine6 angiotensin II, which is proposed as an AT2 receptor agonist, did not induce contraction. It is concluded that the AT1 receptor predominantly mediates angiotensin-induced contraction in epididymal rat vas deferens.
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PMID:Characterization of contractile response to angiotensin in epididymal rat vas deferens. 858 70


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