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)

The effects of cholinomimetic and non-cholinomimetic agents on spatial memory using a novel task in the 12-arm radial maze were investigated. The task was designed to reduce the tendency to use non-spatial strategies. Animals were repeatedly trained to retrieve food rewards from three arms, until a criterion level of performance was reached. Scopolamine (0.03 and 0.1 mg/kg SC), but not N-methylscopolamine (0.1 mg/kg SC) disrupted performance of this task. Physostigmine (0.3 mg/kg SC) and pilocarpine (30 mg/kg SC) completely reversed the deficit of performance produced by scopolamine. Furthermore, the ACE inhibitor Hoe 288 (10 nmol ICV) and the angiotensin AT1 receptor antagonist losartan (10 mg/kg SC) also significantly attenuated the scopolamine-induced deficit. These results show that this novel task in the radial maze is sensitive to the disruptive effects of scopolamine and can identify cognitive enhancing effects of both cholinomimetic and non-cholinomimetic drugs. Thus, this maze task provides a useful model for the evaluation of novel cognitive enhancing agents.
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PMID:Attenuation of scopolamine-induced spatial memory deficits in the rat by cholinomimetic and non-cholinomimetic drugs using a novel task in the 12-arm radial maze. 787 Sep 85

Suppression of endogenous levels of angiotensin II by angiotensin converting enzyme inhibition, may result in up-regulation of vascular AT1 receptors. We have evaluated the effects of orally administered enalapril on angiotensin II induced vasoconstriction in the human forearm. Subjects received in random order, enalapril (20 mg) or matched placebo daily for 2 weeks. Forearm blood flow response to increasing doses of angiotensin II was measured using venous occlusion plethysmography at the beginning of the study and at the end of each 2 week treatment period. Treatment with enalapril significantly reduced plasma angiotensin II levels and supine blood pressure compared with placebo. The percentage reductions in forearm blood flow in the infused arm, in response to the maximum dose of angiotensin II (50,000 fmol min-1) were 48.1 +/- 3.6% at baseline, 57.5 +/- 3.6% on placebo and 54.5 +/- 4.2% on enalapril. The differences were not significantly different. This demonstrates that suppression of plasma angiotensin II for a 14 day period does not enhance the response to exogenous intra-arterial angiotensin II in the human forearm of healthy salt replete subjects.
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PMID:Angiotensin converting enzyme inhibition does not affect the response to exogenous angiotensin II in the human forearm. 789 82

Immortalized rat proximal tubule cell (IRPTC) lines should be useful for investigation of proximal tubule (PT) regulation and function but previously have been unavailable. We now report the establishment and characterization of an immortalized transformed, temperature-sensitive IRPTC cell line containing renin-angiotensin system (RAS) components. Primary PT cells prepared from male Wistar rats (4-5 wk old) after collagenase digestion, sieving, and Percoll gradient were cultured on collagen-coated T-75 flasks in Dulbecco's modified Eagle's medium containing 5% fetal calf serum. Subconfluent PT cells were transfected with the temperature-sensitive SV40 mutant viruses (tsA SV40) by direct exposure. After 7-8 wk, several clones were obtained, from which one has been characterized and designated as line 3-2. This cell line appears stable up to 45 passages. Clonal cells transformed with this virus exhibit a transformed phenotype at a permissive temperature of 34 degrees C and grow in multiple layers. When the cells are subsequently placed at a nonpermissive temperature of 41 degrees C, they return to morphology similar to that of untransformed cells of the same lineage. At either 34 degrees C or 41 degrees C, this cell line expresses a variety of PT markers including alkaline phosphatase, cytokeratin, carbonic anhydrase, and glucose transporter isoform 2 (GLUT2), while not expressing factor VIII. Uniquely, these cells also appear to express PT proteins gp330 and CHIP28, markers which are usually lost in cultured cells. Furthermore, the cell line expresses protein and mRNA components of RAS, including angiotensinogen, angiotensin converting enzyme, and renin. The IRPTC cell line expresses few angiotensin II (ANG II) receptors at 34 degrees C, the permissive temperature. However, at the nonpermissive temperature, 41 degrees C, IRPTC expresses ANG II receptor (dissociation constant of 0.7 nM; maximum binding capacity of 265 fmol/mg protein). ANG II (10(-8) M) induced a transient rise in cytoplasmic Ca2+ concentration, which was nearly abolished with losartan but not PD-123319, suggesting this finding is AT1 receptor mediated. This cell line should provide an excellent model of PT and should make it possible to study the cell and molecular biology of the RAS, as well as other regulatory systems of the PT.
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PMID:Temperature-sensitive SV40 immortalized rat proximal tubule cell line has functional renin-angiotensin system. 790 Aug 43

We have shown that acute (24-hr) unilateral ureteral obstruction (UUO) induces the genes encoding for renin, in juxtaglomerular apparatuses and in tubules, for angiotensin converting enzyme in vascular endothelial cells, and for angiotensinogen in perivascular fat. These molecular changes occur in temporal association to marked reductions in renal blood flow (RBF) and glomerular filtration rate (GFR), suggesting that angiotensin II (Ang II) is at least partly responsible for the renal vasoconstriction. We tested the hypothesis that down-regulation of the Ang II type-1 receptor (AT1-R) gene occurs in UUO in response to Ang II, by examining the effects of an ACE inhibitor [lisinopril (Li), 5 mg/kg/day] and of the specific nonpeptidic AT1-R blocker, losartan (Lo) (10 mg/kg/day). UUO or sham operated (which included manipulation but not obstruction of the ureter) rats (S) were studied. Northern blot analysis of the steady state concentration of AT1-R mRNA corrected for GAPDH mRNA showed a marked decrease in receptor expression (-77%, N = 4, P < 0.01) in the obstructed kidney (UUO) compared to S; sham diminished gene expression modestly compared to the contralateral kidneys (C) of UUO. In situ hybridization for AT1-R mRNA also showed diminished expression in UUO compared to C kidneys (N = 4). Treatment of UUO rats (N = 4) with Lo increased AT1-R mRNA five times above the levels in UUO rats receiving vehicle; the increase induced by Li was 50% that of Lo; S (N = 4) and C (N = 4) did not change. Losartan, but not vehicle treatment increased RBF (sixfold) and GFR (fivefold) in the UUO kidneys.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Regulation of the renal angiotensin II receptor gene in acute unilateral ureteral obstruction. 793 8

Endothelin-1 (ET-1) and angiotensin II (AII) are potent vasoconstrictor hormones which regulate tissue perfusion and blood pressure. We pharmacologically characterized endothelin and angiotensin receptors mediating contractions of human mammary resistance arteries in myographs for isometric tension recording. ET-1 caused potent contractions. The concentration response curve was shifted to the right by ETA antagonist FR 139317, but a high sensitivity, low efficacy component remained. After incubation with ETB agonist sarafotoxin (S6c) this component of the concentration response curve resistant to FR 139317 disappeared. The ETA/ETB-receptor antagonist bosentan shifted the entire concentration response curve to the right. AI and AII caused marked contractions. The effects of AI were reduced by the ACE inhibitor benazeprilat, while those of AII were prevented by valsartan, an AT1 antagonist. In summary, in human resistance arteries, contractions to ET-1 are mediated by ETA- and ETB-receptors while those to AII are exclusively mediated by AT1-receptors.
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PMID:Characterization of contractile endothelin and angiotensin receptors in human resistance arteries: evidence for two endothelin and one angiotensin receptor. 798 May 30

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

1. Angiotensin II (AII) reduces blood flow, modulates vascular remodelling and is a growth factor. Human inflammatory arthritides are characterized by synovial hypoperfusion, hypoxia and proliferation. We aimed to localize and characterize receptors for AII in human synovium. 2. We used quantitative in vitro receptor autoradiography with [125I]-(Sar1, Ile8)AII and [125I]-AII on human synovium from patients with chondromalacia patellae, osteoarthritis and rheumatoid arthritis. 3. [125I]-(Sar1, Ile8)AII and [125I]-AII bound to similar sites on synovial blood vessels, lining cells and stroma. Binding to microvessels (< 100 microns diameter) was more dense than to arteriolar media, and vascular binding was more dense than that to lining cells and stroma. 4. Microvessels and arterioles which displayed angiotensin converting enzyme-like immunoreactivity also displayed specific binding of [125I]-(Sar1, Ile8)AII. 5. Specific binding of [125I]-(Sar1, Ile8)AII to each structure was completely inhibited by 10 microM dithiothreitol and was inhibited by unlabelled ligands with the rank order of potency (Sar1, Ile8)AII > AII > losartan = SKF108566 > PD123319 indicating an AT1 subclass of angiotensin receptor. 6. GTP gamma S (1 microM) abolished specific binding of [125I]-AII and abolished the high affinity component of the binding inhibition curve for AII against [125I]-(Sar1, Ile8)AII, indicating G protein coupling. 7. The distribution of [125I]-(Sar1, Ile8)AII binding sites was similar in all disease groups and no significant differences in binding densities, affinities or specificities were observed between disease groups. 8. Locally generated AII may act on synovial AT1 receptors to modulate synovial perfusion and growth. Specific AT1 receptor antagonists should help elucidate the role of angiotensins in human arthritis.
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PMID:AT1 receptor characteristics of angiotensin analogue binding in human synovium. 807 62

The pharmacological properties of FK 739, a new angiotensin II-receptor antagonist, were examined. FK 739 inhibited the specific binding of [125I]-angiotensin II to rat aortic smooth muscle cell membrane with an IC50 value of 8.6 nM, but did not displace the specific binding of [125I]-angiotensin II to bovine cerebellum membrane. In isolated helical strips of rabbit aorta, FK 739 shifted the concentration-response curve of angiotensin II-induced contraction in parallel to the right, and the values of the slope and pA2 were 1.06 and 8.45, respectively. In in vivo studies, oral administration of FK 739 at 10 mg/kg significantly inhibited the angiotensin I-induced pressor response in normotensive rats and dogs, and it caused a fall of mean blood pressure in renal hypertensive rats and dogs. In spontaneously hypertensive rats, FK 739 at 32 and 100 mg/kg significantly decreased the mean blood pressure in a dose-dependent manner. Additionally, we studied whether FK 739 would cause side effects such as dry cough, like other ACE inhibitors did. Oral administration of FK 739 (10 and 32 mg/kg) did not affect the capsaicin-induced bronchial edema. On the other hand, captopril (10 mg/kg) significantly enhanced capsaicin-induced bronchial edema. These results indicate that FK 739 is a potent and competitive antagonist for AT1-type receptors, and suggest that FK 739 might be a safe and useful agent for the treatment of hypertension in clinical trials.
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PMID:The pharmacological characterization of FK 739, a new angiotensin II-receptor antagonist. 810 26

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


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