Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.7.48 (transcriptase)
 9,479 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Our aim was to characterize and determine the function of endothelin (ET) receptor subtypes in human vascular tissue. Reverse transcriptase-polymerase chain reaction with nested oligonucleotide primers detected the presence of mRNA encoding both ETA and ETB receptors in the media from aorta and pulmonary and coronary arteries. In situ hybridization confirmed the presence of mRNA for both subtypes in the media of coronary arteries. Saturation binding assays using 125I-ET-1 found a single population of high-affinity ET receptors (n = three patients, +/- SEM) in aorta (Kd = 0.507 +/- 0.020 nM; Bmax = 9 +/- 4 fmol/mg protein) and pulmonary (Kd = 0.845 +/- 0.245 nM; Bmax = 15 +/- 10 fmol/mg protein) and coronary arteries (Kd = 0.141 +/- 0.020 nM; Bmax = 71 +/- 21 fmol/mg protein). Using media from coronary arteries, the ETA-selective ligand BQ123 (cyclo[D-Asp-L-Pro-D-Val-L-Leu-D-Trp]) and the ETB-selective ligand BQ3020 (Ala11,15-Ac-ET-1[6-21]) both produced biphasic competition binding curves against 125I-ET-1, confirming the presence of high- and low-affinity sites corresponding to the two subtypes: BQ123 (KdETA = 0.85 +/- 0.03 nM; KdETB = 7.58 +/- 2.27 microM; ETA/ETB, 87%:13%) and BQ3020 (KdETA = 0.22 +/- 0.04 microM; KdETB = 0.77 +/- 0.34 nM; ETA/ETB, 62%:38%). BQ123 (0.1 microM) caused a significant parallel rightward shift of ET-1-induced vasoconstriction of coronary arteries in vitro, but BQ3020 and Ala1,3,11,15-ET-1 failed to show any agonist activity when tested at concentrations of < or = 3 microM in three vessels.(ABSTRACT TRUNCATED AT 250 WORDS)
J Cardiovasc Pharmacol 1993
PMID:Human endothelin receptors characterized using reverse transcriptase-polymerase chain reaction, in situ hybridization, and subtype-selective ligands BQ123 and BQ3020: evidence for expression of ETB receptors in human vascular smooth muscle. 750 50

The expression and immunoreactivity of endothelin-converting enzyme (ECE) were examined in the renal tissue of rats with experimental congestive heart failure (CHF). Reverse transcriptase polymerase chain reaction (RT-PCR) revealed that ECE mRNA was more abundant (about twofold) in the renal medulla than in the cortex. Induction of heart failure caused a significant enhancement in the expression of this key enzyme in the renal cortex of rats with compensated CHF (delta + 28%) and in animals with decompensated heart failure (delta + 58%). An identical trend was also observed in the renal medulla, although these increases were moderate compared to those in the cortex. Similar findings were observed with Western blot techniques applying two monoclonal antibodies to rat ECE (AEC32-236 and AEC27-121). Taken together, these data suggest that upregulation of ECE is an important component in the activated renal ET system in CHF.
J Cardiovasc Pharmacol 1998
PMID:Renal endothelin-converting enzyme in rats with congestive heart failure. 959 92

Sarafotoxin S6c [STXS6c; a selective endothelin-B (ETB) receptor agonist] causes constriction of isolated pulmonary arteries. In perforated-patch experiments on pulmonary arterial myocytes, ET-1 and STXS6c induced a gradual inhibition of the delayed rectifier K current (IKV), the profile of which resembled that carried by Kv1.5. Reverse-transcriptase polymerase chain reaction (RT-PCR) experiments revealed mRNA encoding this channel, and immunolocalization experiments demonstrated expression of the channel protein in pulmonary arterial smooth muscle. It is tempting to speculate that ETB receptor coupling to Kv1.5 may be implicated in contraction after stimulation of these receptors.
J Cardiovasc Pharmacol 1998
PMID:Endothelin-1, delayed rectifier K channels, and pulmonary arterial smooth muscle. 959 7

Chagas' disease, caused by the parasite Trypanosoma cruzi, is an important cause of heart disease. Previous studies from this laboratory revealed that microvascular spasm and myocardial ischemia were observed in infected mice. Infection of endothelial cells with this parasite increased the synthesis of biologically active endothelin-1 (ET-1). Therefore. in the myocardium of T. cruzi-infected mice, we examined ET-1 expression and the p42/44-mitogen activated protein kinase (MAPK)-AP-1 pathway that regulates the expression of ET-1. There was parasitism and myonecrosis in the myocardium of infected C57BL/6 mice. Reverse transcriptase polymerase chain reaction (RT-PCR) analysis revealed elevated mRNA expression of transcription factor AP-1 (c-jun and c-fos) and increased AP-1 DNA binding activity as determined by electrophoretic mobility shift assay (EMSA). Western blot analysis demonstrated an increase in the phosphorylated forms of extracellular signal-regulated kinase (ERK1/2). ET-1 mRNA was upregulated in the myocardium of infected mice. Immunohistochemical and immunoelectron microscopy using anti-ET-1 antibody detected increased expression in cardiac myocytes and endothelium of these mice. These data suggest that ET-1 contributes to chagasic cardiomyopathy and that the mechanism of the increased expression of ET-1 is a result of the activation of the MAPK pathway by T. cruzi infection.
J Cardiovasc Pharmacol 2000 Nov
PMID:Trypanosoma cruzi infection (Chagas' disease) of mice causes activation of the mitogen-activated protein kinase cascade and expression of endothelin-1 in the myocardium. 1107 62

Endothelin (ET) receptor antagonists are nephroprotective in renal damage models of the rat. It is unknown whether ET receptor antagonists are also beneficial in human renal diseases. Major differences exist between the ET systems in rats and humans, therefore this study was designed to characterize the ET receptors expressed on human adult mesangial cells (HMCs). HMCs cultures are a surrogate model for the development of glomerulosclerosis. Binding experiments with [125I]ET-1 in the presence or the absence of the test compounds [endothelin-1, -3 (ET-1, ET-3), sarafotoxin 6c (S6c), or BQ123] revealed an affinity (IC50 values) of 10.5 nm for ET-1 and 87.6 nm for ET-3. The affinities of the ET(B) agonist S6c and the ET(A) antagonist BQ123 were 85.9 nm and > 10 microm, respectively. Thus, the ET receptor on HMCs shows an ET(B)-like pharmacology, but in contrast to the classical ET(B)-receptor the affinities are low. No affinity for BQ123 up to > 10 microm excludes the presence of ET(A)-receptors. Functional studies using microfluorimetry (fura-2 method) showed comparable biphasic calcium signals induced by 10 nm ET-1, ET-3 and S6c. This effect could not be inhibited by BQ123, but by the ET(B) antagonist BQ788. Reverse transcriptase polymerase chain reaction (RT-PCR) studies under different culture conditions showed that both ET(A)- and ET(B)-receptor mRNAs are expressed in HMCs. The amount of ET(A)-receptor mRNA increased 2.7-fold and that of the ET(B)-receptor mRNA 7.1-fold after stimulation with 10% fetal calf serum (FCS). ET-1, ET-3 and S6c stimulated HMCs growth (ET-1 > S6c > ET-3), but the magnitude of the effect of ET-1 is lower than reported in rat mesangial cells (rat MCs). The effect on HMCs growth could be inhibited by BQ788, but not by BQ123. Our data provide evidence for the expression of ET(B)-receptors on HMCs that are functionally active. This finding differs from the ET receptor expression in rat MCs as reported by others.
J Cardiovasc Pharmacol 2000 Nov
PMID:Adult human mesangial cells (HMCs) express endothelin-B-receptors which mediate endothelin-1-induced cell growth. 1107 85

The effects of parathyroid hormone (PTH) on tension and intracellular Ca level ([Ca ] ) were examined in ring preparations of rat mesenteric artery using isometric tension recording and the fura-2 method, respectively. The PTH (30 n ) elicited relaxation in arterial rings precontracted by phenylephrine regardless of the presence or absence of endothelium. In the endothelium-denuded arterial rings precontracted by 3 micro M of phenylephrine or 60 m of potassium chloride (KCl), PTH-related protein and PTH produced concentration-dependent relaxation to the same extent, but inhibited contraction induced by phenylephrine more effectively than that induced by KCl. Phenylephrine-induced tonic contraction was changed to a phasic one with decreased peak tension in the presence of PTH. Similar changes were observed with extracellular Ca removal or methoxyverapamil plus SK&F96365, respective of voltage-gated and receptor-operated Ca channel inhibitors. Phenylephrine evoked a concentration-dependent contraction concomitant with an increase in [Ca ]. PTH reduced both responses to the same extent. In a Ca -free solution, PTH inhibited a phasic contraction and a transient increase in [Ca ] in response to phenylephrine but not caffeine. Reverse transcriptase-polymerase chain reaction showed that PTH and PTH receptors were expressed in the rat mesenteric artery. In this tissue, PTH increased cyclic adenosine monophosphate (cAMP) levels. These results suggest that the inhibitory effect of PTH on alpha -adrenoceptor-mediated contraction results from the inhibition of Ca influx through receptor-operated and voltage-gated Ca channels, and Ca release from Ca stores, probably via increased cAMP in the rat mesenteric artery.
J Cardiovasc Pharmacol 2002 Oct
PMID:Relaxant mechanisms of parathyroid hormone in rat mesenteric artery. 1235 17

Nucleoside reverse-transcriptase inhibitors (NRTIs) in combination with other antiretrovirals (HAART) are the cornerstones of current AIDS therapy, but extensive use brought mitochondrial side effects to light. Clinical experience, pharmacological, cell, and molecular biological evidence links altered mitochondrial (mt-) DNA replication to the toxicity of NRTIs in many tissues, and conversely, mtDNA replication defects and mtDNA depletion in target tissues are observed. Organ-specific pathological changes or diverse systemic effects result from and are frequently attributed to HAART in which NRTIs are included. The shared features of mtDNA depletion and energy depletion became key observations and related the clinical and in vivo experimental findings to inhibition of mtDNA replication by NRTI triphosphates in vitro. Subsequent to those findings, other observations suggested that mitochondrial energy deprivation is concomitant with or the result of mitochondrial oxidative stress in AIDS (from HIV, for example) or from NRTI therapy itself.
Prog Cardiovasc Dis
PMID:Mitochondrial DNA replication, nucleoside reverse-transcriptase inhibitors, and AIDS cardiomyopathy. 1263 94

The aims of this study were to determine the cysteinyl leukotriene (CysLT) receptors expressed in the human saphenous vein, to examine contractile response to LTC4 and LTD4, to evaluate antagonist activity of montelukast, a specific CysLT1 receptor antagonist used in asthma, and to characterize the CysLT receptors involved in the contractile response. The analysis by reverse-transcriptase polymerase chain reaction indicated that CysLT1 and CysLT2 receptors are expressed by saphenous veins. In varicose vein rings, the potencies (pD2) of LTC4 and LTD4 were similar: 7.4 +/- 0.2 and 7.4 +/- 0.1, respectively. Pretreatment with acivicin, a gamma-glutamyl transpeptidase (gamma-GT) inhibitor, to prevent potential metabolism of LTC4 to LTD4, did not alter the response to LTC4. In nondistended vein rings from patients undergoing arterial bypass, the LTC4 pD2 was 7.8 +/- 0.1, and pretreatment with S-hexyl-GSH, a potent gamma-GT inhibitor, caused a fourfold rightward shift of the LTC4 concentration-response curve. In varicose and nondistended saphenous vein rings, montelukast (10(-8) and 10(-7) M) exerted a potent activity against LTD4 and LTC4, in the presence or absence of gamma-GT inhibitors. In varicose vein rings, the two active metabolites of montelukast also exerted antagonist activities with potencies similar to montelukast. BAY u9773 (CysLT2 agonist/dual CysLT1/CysLT2 antagonist) did not cause contraction and inhibited the LTC4- and LTD4-induced contractions. In conclusion, human saphenous veins express CysLT1 and CysLT2 receptors, but only CysLT1 receptors are implicated in the contraction.
J Cardiovasc Pharmacol 2004 Jan
PMID:Characterization of cysteinyl leukotriene receptors on human saphenous veins: antagonist activity of montelukast and its metabolites. 1466 76

The development of nitrate tolerance has been found to be associated with vascular production of superoxide anion (O2-*), generated mainly by the eNOS and NADPH oxidase pathways. The aim of our study was to investigate whether long-term angiotensin-converting enzyme inhibition by ramipril is able to protect against nitrate tolerance in the aortas of eNOS-deficient (eNOS-/-) mice and to assess the implication of the NADPH oxidase pathway. Therefore, 3 types of treatment were given to wild-type (WT) and eNOS-/- mice: group 1 received ramipril for 5 weeks and a co-treatment with ramirpil plus nitroglycerine (NTG) during the last 4 days, group 2 received only NTG, and group 3 served as control. Relaxations to NTG (0.1 nmol/L to 0.1 mmol/L) were determined on U44619, a thromboxane analogue, precontracted rings, and O2-* production were assessed on aorta homogenates with the lucigenin-enhanced chemiluminescence technique. Cyclic guanosine monophosphate and reverse-transcriptase-polymerase chain reaction analyses were performed on whole mouse aortas. In WT group 2, the concentration-effect curves to NTG were significantly shifted to the right: the pD2 was 6.16 +/- 0.17 (n = 6) vs 6.81 +/- 0.10 (n = 6) in WT group 3 (not exposed to NTG; P < 0.05) and O2-* production was enhanced from 100% +/- 11% (n = 9) to 191% +/- 21% (n = 6; P < 0.01). In contrast, in WT group 1, the rightward shift was abolished: the pD2 value was 6.73 +/- 0.13 (n = 6; NS vs group 3 WT) and O2-* production was 117% +/- 6% (n = 7; NS vs group 3 WT). In eNOS groups 1 and 3, similar data were observed: the pD2 values were 7.58 +/- 0.08 and 7.38 +/- 0.11 (NS) vs 6.89 +/- 0.20 in eNOS group 2 (n = 6; P < 0.01). In the WT mice aortas, ramipril treatment significantly increased the cyclic guanosine monophosphate levels (reflecting nitric oxide availability), which returned to control values after in vivo co-treatment with a bradykinin BK2 antagonist (Icatibant). In both strains, candesartan, an AT1 blocker, was also able to protect against the development of nitrate tolerance. Moreover, before NTG exposure, ramipril treatment decreased p22phox and gp91phox (essential NADPH oxidase subunits) mRNA expression in aortas from both mice strains. In conclusion, long-term ramipril treatment in mice protects against the development of nitrate tolerance by counteracting NTG-induced increase in O2 production, which involves a direct interaction with the NADPH oxidase pathway and seems to be completely independent of the eNOS pathway.
J Cardiovasc Pharmacol 2006 Jul
PMID:Ramipril treatment protects against nitrate-induced oxidative stress in eNOS-/- mice: An implication of the NADPH oxidase pathway. 1689 13

F12511(S)-2',3',5'-trimethyl-4'-hydroxy-alpha-dodecylthio-alpha-phenylacetanilide (F12511) is a new Acyl-CoA cholesterol acyltransferase (ACAT) inhibitor that not only reduces the plasma cholesterol levels but also has anti-atherosclerotic actions in animals models. The study's aim was to analyze if F12511 may directly modify the ability of tumor necrosis factor--alpha (TNF-alpha)-incubated bovine aortic endothelial cells (BAEC) to express endothelial nitric oxide synthase (eNOS) protein and inflammatory-related proteins such as platelet endothelial cell adhesion molecule (PECAM) and CD40 ligand (CD40L). The addition of increasing concentrations of F12511 (10 to 10 mol/L) failed to modify the level of eNOS protein expressed in control BAEC. TNF-alpha (10 ng/mL) reduced the expression of eNOS protein. In TNF-alpha--incubated BAEC, F12511 protected eNOS expression in a concentration-dependent manner. TNF-alpha stimulated the expression of both CD40L and PECAM in cultured BAEC. F12511 (10 mol/L) failed to modify the expression of CD40L and PECAM in control and TNF-alpha-incubated BAEC. Reverse transcriptase polymerase chain reaction showed a marked expression of the ACAT-2 isoform and absent of expression of the ACAT-1 isoform in BAEC. The presence of ACAT-2 isoform in BAEC was further confirmed by Western blot. F12511 failed to modify the expression of the proinflammatory associated proteins PECAM and CD40L in the endothelium but protected eNOS expression in the endothelial cells exposed to inflammatory conditions.
J Cardiovasc Pharmacol 2006 Sep
PMID:Direct effect of F12511, a systemic inhibitor of Acyl-CoA cholesterol acyltransferase on bovine aortic endothelial cells. 1703 Dec 67


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