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PubMed2002

Biological models and genes of tumor reversion: cellular reprogramming through tpt1/TCTP and SIAH-1.

Tumor reversion is the process by which some cancer cells lose their malignant phenotype. This study was aimed at defining some of the molecular and phenotypic properties of this process. Biological models of tumor reversion were isolated from human leukemia and breast cancer cell lines by using the H-1 parvovirus as a selective agent. Differential gene expression analysis was performed between the parental malignant cells and their revertants or alternatively between these parental cells and their SIAH-1 transfectant counterparts. These SIAH-1 transfectants have a suppressed malignant phenotype and were used as a control for a viral-free system. Two hundred sixty-three genes were found to be either activated or inhibited during the reversion process, as confirmed by Northern blot analysis or quantitative PCR. Of these, 32% were differentially expressed in all systems, irrespective of whether parvovirus-selected, SIAH-1 overexpressing, or p53 mutant or wild-type cell lines were used, suggesting the existence of a universal mechanism underlying tumor reversion. Translationally Controlled Tumor Protein (tpt1/TCTP) has the strongest differential expression, down-regulated in the reversion of U937- and SIAH-1-overexpressing cells. Inhibition of TCTP expression by anti-sense cDNA or small interfering RNA molecules results in suppression of the malignant phenotype and in cellular reorganization, similar to the effect of SIAH-1. Hence, tumor reversion can be defined at the molecular level, not just as the reversal of malignant transformation, but as a biological process in its own right involving a cellular reprogramming mechanism, overriding genetic changes in cancer, by triggering an alternative pathway leading to suppression of tumorigenicity.

Basement Membrane↗
PubMed1974

Separation of ribonuclease H and RNA directed DNA polymerase (reverse transcriptase) of murine type-C RNA tumor viruses.

Ribonuclease H (RNA.DNA-hybrid ribonucleotidohydrolase, EC 3.1.4.34) has been reported to copurify with reverse transcriptase (RNA directed DNA polymerase) of RNA tumor viruses. In addition, viral specific ribonuclease H and reverse transcriptase of avian type-C viruses are thought to be part of the same polypeptide. In this report we show that a fraction of the ribonuclease H activity from Rauscher murine leukemia and Kirsten murine sarcoma viruses was separated from reverse transcriptase by anion exchange chromatography while the remaining portion co-purified with the viral polymerase. The amount of this co-purified nuclease activity was about 4- to 8-fold lower than the activity found in avian myeloblastosis virus (with respect to the ratio of ribonuclease H to reverse transcriptase) and this nuclease activity can only be detected by using labeled substrate of high specific radioactivity. However, a complete separation of ribonuclease H activity from reverse transcriptase was obtained by purifying core structures of the virus by sucrose density gradient centrifugation. While reverse transcriptase was present in the cores, there was no detectable ribonuclease H. Furthermore, a specific antibody against Rauscher leukemia virus reverse transcriptase did not inhibit any virion associated ribonuclease H activity. Our results suggest that in these virions these two enzyme activities reside in two separate molecules and probably in two different compartments of the virus. These findings emphasize a basic difference between the avian and murine type-C virus DNA polymerases.

Antibodies, Viral↗
PubMed1973

Electrophysiological control of reversed ciliary beating in Paramecium.

Quantitative relations between ciliary reversal and membrane responses were examined in electrically stimulated paramecia. Specimens bathed in 1 mM CaCl(2), 1 mM KCl, and 1 mM Tris-HCl, pH 7.2, were filmed at 250 frames per second while depolarizing current pulses were injected. At current intensities producing only electrotonic shifts the cilia failed to respond. Stimuli which elicited a regenerative response were followed by a period of reversed ciliary beating. With increasing stimulus intensities the latency of ciliary reversal dropped from 30 to 4 ms or less, and the duration of reversal increased from 50 ms to 2.4 s or more; the corresponding regenerative responses increased in amplitude and rate of rise. With progressively larger intracellular positive pulses, electric stimulation became less effective, producing responses with a progressive increase in latency and decrease in duration of reversed beating of the cilia. When 100-ms pulses shifted the membrane potential to +70 mV or more, ciliary reversal was suppressed until the end of the pulse. "Off" responses then occurred with a latency of 2-4 ms independent of further increases in positive potential displacement. These results suggest that ciliary reversal is coupled to membrane depolarization by the influx of ions which produces the regenerative depolarization of the surface membrane. According to this view suppression of the ciliary response during stimulation occurs when the membrane potential approaches the equilibrium potential of the coupling ion, thereby retarding its influx. Previous data together with the present findings suggest that this ion is Ca(2+).

Animals↗
PubMed2004

Long HIV type 1 reverse transcripts can accumulate stably within resting CD4+ T cells while short ones are degraded.

We utilized quantitative methods to compare the efficiency of reverse transcription and stability of viral DNA within resting and activated T cells. Highly purified resting CD4(+) T cells and activated T cells from healthy donors were spinoculated with HIV-1(YU-2), then cultured in conditions that maintain both the viability and the quiescence of the resting cells. Spreading infection was suppressed, then kinetic PCR was used to relate the rates of synthesis of short (strong-stop, RU5) and long (gag or U3-gag second strand transfer) viral DNA to the mean number of virions initially bound to each type of cell. As shown previously, activated cells support an initial burst of high-level reverse transcription, which is then followed by a approximately 10-fold decay in cDNA levels over 4.5 days. In resting T cells, although the synthesis of late reverse transcripts was initially approximately 1000-fold less efficient than in activated T cells, the number of these cDNAs per bound input virion rose 10-fold as culture was extended to 4.5 days. The number of late reverse transcripts remained constant for 3 days after the addition of efavirinez, reflecting enhanced stability. In contrast, the short strong-step reverse transcripts were mostly degraded. Thus, late HIV-1 reverse transcripts can accumulate stably in resting T cells in the absence of detectable T cell activation. Defining the underlying basis for the stabilization of late reverse transcripts, and their associated nucleoprotein complexes, may be pertinent to the accumulation of reservoirs of latent HIV-1 in patients, and could provide a target for future therapies.

CD4-Positive T-Lymphocytes↗
PubMed1993

Human immunodeficiency virus type 1 infection requires reverse transcription of nascent viral RNA.

We have previously shown that during human immunodeficiency virus type 1 (HIV-1) infection in vitro continued reverse transcription is required for stable HIV-1 production, but entry by progeny virus is not. To determine the source of the viral RNA reverse-transcribed late in infection, we employed inhibitors of HIV-1 transmission, reverse transcription, and proteolysis of the Gag-Pol polyprotein to interrupt HIV-1 infection in vitro. The kinetics of synthesis of viral DNA, RNA, and proteins was examined. During single-cycle infection, inhibition of reverse transcription 24-72 hr after infection delayed production of viral RNA and protein 10 days. Although viral DNA was detected in Southern blots, inhibition of Gag-Pol processing or transient inhibition of reverse transcription blocked its expression. We propose that after initial reverse transcription of input virion RNA is complete, newly synthesized HIV-1 RNA is reverse-transcribed before its export in virions to yield the viral DNA required for stable HIV-1 production.

Cells, Cultured↗
PubMed2004

Arrival, reversal, and departure of neurofilaments at the tips of growing axons.

We have investigated the movement of green fluorescent protein-tagged neurofilaments at the distal ends of growing axons by using time-lapse fluorescence imaging. The filaments moved in a rapid, infrequent, and asynchronous manner in either an anterograde or retrograde direction (60% anterograde, 40% retrograde). Most of the anterograde filaments entered the growth cone and most of the retrograde filaments originated in the growth cone. In a small number of cases we were able to observe neurofilaments reverse direction, and all of these reversals occurred in or close to the growth cone. We conclude that neurofilament polymers are delivered rapidly and infrequently to the tips of growing axons and that some of these polymers reverse direction in the growth cone and move back into the axon. We propose that 1) growth cones are a preferential site of neurofilament reversal in distal axons, 2) most retrograde neurofilaments in distal axons originate by reversal of anterograde filaments in the growth cone, 3) those anterograde filaments that do not reverse direction are recruited to form the neurofilament cytoskeleton of the newly forming axon, and 4) the net delivery of neurofilament polymers to growth cones may be controlled by regulating the reversal frequency.

Animals↗
PubMed1997

The reversible Hill equation: how to incorporate cooperative enzymes into metabolic models.

MOTIVATION: Realistic simulation of the kinetic properties of metabolic pathways requires rate equations to be expressed in reversible form, because substrate and product elasticities are drastically different in reversible and irreversible reactions. This presents no special problem for reactions that follow reversible Michaelis-Menten kinetics, but for enzymes showing cooperative kinetics the full reversible rate equations are extremely complicated, and anyway in virtually all cases the full equations are unknown because sufficiently complete kinetic studies have not been carried out. There is a need, therefore, for approximate reversible equations that allow convenient simulation without violating thermodynamic constraints. RESULTS: We show how the irreversible Hill equation can be generalized to a reversible form, including effects of modifiers. The proposed equation leads to behaviour virtually indistinguishable from that predicted by a kinetic form of the Adair equation, despite the fact that the latter is a far more complicated equation. By contrast, a reversible form of the Monod-Wyman-Changeux equation that has sometimes been used leads to predictions for the effects of modifiers at high substrate concentration that differ qualitatively from those given by the Adair equation.

Binding Sites↗
PubMed1998

Human cerebral activity evoked by motion reversal and motion onset. A PET study.

In this PET study, we have investigated the human brain activity evoked by a visual motion paradigm commonly used to measure motion-related visual evoked potentials (VEPs). Because standard PET activation studies have been performed with motion along four axes, we first determined the pattern of brain activation when motion was restricted to a single axis. Motion back and forward along a single horizontal axis compared with a static condition revealed weak differential activations in the cuneus and the parietal cortex. Human area MT/V5 (middle temporal area) was hardly activated at all in this subtraction. Additional functional MRI experiments proved that MT/V5 activity is significantly higher for motion along four axes than for motion along a single axis. Secondly, we attempted to isolate the pattern of brain activity related to the reversal of motion direction and to the onset of motion, i.e. two transient motion components commonly used in measuring motion-related VEPs. To that end, we added a continuous linear contrast modulation, that reached maximum contrast at reversal or onset of motion, and compared both conditions with a contrast-modulated static or continuous motion condition. Subtraction of the static random dot pattern condition from the single-axis motion reversal condition, both contrast-modulated, revealed three significant activations: the anterior parieto-occipital sulcus, the lateral sulcus and the anterior claustrum. Additional analysis showed that these activations were not due to motion appearance or disappearance, but were due to the combination of motion reversal and contrast modulation. Hence, these activations do not reflect the motion reversal transient per se. In order to isolate a metabolic response to the reversal transient per se, we used a conjunction analysis, which suggests that activity in human MT/V5, the cuneus and a parietal insular region could underlie the motion reversal VEP in our experiments. Subtraction of the static random dot pattern condition from the single-axis motion onset condition, both contrast-modulated, revealed a single significant activation in the posterior cingulate cortex. Although the significance of this activation is unclear, it adds further evidence for the visual function of this region.

Adult↗
PubMed2005

Attractiveness ratings of anterior open bites and reverse overjets using the aesthetic component of the Index of Orthodontic Treatment Need.

This study was carried out to determine the level of attractiveness of anterior open bites (AOB) and reverse overjets of varying severity. A sample of 180 non-dental students (101 females and 79 males; average age 20 +/- 0.75 years) and 45 dental professionals (12 females and 33 males; average age 35.5 +/- 5.07 years) was asked to complete a questionnaire to rate the level of attractiveness of AOB and reverse overjets of varying severity using the aesthetic component (AC) of the Index of Orthodontic Treatment Need (IOTN). Photographs of mild and severe AOB and reverse overjets were projected onto a white screen in a lecture theatre (15 seconds each with a 5 second interval between images). The participants were asked to record the AC grade at which they thought the projected picture of the AOB or reverse overjets had similar attractiveness. Dental awareness of non-dental students was determined by asking them their opinion on how important it was to have straight teeth (very unimportant, unimportant, important, very important), about their personal or close family members' orthodontic experiences and if they thought they were in need of any orthodontic treatment. A chi-square test was applied to record any differences between sexes and between the different groups. Backward stepwise linear regression analysis was used to determine the relationship between the students' ratings of the photographs and their dental awareness. The majority of non-dental students rated a mild AOB (93 per cent) and mild reverse overjet (96 per cent) to be aesthetically acceptable. A mild AOB and mild reverse overjet were found to be acceptable by 40 and 58 per cent of dental professionals, respectively. The differences in the ratings between dental professionals and non-dental students were significant at P < 0.001.A severe AOB was considered unattractive by both students and dental professionals. However, dental professionals rated it at the more unattractive end of the scale (P < 0.001). A severe reverse overjet was rated by the majority of the subjects as aesthetically unacceptable (85 per cent of the non-dental students and 78 per cent of the dental professionals).

Adult↗
PubMed2002

Phenotypic reversion or death of cancer cells by altering signaling pathways in three-dimensional contexts.

BACKGROUND: We previously used a three-dimensional (3D) reconstituted basement membrane (rBM) assay to demonstrate that tumorigenic HMT-3522 T4-2 human breast cells can be induced to form morphologically normal structures ("reversion") by treatment with inhibitors of beta1 integrin, the epidermal growth factor receptor (EGFR), or mitogen-activated protein kinase (MAPK). We have now used this assay to identify reversion and/or death requirements of several more aggressive human breast cancer cell lines. METHODS: Breast tumor cell lines MCF7, Hs578T, and MDA-MB-231 were cultured in 3D rBM and treated with inhibitors of beta1 integrin, MAPK, or phosphatidylinositol 3-kinase (PI3K). MDA-MB-231 cells, which lack E-cadherin, were transfected with an E-cadherin cDNA. The extent of reversion was assessed by changes in morphology and polarity, growth in 3D rBM or soft agar, level of invasiveness, and tumor formation in nude mice. RESULTS: All three cell lines showed partial reversion (MCF7 the greatest and Hs578T the least) of tumorigenic properties treated with a single beta1 integrin, MAPK, or PI3K inhibitor. Combined inhibition of beta1 integrin and either PI3K or MAPK resulted in nearly complete phenotypic reversion (MDA-MB-231, MCF7) or in cell death (Hs578T). E-cadherin-transfected MDA-MB-231 cells showed partial reversion, but exposure of the transfectants to an inhibitor of beta1 integrin, PI3K, or MAPK led to nearly complete reversion. CONCLUSION: The 3D rBM assay can be used to identify signaling pathways that, when manipulated in concert, can lead to the restoration of morphologically normal breast structures or to death of the tumor cells, even highly metastatic cells. This approach may be useful to design therapeutic intervention strategies for aggressive breast cancers.

Animals↗
PubMed1989

Fidelity of human immunodeficiency virus type I reverse transcriptase in copying natural DNA.

Reverse transcriptase from the human immunodeficiency virus type I (HIV-1) was expressed in E. coli and purified to near homogeneity. The enzyme was shown to contain reverse transcriptase, DNA polymerase and ribonuclease H activities. The DNA polymerase activity converted singly-primed phi X174 (+) DNA into the double-stranded form. Two third of the replication product is ligatable to covalently closed circular DNA (RFIV-form DNA) indicating that DNA synthesis by HIV reverse transcriptase can proceed until the enzyme matches the 5'-end of a pre-existing primer molecule. The in vitro accuracy of HIV reverse transcriptase was measured with the phi X174am16 reversion assay to be 1/7,400. Reversion rates for the individual mispairs were determined from pool bias studies to be 1/8,000 for the dGMP:T template mismatch, 1/35,000 for the dGMP:A template mismatch, 1/45,000 for the dAMP:G template mismatch, 1/73,000 for the dCMP:T template mispair, 1/140,000 for the dCMP:A template mispair, and 1/180,000 for the dGMP:G template mismatch. The dTMP:T template mispair was below the detection limit of the assay indicating a reversion rate of less than 1/300,000 for this particular mispair.

Cloning, Molecular↗
PubMed2006

Selective degradation of reverse gyrase and DNA fragmentation induced by alkylating agent in the archaeon Sulfolobus solfataricus.

Reverse gyrase is a peculiar DNA topoisomerase, specific of hyperthermophilic Archaea and Bacteria, which has the unique ability of introducing positive supercoiling into DNA molecules. Although the function of the enzyme has not been established directly, it has been suggested to be involved in DNA protection and repair. We show here that the enzyme is degraded after treatment of Sulfolobus solfataricus cells with the alkylating agent MMS. MMS-induced reverse gyrase degradation is highly specific, since (i) neither hydroxyurea (HU) nor puromycin have a similar effect, and (ii) topoisomerase VI and two chromatin components are not degraded. Reverse gyrase degradation does not depend on protein synthesis. Experiments in vitro show that direct exposure of cell extracts to MMS does not induce reverse gyrase degradation; instead, extracts from MMS-treated cells contain some factor(s) able to degrade the enzyme in extracts from control cells. In vitro, degradation is blocked by incubation with divalent metal chelators, suggesting that reverse gyrase is selectively degraded by a metal-dependent protease in MMS-treated cells. In addition, we find a striking concurrence of extensive genomic DNA degradation and reverse gyrase loss in MMS-treated cells. These results support the hypothesis that reverse gyrase plays an essential role in DNA thermoprotection and repair in hyperthermophilic organisms.

Alkylating Agents↗
PubMed1978

Antibiotic-induced paralysis of the mouse phrenic nerve-hemidiaphragm preparation, and reversibility by calcium and by neostigmine.

Certain antibiotics can induce neuromuscular paralysis, but the mechanism of this action is largely unknown. The purpose of this study was to compare the neuromuscular blocking potencies and reversibilities of 16 antibiotics in the isolated mouse phrenic nerve-hemidiaphragm preparation. The antibiotics tested were five aminoglycosides (neomycin, gentamicin, streptomycin, dihydrostreptomycin and kanamycin), tetracycline and oxytetracycline, polymyxins B and E, penicillins G and V, cephradine, cephaloridine, erythromycin, lincomycin, and clindamycin. Reversibility of the muscle paralysis by calcium and neostigmine was assessed. All the aminoglycosides resembled magnesium in blocking neuromuscular transmission, the neuromuscular blockade being almost completely reversed (to 64-77 per cent of control) by calcium but only poorly reversed by neostigmine (to 20-67 per cent of control). Neuromuscular blockade produced by the tetracyclines was also reversed by calcium (44-104 per cent) but not by neostigmine (0-15 per cent). Neuromuscular blockade produced by the polymyxins or by lincomycin was only partially reversed by calcium (0-34 per cent). Penicillin V, erythromycin, clindamycin, polymyxin B and the tetracyclines could also produce muscle paralysis by decreasing muscle contractility. This effect on contractility was irreversible by pharmacologic means. Penicillin G, cephradine and cephaloridine possessed negligible paralyzing effects on the nerve-muscle preparation. It is concluded that the different groups of antibiotics tested act by different mechanisms and that only the calcium-induced reversal of aminoglycoside block is predictable.

Animals↗
PubMed1990

Reversal of intense neuromuscular blockade following infusion of atracurium.

In order to evaluate reversal time from very intense neuromuscular blockade caused by a continuous infusion of atracurium, the time course of neostigmine induced reversal from different levels of neuromuscular blockade was evaluated using the post-tetanic count (PTC) and the train-of-four (TOF) in 30 patients anesthetized with nitrous oxide, fentanyl, and thiopental. Reversal time (time from administration of neostigmine at different PTC levels to a TOF ratio of 0.7) was found to depend upon the degree of blockade at the time of reversal. Median reversal time from a PTC of 1-2, 3-4, 5-6, 7-8, 9-10, 11-12, and greater than 13 (but less than 10% twitch height) to a TOF ratio of 0.7 was 31, 23, 19, 18, 14, and 13 min, respectively. Spontaneous recovery from PTC level of 1-2, when atracurium infusion was stopped, to a PTC level at which antagonism was induced and reversal time were both correlated to the square root of the PTC. Total recovery time (spontaneous recovery plus reversal time) was not shortened by an early injection of neostigmine. It is concluded that neostigmine administration during intense neuromuscular blockade following atracurium infusion does not shorten total recovery time and offers no clinical advantages.

Adult↗
PubMed1996

Residual block after mivacurium with or without edrophonium reversal in adults and children.

BACKGROUND: The rapid recovery from mivacurium- induced neuromuscular block has encouraged omission of its reversal. The purpose of this study was to determine, in children and in adults, whether failure to reverse mivacurium neuromuscular block was associated with residual neuromuscular block on arrival in the postanesthesia care unit. METHODS: In 50 children, aged 2-12 yr, and 50 adults, aged 20-60 yr, anesthesia was induced and maintained with propofol and fentanyl, and neuromuscular block was achieved by an infusion of mivacurium, to maintain one or two visible responses to train-of-four (TOF) stimulation of the ulnar nerve. At the end of surgery, mivacurium infusion was stopped, and 10 min later, reversal was attempted with saline or 0.5 mg x kg(-1) edrophonium by random allocation. On arrival in the postanesthesia care unit, a blinded observer assessed patients clinically and by stimulation of the ulnar nerve with a Datex electromyogram in the uncalibrated TOF mode. RESULTS: Children arrived in the postanesthesia care unit 8.2 +/- 3-4 min after reversal of neuromuscular block and showed no sign of weakness, either clinically or by TOF stimulation. Although TOF ratio was greater in children who had received edrophonium (1.00 +/- 0.05 vs. 0.93 +/- 0.01, P<0.01), TOF was >0.7 in all children. Adults arrived in the postanesthesia care unit 12.9 +/- 5.3 min after reversal of neuromuscular block(P<0.01 vs. children). Six in the saline group demonstrated weakness (two required immediate reversal of neuromuscular block, and TOF was <0.7 in four others), compared with TOF <0.7 in only one of the edrophonium group (P<0.05). CONCLUSIONS: This study demonstrated that, in adults, failure to reverse mivacurium neuromuscular block was associated with an increased incidence of residual block. Such weakness was not observed in children receiving similar anesthetic and neuromuscular blocking regimens.

Adult↗
PubMed2006

Naloxone reversal of buprenorphine-induced respiratory depression.

BACKGROUND: The objective of this investigation was to examine the ability of the opioid antagonist naloxone to reverse respiratory depression produced by the mu-opioid analgesic, buprenorphine, in healthy volunteers. The studies were designed in light of the claims that buprenorphine is relatively resistant to the effects of naloxone. METHODS: In a first attempt, the effect of an intravenous bolus dose of 0.8 mg naloxone was assessed on 0.2 mg buprenorphine-induced respiratory depression. Next, the effect of increasing naloxone doses (0.5-7 mg, given over 30 min) on 0.2 mg buprenorphine-induced respiratory depression was tested. Subsequently, continuous naloxone infusions were applied to reverse respiratory depression from 0.2 and 0.4 mg buprenorphine. All doses are per 70 kg. Respiration was measured against a background of constant increased end-tidal carbon dioxide concentration. RESULTS: An intravenous naloxone dose of 0.8 mg had no effect on respiratory depression from buprenorphine. Increasing doses of naloxone given over 30 min produced full reversal of buprenorphine effect in the dose range of 2-4 mg naloxone. Further increasing the naloxone dose (doses of 5 mg or greater) caused a decline in reversal activity. Naloxone bolus doses of 2-3 mg, followed by a continuous infusion of 4 mg/h, caused full reversal within 40-60 min of both 0.2 and 0.4 mg buprenorphine-induced respiratory depression. CONCLUSIONS: Reversal of buprenorphine effect is possible but depends on the buprenorphine dose and the correct naloxone dose window. Because respiratory depression from buprenorphine may outlast the effects of naloxone boluses or short infusions, a continuous infusion of naloxone may be required to maintain reversal of respiratory depression.

Adult↗
PubMed1985

Endothelial preservation in reversed and in situ autogenous vein grafts. A quantitative experimental study.

The hypothesis that superior endothelial preservation occurs when in situ (as opposed to harvested and reversed) autogenous veins are used as arterial grafts was investigated in a canine model by quantitating endothelial loss as seen on scanning electron micrographs. In situ grafts were compared to atraumatically dissected, nondistended, reversed grafts and to grafts distended to 500 mmHg pressure. Two hours after arterial transplantation, endothelial denudation averaged 3.9 +/- 6.7% on in situ grafts, 18.6 +/- 5.9% on reversed grafts (p less than 0.01), and 35.3 +/- 5.4% on reversed and distended grafts (p less than 0.001). At 24 hours after grafting, a significant increase (p less than 0.01) in endothelial destruction on in situ grafts resulted in a smaller, yet still significant difference in endothelial preservation between in situ and reversed grafts (15.2 +/- 9.5% vs. 25.1 +/- 23.4%, p less than 0.05). Endothelial healing was largely accomplished at 2 weeks regardless of technique. No difference in endothelial fibrinolytic activity could be detected between in situ and gently handled, reversed grafts at 24 hours or 6 weeks after surgery. An obligatory, although modest, degree of endothelial destruction occurred on the undissected portion of in situ grafts as a consequence of exposure to arterial hemodynamics. However, in the immediate postoperative period, endothelial preservation on in situ grafts surpassed that seen in even the most gently handled reversed vein grafts.

Animals↗
PubMed2000

'Irreversible' endothelin-1 binding does not prohibit ABT-627 from reversing endothelin-1-induced effects.

Endothelin-1 (ET-1) is thought to play a role in a wide range of pathological conditions. One of the distinct characteristics of ET-1 is its long-lasting vasoconstrictor action, which is presumably caused by the irreversible binding of ET-1 to ET receptors and by the functional effects of internalized ET receptors. ABT-627 is a potent endothelin-A (ET(A))-selective antagonist with a Ki value at 0.034 nM for the human ET(A) receptor, and is currently being used in clinical studies for prostate cancer. Unlike ET-1, the binding of 125I-labeled ABT-627 to human ET(A) receptors expressed in Chinese hamster ovary (CHO) cells is reversible, and the dissociation half-life for the ligand/receptor complex is 2 h. Interestingly, the binding of both ET-1 and ABT-627 to the ET(A)-receptor results in partial receptor internalization but only ET-1 is capable of triggering intracellular functional responses. Although ABT-627 binding to membranes is more reversible than ET-1 binding, ABT-627 is able to reverse an ET-1-induced contraction in rat aortic rings in a dose-dependent manner, and at 1 microM produces nearly complete reversal of the constrictor effects of 10 nM ET-1 within 60 min. Similarly, in vivo studies show that ABT-627 (0.01 and 0.1 mg/kg/min i.v.) reverses the ET-1-induced increase in arterial pressure in anesthetized, ganglionic-blocked rats, and after 60 min, ABT-627 essentially normalizes pressure. Our data show that ABT-627 is capable of reversing an established response induced by ET-1 and is useful in reversing pathological conditions involving ET-1.

Animals↗