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PubMed1990

Activation of excitatory amino acid inputs to supraoptic neurons. I. Induced increases in dye-coupling in lactating, but not virgin or male rats.

Mitral cells of the main and accessory olfactory bulbs have been shown to project monosynaptically to the supraoptic nucleus (SON) via the lateral olfactory tract (LOT) which uses excitatory amino acid transmitters. Data collected during characterization of these projections suggested that synaptic activation of SON neurons via LOT stimulation in slices influenced the incidence of dye-coupling. The present study pursued this suggestion using horizontally cut slices from male, virgin female and lactating rats. Neurons were confirmed to be excited by electrical stimulation of the tract, injected with Lucifer yellow, and synaptically activated for 10 min at 10 Hz (n = 92). Another 94 neurons were similarly confirmed and injected, but received no further stimulation. In an additional 8 slices, injected neurons were antidromically activated for 10 min at 10 Hz. Analyses done on 194 injected neurons from the 3 groups showed that synaptic activation resulted in a significant (P less than 0.01) increase in the incidence of coupling only in tissue from lactating rats. This increase was entirely due to larger numbers of cells being coupled dendrodendritically to the injected cells in the stimulated slices. Antidromic activation did not influence coupling. Increased coupling occurred among both oxytocin and vasopressin cell types. This is the first report of increased coupling resulting from synaptic activation in mammalian CNS. Changes seen only in lactating rats may be related to their altered SON ultrastructural morphology (i.e. dendritic bundling). Strong olfactory and vomeronasal input associated with some maternal behaviors may increase neuronal coupling and enhance hormone release in response to other incoming stimuli (e.g. suckling, dehydration).

Action Potentials↗

PubMed1990

Dye coupling between mouse Schwann cells.

Dye coupling and voltage-dependent ionic currents were evaluated simultaneously in mouse Schwann cells using patch pipettes containing Lucifer yellow. Dye coupling was examined in different types of cultured Schwann cells: cells not associated with axons, non-myelinating cells associated with axons, and myelinating cells. Myelinating and non-myelinating cells were also examined in freshly dissociated adult nerves. The incidence of dye coupling was higher in embryonic dorsal root ganglia (DRG) than in neonatal sciatic nerves. In both types of cultures the incidence of dye coupling decreased with time. In DRG cultures voltage-dependent K+ currents were observed in the Schwann cells, except in some of the myelinating cells, suggesting that K+ currents disappear as myelin formation progresses, and dye coupling was eliminated in myelinating cells. In freshly dissociated adult nerves, large myelinating Schwann cells lacked both K+ currents and dye coupling which were preserved in non-myelinating cells. Although the association between dye coupling and voltage-dependent K+ channels in non-myelinating cells is not clear, Schwann cells which had differentiated to engage in myelin formation lost both properties.

Animals↗

PubMed1986

Intercellular junctional coupling in preimplantation mouse embryos: effect of blocking transcription or translation.

Gap junction formation in cleavage stage mouse embryos was examined by testing for ionic coupling or by observing the intercellular movement of the fluorescent dye, Lucifer yellow CH. Our results confirm that embryo-wide cell coupling, mediated by cell-to-cell membrane channels (gap junctions), is acquired in the 8-cell stage after compaction has begun. However, not all partially compacted embryos were found to be ionically or dye coupled, suggesting that the initiation of gap junction assembly is not necessarily triggered by the onset of cell flattening. The rate of fluorescent dye movement throughout the embryo was found to increase as embryos proceed through compaction and beyond, indicating that the number of gap junctional channels between blastomeres increases as development progresses. The inhibitors alpha-amanitin and cycloheximide were used to assess the requirement of new transcription and protein synthesis, respectively, for the onset of intercellular coupling and its progressive increase during compaction. Treatment conditions were chosen to bring about suppression of mRNA and protein synthesis within 2 hr. Ionic coupling was detected in almost all compacted 8-cell embryos treated with either inhibitor from the 4-cell stage. On the other hand, dye coupling was weak or undetectable in such embryos. We propose that a limited supply of junctional components is present by the 4-cell stage to serve as a pool of precursors for the first gap junctions to be assembled in the 8-cell stage. However, it is apparent that continued embryonic gene expression is required for the full extent of junctional coupling to be established.

Amanitins↗

PubMed1987

Evidence for modulation of cell-to-cell electrical coupling by cAMP in mouse islets of Langerhans.

The effects of forskolin on electrical coupling among pancreatic beta-cells were studied. Two microelectrodes were used to measure membrane potentials simultaneously in pairs of islet beta-cells. Intracellular injection of a current pulse (delta I) elicited a membrane response delta V1 in the injected cell and also a response delta V2 in a nearby beta-cell confirming the existence of cell-to-cell electrical coupling among islet beta-cells. In the presence of glucose (7 mM), application of forskolin evoked a transient depolarization of the membrane and electrical activity suggesting that the drug induced a partial inhibition of the beta-cell membrane K+ conductance. Concomitant with this depolarization of the membrane there was a marked decrease in beta-cell input resistance (delta V2/delta I) suggesting that exposure to forskolin enhanced intercellular coupling. Direct measurements of the coupling ratio delta V2/delta V1 provided further support to the idea that forskolin enhances electrical coupling among islet cells. Indeed, application of forskolin reversibly increased the coupling ratio. These results suggest that cAMP might be involved in the modulation of electrical coupling among islet beta-cells.

Adenylyl Cyclases↗

PubMed1996

Receptor subtype and density determine the coupling repertoire of the 5-HT2 receptor subfamily.

The 5-Hydroxytryptamine (5-HT)2C receptor (originally known as the 5-HT1C receptor) is a member of the 5-HT2 subfamily of G protein coupled receptors, which is known to couple to phospholipase C. Within the 5-HT2 subfamily, only the 5-HT2C receptor also coupled to inhibition of forskolin-stimulated cAMP production when expressed at high density (12 pmol/mg membrane protein) in stably transformed AV12 cells. The 5-HT2C receptor coupled with high efficacy to both phospholipase C as measured by IP3 (inositol 1,4,5-trisphosphate) production and to inhibition of forskolin-stimulated cAMP production (EC50 = 2.98 nM +/- 0.9 and IC50 = 47.99 nM +/- 10.25 respectively). The 5-HT2A and 5-HT2B receptors, while coupling to phospholipase C with high affinity (EC50s of 19.24 nM +/- 6.44 and 1.24 nM +/- 0.136 respectively), did not decrease adenylyl cyclase activity. The 5-HT2C receptor actions in both systems showed the expected pharmacology for the 5-HT2C receptor, e.g., mesulergine antagonized the effects of 5-HT and spiperone did not. Preincubation of cells with PTX showed that the G protein coupling of the 5-HT2C receptor to phospholipase C is PTX insensitive, while the G protein coupling to inhibition of adenylyl cyclase is PTX sensitive, even to concentrations as low as 20 ng/ml of PTX. PTX pretreatment of the 5-HT2C bearing cells also unmasked a small stimulatory effect on adenylyl cyclase. When expressed at low density the 5-HT2C receptor potentiated forskolin-stimulated cAMP production by 2 fold while still maintaining its ability to enhance PI hydrolysis. A more modest potentiation of cAMP production was noted with low density expression of the 5-HT2B receptor. Thus the ability of the 5-HT2C receptor to interact with several effectors through at least two different G proteins is, in part, receptor subtype specific but also influenced by receptor density.

Animals↗

PubMed1995

Immunogenetic study of couples with recurrent spontaneous abortions.

OBJECTIVES: Clinical observations suggest that genetic and immunologic disparity could be a factor in fecundity. The HLA system (HLA) is polymorphic and TLX (Trophoblast Lymphocyte Cross-Reactive), which is also polymorphic, seems to be linked to it. The immunologic hypothesis follows that excessive HLA and TLX-sharing could explain the rejection of a semi-allogenic blastocyst. Study objectives are therefore twofold; To determine whether or not there is significant HLA-sharing between spouses with unexplained recurrent spontaneous abortions (RSA) and to determine whether or not there is an association between some HLA specificities and RSA. STUDY DESIGN: The study includes only Caucasian couples that have had three successive spontaneous abortions. These were distributed in two groups: Group E: 18 couples either with known aetiology or with secondary RSA; Group U: seven couples with unexplained primary RSA; Control group C: 21 couples with at least two children and no spontaneous abortions. Tissue typing for HLA-A and B molecules was performed using serotyping methodology based on lymphocytotoxicity reaction. The different DRB1 alleles (class II) were determined by oligotyping with a non-radioactive reverse dot-blot methodology. RESULTS: Statistical comparison shows that the number of couples without shared specificity is not significantly different between the three groups for each locus independently and for the set of three. Our results show also that the allelic frequencies are not significantly different between the three groups. CONCLUSIONS: There is no higher HLA-sharing in couples with RSA than in fertile couples. Similarly, no particular HLA specificity can be associated with the RSA.

Abortion, Habitual↗

PubMed1992

Coupling of antibody-binding fragments to solid-phase supports: site-directed binding of F(ab')2 fragments.

A method to covalently bind antibody fragments, via their carboxyl termini to solid supports, is presented. The strategy involves: (1) reversibly blocking all the accessible carboxyl groups on the antibody molecule with phenylhydrazine, (2) exposing the carboxyl termini of the fragment by enzymatic digestion with pepsin and (3) subsequently coupling the fragment to an appropriate support. Experiments with an anti-bovine serum albumin monoclonal antibody and C-14 phenylhydrazine revealed that the blocking step was nearly completely reversible with a dilute solution of FeCl3. Radioiodinated blocked F(ab')2 fragments were then coupled to an amino-functionalized Sepharose 4B column, and characterized as to their coupling capacity (mass of protein coupled/ml of bead), and antigen-binding activity. The coupling capacity of the blocked fragments was found to be 12%, half the coupling efficiency of unmodified radioiodinated F(ab')2. The antigen-binding capacity (mol antigen bound per mol antibody coupled) for the blocked F(ab')2, on the other hand, was found to be 1.9, which was approx. 3.5-times greater than for the unmodified F(ab')2. Comparisons with other conventional coupling techniques were also made. These preliminary studies suggest that this technique can provide one with the means to obtain more uniform and active populations of immobilized antibody fragments.

Antibodies, Monoclonal↗

PubMed1992

Tolerance to acetylcholine receptor induced by AChR-coupled syngeneic cells.

Intravenous administration of acetylcholine receptor (AChR)-coupled syngeneic spleen cells induced AChR-specific tolerance in Lewis rats. Injection of 20 x 10(6) AChR-coupled spleen cells resulted in a significant reduction of the antibody response to AChR when the animals were subsequently immunized with AChR (up to 66% inhibition). Tolerance induced by AChR-coupled cells was antigen-specific: challenge with AChR plus an unrelated antigen, ovalbumin (OVA), resulted in significantly reduced serum antibody titers to AChR but normal or enhanced titers to OVA, compared to controls. Lymphocytes from these rats showed substantially reduced proliferative responses in vitro to AChR, and normal or enhanced responses to OVA. To investigate the role of Ia antigens in tolerance induction, AChR was coupled to Ia-positive or Ia-negative spleen cells. Injection of AChR-coupled Ia-positive cells induced antigen-specific tolerance to AChR; challenge with AChR plus OVA resulted in reduced serum antibody titers and lymphoproliferative responses to AChR, and normal or enhanced titers and cellular responses to OVA. Injection of AChR-coupled Ia-negative cells did not induce tolerance to AChR. These results demonstrate that AChR, which is known to be highly immunogenic, can be rendered tolerogenic without denaturation or linkage to toxic substances. The possible mechanisms of tolerance induced by AChR-coupled spleen cells are discussed.

Animals↗

PubMed1982

The coupling of bone formation to bone resorption: a critical analysis of the concept and of its relevance to the pathogenesis of osteoporosis.

The approximate equality of whole-body rates of formation and resorption over a wide range, a phenomenon frequently but inaccurately referred to as coupling, depends on the prompt and approximately complete refilling of each new resorption cavity with new bone. This focal regulation of bone balance requires an adequate supply of new osteoblasts at the right place at the right time, a process which presumably depends both on the availability of precursor cells and on some form of coupling signal. It also requires that each new osteoblast is able to make a normal amount of bone matrix, a process which is probably unrelated to coupling. The defect in bone formation that occurs in normal aging (and is exaggerated in osteoporosis) is too small a total work output by each new team of osteoblasts, so that refilling of resorption cavities is incomplete. Whether too few osteoblasts are assembled, which could result from a defect in a coupling signal or from deficiency of osteoblast precursors, or whether each osteoblast makes a subnormal amount of bone is unknown. Defective coupling, in the sense of a delay in the focal onset of bone formation after completion of resorption does occur in many patients with osteoporosis but makes only a minor contribution to bone loss. Imbalance between whole-body rates of resorption and formation in the absence of a coupling defect can also result from exaggerated depth of resorption cavities leading to perforation of trabecular plates and removal of some of the surfaces on which new bone is formed. The possible role of defective coupling in the pathogenesis of osteoporosis is still to be established.

Age Factors↗

PubMed1988

Artificial insemination using donor semen and the issue of secrecy: the views of donors and recipient couples.

The issue of secrecy and artificial insemination using donor semen has psychosocial, moral and legal implications. These implications are explored within the context of New Zealand AID practice, and particularly, recent legislation aimed at clarifying the status of the child. The results of two studies, one covering 37 donors involved in six AID programmes and the other covering 55 couples who had been accepted into one of the same six programmes, insomuch as they relate to issues of secrecy, are reported. Recipient couples and donors, while thinking that secrecy is important, have told other people-a not dissimilar situation to what occurred in the adoption field 25 years ago. Forty-one per cent of recipient couples and donors do not believe children should be told of their origins. A high 46% of couples had not yet decided if they would tell their child. Donors are almost equally divided over the child's right to non-identifying information about them. Donors are more likely than recipient couples to believe that the child who knows s/he has been conceived via AID will want information about them. Only 11% of donors and 5% of couples believe a child would want to know the identity of the donor, although for three quarters of both groups the issue is far from clear. Donors were not as opposed to the possibility of tracing occurring as some doctors suggest. Response to questions concerning the legal position suggests there is considerable confusion amongst both groups. The overwhelming majority of couples were intending to place the husband's name on the birth certificate, regarding him as the father.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1987

Incidence of dye coupling among magnocellular paraventricular nucleus neurons in male rats is testosterone dependent.

Recently published work in the rat has shown that: the incidence of electrical coupling, as measured by dye coupling, is decreased from control levels by 8 days of drinking hypertonic saline; an index of circulating testosterone, seminal vesicle weight, is also decreased by 8 days of saline drinking; and both plasma and urinary vasopressin levels are reduced in castrated males, but can be returned to normal with testosterone replacement. These findings have led to the hypothesis that dye coupling, particularly that involving vasopressinergic cells, may be affected by gonadal steroids. We have investigated the effects of castration and testosterone replacement on the incidence of dye coupling among the neurons of the predominantly vasopressinergic magnocellular lateral paraventricular nucleus in slices of male rat hypothalamus. Incidence of dye coupling in this nucleus of castrated rats was found to be decreased by 67% from sham castrated control levels. Testosterone-filled Silastic capsules (but not empty capsules) implanted subcutaneously at the time of castration abolished the effect of castration on dye coupling. We conclude that testosterone has a powerful influence upon coupling among PVN vasopressinergic neurons and may participate in the control of vasopressin release in intact animals.

Animals↗

PubMed1994

Reporting of HIV risk behaviors by injection drug using heterosexual couples in methadone maintenance.

This study sought to identify differences within injection drug using (IDU) couples in reporting of sexual and needle risk behavior. Subjects were thirty-nine heterosexual couples entering methadone maintenance. In 33.3% of couples, one member reported sharing needles while the other member reported no sharing. In 12.9% of couples, one member reported sharing injection equipment, while the other member reported no sharing. Agreement was 77.4% between members of monogamous couples regarding frequency of condom use, 80.7% regarding vaginal intercourse with condoms, and 25.8% regarding vaginal intercourse without condoms. Within couples, a number of differences between members of the couple in injection equipment sharing were noted, suggesting that individuals who attempt to protect themselves by not sharing injection equipment may be placed at risk by their sexual partners. Further clinical and research efforts should be directed toward reducing barriers to behavior that would protect both partners. Implications for self-report measurement of HIV risk behavior and for preventive interventions are discussed.

Adult↗

PubMed1992

Ionic coupling among cells in the organ of Corti.

Gap junctions have been demonstrated morphologically among the supporting cells of the mammalian organ of Corti but, in contradistinction to reptiles, evidence for their existence between the supporting cells and hair cells is equivocal. The literature is ambiguous with respect to electrical coupling and dye coupling among the supporting cells, and no coupling of either kind has been demonstrated for the hair cells. We found strong coupling of both kinds among the supporting cells in the cochleas of live Mongolian gerbils and a less stable coupling between the supporting cells and the outer hair cells. The electrical coupling was established by recording alternating receptor potentials in the hair cells and following their decrement in the population of Hensen's cells; the dye coupling, by injecting Lucifer yellow electrophoretically into the hair cells or the supporting cells and investigating its spread to the neighboring cells. The electrical recordings were made by means of microelectrodes filled with either 1.5 or 3 M KCl or 1 M LiCl with 6% Lucifer yellow, the latter used for dye injection. The electrode resistances ranged from about 20 to 60 M omega in the first instance, and from about 50 to 110 M omega, in the second. The electrodes were inserted into the organ of Corti through scala media according to the method of Dallos, Santos-Sacchi and Flock (1982) modified by us. The alternating potential in Hensen's cells was usually larger than in the outer tunnel of Corti and remained practically constant up to the outer margin of the Hensen's-cell population. Its phase was the same as in the outer hair cells. When the dye was injected into a Hensen's cell, it always spread to neighboring Hensen's cells and often to Deiter's cells. Dye injected into outer hair cells (identified according to anatomical and physiological criteria) also spread to Deiter's and Hensen's cells and, usually, to other outer hair cells. Stained cells were identified in surface preparations and, on two occasions, in serial sections from plastic embedded cochleas.

Animals↗

PubMed1993

Electrophysiologic variables characterizing the induction of ventricular tachycardia versus ventricular fibrillation after myocardial infarction: relation between ventricular late potentials and coupling intervals for the induction of sustained ventricular tachyarrhythmias.

OBJECTIVES: The aim of this study was to analyze the relations between the presence of ventricular conduction delay and the necessary coupling intervals for the induction of sustained ventricular tachyarrhythmias. METHODS: The electrophysiologic and signal-averaged electrocardiographic (ECG) data from 83 patients with previous myocardial infarction and inducible sustained monomorphic ventricular tachycardia (n = 71) and ventricular fibrillation (n = 12) were analyzed. RESULTS: The sum of the coupling intervals needed for inducing ventricular tachycardia and ventricular fibrillation was 485 +/- 59 ms and 387 +/- 36 ms, respectively (p < 0.001). The mean difference between the effective refractory period and the second coupling interval for the induction of ventricular tachycardia and ventricular fibrillation was -3 +/- 40 ms and 24 +/- 29 ms, respectively (p < 0.02). QRS duration and duration of terminal low amplitude signals of the QRS complex (p < 0.004) were longer in patients with inducible ventricular tachycardia than in patients with inducible ventricular fibrillation. The root mean square of the voltage during the last 40 ms of QRS complex was lower in patients with inducible ventricular tachycardia than in patients with inducible ventricular fibrillation (p < 0.007). Patients with inducible ventricular tachycardia presented with a greater prevalence of ventricular late potentials than that of patients with inducible ventricular fibrillation (p < 0.007). For arrhythmia induction, significantly shorter coupling intervals were necessary in patients without than in patients with ventricular late potentials. A positive correlation was found between the cycle length of the induced ventricular tachycardia and the filtered QRS duration as well as with the sum of the coupling intervals. CONCLUSIONS: Induction of ventricular fibrillation requires shorter coupling intervals than does induction of ventricular tachycardia. The presence of ventricular conduction delay seems to be a marker of facilitated induction of sustained monomorphic ventricular tachycardia rather than of ventricular fibrillation. The coupling intervals required to induce ventricular tachycardia or fibrillation are longer in patients with than in those without an abnormal signal-averaged ECG.

Adult↗

PubMed1994

Relation between ventriculoarterial coupling and myocardial energetics in patients with idiopathic dilated cardiomyopathy.

OBJECTIVES: The purpose of this study was to evaluate left ventricular contractility, arterial loading conditions and the way their interaction affects myocardial energetics. BACKGROUND: Ventriculoarterial coupling, defined as the ratio of effective arterial elastance to left ventricular end-systolic elastance, is known to reflect the mechanoenergetic performance of the heart. However, relations between the coupling and efficiencies of energy transfer from oxygen consumption to hydraulic energy have not been fully investigated in failing hearts. METHODS: Pressure-volume data were measured in 23 patients with idiopathic dilated cardiomyopathy by using a conductance catheter, and myocardial oxygen consumption was obtained simultaneously in 16 patients by a double-thermistor coronary sinus catheter. End-systolic elastance was determined by transient inferior cava occlusion. RESULTS: Data are reported as mean value +/- SE. Ventriculoarterial coupling at baseline was 3.24 +/- 0.28. It decreased from 3.12 +/- 0.43 to 1.86 +/- 0.15 (p < 0.05) for the group receiving dobutamine infusion and from 3.16 +/- 0.45 to 1.78 +/- 0.22 (p < 0.01) for the group receiving the oral phosphodiesterase inhibitor MS-857. The ratio of pressure-volume area to myocardial oxygen consumption had a positive correlation with ventriculoarterial coupling. The ratio of external work to pressure-volume area had a hyperbolic correlation with the coupling. The mechanical efficiency defined as the ratio of external work to myocardial oxygen consumption remained within a narrow range (16.4 +/- 1.2%). CONCLUSIONS: The degree of ventriculoarterial coupling is far from optimal and the cardiovascular performance is severely depressed mechanically and energetically in patients with idiopathic dilated cardiomyopathy. Although inotropic agents improve the coupling, they have a minimal effect on mechanical efficiency.

Cardiac Catheterization↗

PubMed2004

Loss of synchronization in partially coupled Hodgkin-Huxley equations.

We study the loss of synchronization of two partially coupled space-clamped Hodgkin-Huxley equations, with symmetric coupling. This models the coupling of two cells through an electrical synapse. For strong enough coupling it is known that all solutions of the equations approach a state where the two cells are perfectly synchronized, having the same behaviour at each moment. We describe the local bifurcations that arise when the coupling strength is reduced, using a mixture of analytical and numerical methods. We find that perfect synchrony is retained for very small positive values of the coupling strength, for almost all initial conditions. Although perfect synchrony is lost for negative values of the coupling constant, the system always retains some degree of synchronization until it becomes totally unstable. This happens in two ways: in many cases for almost all initial conditions the solutions still approach a perfectly synchronized state. Even when this is not true, the attracting solutions are still synchronized, with a half-period phase shift.

Kinetics↗

PubMed2005

Changes in foot and lower limb coupling due to systematic variations in step width.

BACKGROUND: Motion at the midfoot joints can contribute significantly to overall foot motion during gait. However, there is little information regarding the kinematic coupling relationship at the midfoot. The purpose of the present study was to determine whether the coupling relationship at the midfoot and subtalar joints was affected when step width was manipulated during running. METHODS: Twelve subjects ran over-ground at self-selected speeds using three different step widths (normal, wide, cross-over). Coupling at the midfoot (forefoot relative to rearfoot) and subtalar (rearfoot relative to shank) joints was assessed using cross-correlation techniques. FINDINGS: Rearfoot kinematics were significantly different from normal running in cross-over running (P<0.05) but not in wide running. However, coupling between rearfoot eversion/inversion and shank rotation was consistently high (r>0.917), regardless of step width. This was also the case for coupling between rearfoot frontal plane motion and forefoot sagittal plane (r<-0.852) and forefoot transverse plane (r>0.946) motion. There was little evidence of coupling between rearfoot frontal plane motion and forefoot frontal plane motion in any of the conditions. INTERPRETATION: Forefoot frontal plane motion appeared to have little effect on rearfoot frontal plane motion and thus, had no effect on motion at the subtalar joint. The strong coupling of forefoot sagittal and transverse plane motions with rearfoot frontal plane motion suggests that forefoot motion exerts an important influence on subtalar joint kinematics.

Adult↗

PubMed2006

Doxorubicin coupled to lactosaminated albumin: Effects on rats with liver fibrosis and cirrhosis.

BACKGROUND: The conjugate of doxorubicin with lactosaminated human albumin has the potential of increasing the doxorubicin efficacy in the treatment of hepatocellular carcinomas expressing the asialoglycoprotein receptor. However, coupled doxorubicin also accumulates in the liver, which might damage hepatocytes. AIMS: To verify whether coupled doxorubicin impairs liver function in rats with liver fibrosis and cirrhosis. METHODS: Coupled doxorubicin was administered using the same schedule which exerted an antineoplastic effect on rat hepatocellular carcinomas (4-weekly injections of doxorubicin at 1 microg/g). Liver fibrosis/cirrhosis was produced by carbon tetrachloride (CCl4) poisoning. Liver samples were studied histologically. Serum parameters of liver function and viability were determined. RESULTS: In normal rats, administration of coupled doxorubicin neither caused microscopic changes of hepatocytes nor modified serum liver parameters. In rats with fibrosis/cirrhosis, although a selective doxorubicin accumulation within the liver followed coupled doxorubicin administration, the drug did not have a detrimental effect on the histology of the liver and, among serum liver tests, only alanine aminotransferase and aspartate aminotransferase levels were moderately modified. CONCLUSIONS: Coupled doxorubicin can be administered to rats with liver fibrosis/cirrhosis without inducing a severe liver damage. If further studies will confirm the efficacy and safety of this compound, coupled doxorubicin therapy may open a new perspective in the treatment of hepatocellular carcinoma.

Animals↗