PubMed Health⌕ Search

Biomedical subjects

Gábor Szabó

Publications and source records attributed to Gábor Szabó.

At least 19 recordsLinked to original sources

Novel interneuronal network in the mouse posterior piriform cortex.

The neural circuits of the piriform cortex mediate field potential oscillations and complex functions related to integrating odor cues with behavior, affective states, and multisensory processing. Previous anatomical studies have established major neural pathways linking the piriform cortex to other cortical and subcortical regions and major glutamatergic and GABAergic neuronal subtypes within the piriform circuits. However, the quantitative properties of diverse piriform interneurons are unknown. Using quantitative neural anatomical analysis and electrophysiological recording applied to a GAD65-EGFP transgenic mouse expressing GFP (green fluorescent protein) under the control of the GAD65 promoter, here we report a novel inhibitory network that is composed of neurons positive for GAD65-EGFP in the posterior piriform cortex (PPC). These interneurons had stereotyped dendritic and axonal properties that were distinct from basket cells or interneurons expressing various calcium-binding proteins (parvalbumin, calbindin, and calretinin) within the PPC. The GAD65-GFP neurons are GABAergic and outnumbered any other interneurons (expressing parvalbumin, calbindin, and calretinin) we studied. The firing pattern of these interneurons was highly homogenous and is similar to the regular-spiking nonpyramidal (RSNP) interneurons reported in primary sensory and other neocortical regions. Robust dye coupling among these interneurons and expression of connexin 36 suggested that they form electrically coupled networks. The predominant targets of descending axons of these interneurons were the dendrites of Layer III principal cells. Additionally, synapses were found on dendrites and somata of deep Layer II principal neurons and Layer III basket cells. A similar interneuronal subtype was also found in GAD65-EGFP-negative mouse. The extensive dendritic bifurcation at superficial lamina IA among horizontal afferent fibers and unique axonal targeting pattern suggests that these interneurons may play a role in direct feedforward inhibitory and disinhibitory olfactory processing. We conclude that the GAD65-GFP neurons may play distinct roles in regulating information flow and olfactory-related oscillation within the PPC in vivo.

Animals↗

The peroxynitrite decomposition catalyst FP15 improves ageing-associated cardiac and vascular dysfunction.

Overproduction of oxidants and free radicals in ageing tissues induces nitro-oxidative stress, which has recently been implicated in the pathogenesis of cardiovascular dysfunction associated with ageing. Peroxynitrite, a strong cytotoxic oxidant damages proteins and DNA and activates several pathways causing tissue injury, including the peroxynitrite-poly(ADP-ribose) polymerase (PARP) pathway. In this study, we investigated the effectiveness of the peroxynitrite decomposition catalyst FP15 on ageing-associated cardiac and vascular dysfunction. Young and ageing rats were treated with vehicle or FP15 intraperitoneally. Using a microtip Millar pressure catheter we performed left ventricular blood pressure analysis to assess systolic and diastolic function. Endothelium-dependent and -independent vasorelaxation of isolated aortic rings were investigated by using acetylcholine and sodium nitroprusside. Ageing animals showed a marked reduction of systolic and diastolic cardiac function and loss of endothelium-dependent relaxant responsiveness of aortic rings. FP15-treatment significantly improved cardiac performance and endothelial function. Immunohistochemical staining confirmed that FP15 effectively reduced nitrosative stress and prevented the activation of PARP in the aortic wall of ageing rats. Our results demonstrate the importance of endogenous peroxynitrite-overproduction in the pathogenesis of ageing-associated cardiovascular dysfunction. Pharmacological decomposition of peroxynitrite by FP15 may represent a novel therapeutic utility to improve cardiac and vascular dysfunction associated with ageing.

Acetylcholine↗

Poly(ADP-ribose) polymerase inhibition combined with irradiation: a dual treatment concept to prevent neointimal hyperplasia after endarterectomy.

PURPOSE: In a rat model of endarterectomy we investigated the potential role of the peroxynitrite-poly(ADP-ribose) polymerase (PARP) pathway in neointima formation and the effects of irradiation, pharmacologic inhibition of PARP, or combined pharmacologic inhibition of PARP and irradiation on vascular remodeling. METHODS AND MATERIALS: Carotid endarterectomy was performed by incision of the left carotid artery with removal of intima in Sprague-Dawley rats. Six groups were studied: sham-operated rats (n = 10), control endarterectomized rats (n = 10), or endarterectomized rats irradiated with 15 Gy (n = 10), or treated with PARP inhibitor, INO-1001 (5 mg/kg/day) (n = 10), or with combined treatment with INO-1001 and irradiation with 5 Gy (n = 10) or with 15 Gy (n = 10). After 21 days, neointima formation and vascular remodeling were assessed. RESULTS: Neointima formation after endarterectomy was inhibited by postoperative irradiation with 15 Gy and was attenuated by PARP inhibition. However, in parallel to inhibition of neointimal hyperplasia, activation of the peroxynitrite-PARP pathway in the outer vessel wall layers was triggered by postoperative irradiation. Combined pharmacologic PARP inhibition and irradiation with 15 Gy significantly reduced both neointimal hyperplasia and activation of the peroxynitrite-PARP pathway in the outer vessel wall layers. Combination of PARP inhibition and irradiation with 5 Gy was less effective than both PARP inhibition or irradiation with 15 Gy alone. CONCLUSIONS: We conclude, that combined PARP inhibition and irradiation with 15 Gy may be a new dual strategy for prevention of restenosis after surgical vessel reconstruction: combining the strong antiproliferative effect of irradiation and ameliorating irradiation-induced side effects caused by excessive PARP activation.

Animals↗

Complete inhibition of P-glycoprotein by simultaneous treatment with a distinct class of modulators and the UIC2 monoclonal antibody.

P-glycoprotein (Pgp) is one of the active efflux pumps that are able to extrude a large variety of chemotherapeutic drugs from the cells, causing multidrug resistance. The conformation-sensitive UIC2 monoclonal antibody potentially inhibits Pgp-mediated substrate transport. However, this inhibition is usually partial, and its extent is variable because UIC2 binds only to 10 to 40% Pgp present in the cell membrane. The rest of the Pgp molecules become recognized by this antibody only in the presence of certain substrates or modulators, including vinblastine, cyclosporine A (CsA), and SDZ PSC 833 (valspodar). Simultaneous application of any of these modulators and UIC2, followed by the removal of the modulator, results in a completely restored steady-state accumulation of various Pgp substrates (calcein-AM, daunorubicin, and 99mTc-hexakis-2-methoxybutylisonitrile), indicating near 100% inhibition of pump activity. Remarkably, the inhibitory binding of the antibody is brought about by coincubation with concentrations of CsA or SDZ PSC 833 approximately 20 times lower than what is necessary for Pgp inhibition when the modulators are applied alone. The feasibility of such a combinative treatment for in vivo multidrug resistance reversal was substantiated by the dramatic increase of daunorubicin accumulation in xenotransplanted Pgp+ tumors in response to a combined treatment with UIC2 and CsA, both administered at doses ineffective when applied alone. These observations establish the combined application of a class of modulators used at low concentrations and of the UIC2 antibody as a novel, specific, and effective way of blocking Pgp function in vivo.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

Opposite effects of vascular irradiation on inflammatory response and apoptosis induction in the vessel wall layers via the peroxynitrite-poly(ADP-ribose) polymerase pathway.

PURPOSE: We investigated in a surgical rat model of vascular injury the potential role of the peroxynitrite - poly(ADPribose) polymerase (PARP) pathway in inflammatory response and apoptosis induction after vascular gamma irradiation. METHODS: Male Sprague-Dawley rats underwent left carotid endarterectomy with removal of intima: control (n = 10) and were irradiated with 15 Gray (n = 13) or 20 Gray (n = 10) postoperatively and compared with sham-operated rats (n = 10). Additional animals were solely irradiated with 15 Gy (n = 10) and with 20 Gy (n = 10) to distinguish between primary effects of vascular injury and secondary effects due to irradiation. RESULTS: After 21 days, neointima formation was significantly suppressed after irradiation (control: 0.07 mm(2) +/- 0.04 mm(2), 15 Gy: 0.003 mm(2) +/- 0.004 mm(2), 20 Gy: 0.001 mm(2) +/- 0.0006 mm(2), P< 0.0001). However, a significant inflammation of the vessel wall with focal wall necrosis was detected (control: 0.2 +/- 0.15, 15 Gy: 0.82 +/- 1.2, 20 Gy: 1.25 +/- 0.86, P= 0.003). Immunohistochemistry showed significant staining for nitrotyrosine, poly(ADP-ribose) and nuclear translocation of apoptosis-inducing factor in the neointima of the control group. In the irradiated groups these stainings were significantly higher in the media and adventitia compared to the non-irradiated groups. CONCLUSION: Activation of the peroxynitrite-PARP pathway was demonstrated during neointima proliferation in a rat model of surgical vascular injury. Vascular irradiation suppressed neointima formation, but induced significant activation of the peroxynitrite - PARP pathway in the outer vessel wall layers concomitant to inflammation and focal wall necrosis. This may contribute to adverse effects of vascular irradiation such as fibrosis and constrictive remodeling.

Animals↗

Chip-on-beads: flow-cytometric evaluation of chromatin immunoprecipitation.

BACKGROUND: Chromatin immunoprecipitation (ChIP) is a widely used technique for the detection of in vivo DNA-protein interactions underlying epigenetic regulation. The standard readout of ChIP is based on semi-quantitative or quantitative PCR measurements; however, the development of alternative platforms with high throughput potentialities is expected to facilitate the introduction of this method into routine diagnostics. METHODS: We have established a flow-cytometry-based alternative for the evaluation of ChIP data. The method is based on the capture of the products of a conventional PCR run to low cycle numbers, on microbeads. RESULTS: In vivo histone H4 acetylation and H3 lysine 4 methylation was detected at the promoter of the tissue transglutaminase type 2 gene. These results were confirmed by QPCR measurements. The levels of modifications decreased significantly upon apoptosis and were accompanied by the down-regulation of TGM2 mRNA expression. CONCLUSIONS: This method that we named ChIP-on-beads, a combination of flow cytometry and conventional PCR, is a reliable and efficient alternative in the quantitative analysis of ChIP results, especially promising when high throughput monitoring of epigenetic markers of diagnostic importance is required. The method is simple enough to be easily implemented in a routine flow-cytometric laboratory.

Acetylation↗

Properties of a population of GABAergic cells in murine auditory cortex weakly excited by thalamic stimulation.

Feedforward inhibition triggered by thalamocortical (TC) afferents sharpens onset responses and shapes receptive fields of pyramidal cells in auditory cortex (ACx). Previous studies focused only on interneurons located in and around layer IV in primary ACx, target of the dense thalamic projections from ventral medial geniculate. We investigated a population of feedforward interneurons located throughout layers I-V and activated by both afferents from primary and nonprimary thalamus using recordings from auditory TC brain slices obtained from mice expressing green fluorescent protein under control of the glutamic acid decarboxylase (GAD65) promoter in a subpopulation of cortical GABAergic cells. We studied the responses of these interneurons and of pyramidal cells in ACx to thalamic stimulation and to hyper- and depolarizing current pulses. Most interneurons exhibited monosynaptic responses to thalamic stimulation, but this excitation was weak and subthreshold. Interneurons had multipolar dendritic morphology with widespread and dense axonal projections extending several hundred micrometers from the soma. In pyramidal cells from layers II-IV, thalamic excitatory postsynaptic potentials were significantly larger than in interneurons and were superthreshold in 40% of cells, but in these cells, there was no evidence of feedforward inhibition. By contrast, feedforward inhibition was observed in 12 of 18 layer V pyramidal cells. Thus feedforward inhibition in supragranular layers of ACx is weak, and these interneurons require coincident excitation to be activated by thalamic inputs.

Animals↗

Follow-up analysis of pregnancies complicated by HELLP syndrome.

AIM: In this study, we investigated the course of subsequent pregnancies in patients with HELLP syndrome and the development of chronic maternal diseases. RESULTS: The study population consisted of 50 patients who were treated for HELLP syndrome at 1(st) Department of Obstetrics and Gynecology, Semmelweis University between January 1, 1995 and December 31, 2004. There were 35 subsequent pregnancies in 25 patients. Of these there were seven miscarriages, one mid-trimester loss. The incidence of premature birth was 40.7%, and neonatal mortality 7.4%. Preeclampsia recurred in twelve pregnancies; it was mild in eight and severe in four cases. HELLP syndrome re-occurred four times in three patients (14.28%). Recurrent hypertension was observed in 24% of the pregnancies. CONCLUSIONS: Pregnancies after a previous pregnancy complicated by HELLP syndrome carry not only an increased chance for HELLP syndrome but also the development of other pathological obstetric conditions and chronic maternal diseases. Hypertension was found to be a maternal disease of increased incidence (24%) in subsequent pregnancies.

Adult↗

Poly(ADP-ribose) polymerase inhibition reverses vascular dysfunction after gamma-irradiation.

PURPOSE: The generation of reactive oxygen species during gamma-irradiation may induce DNA damage, leading to activation of the nuclear enzyme poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) culminating in endothelial dysfunction. In the present study, we assessed the effect of PARP inhibition on changes in vascular function after acute and short-term irradiation. METHODS AND MATERIALS: In the acute experiments, aortic rings were exposed to 20 Gy of gamma-irradiation. The aortae were harvested after 1 or 7 days. Two additional groups received the ultrapotent PARP inhibitor, INO-1001, for 1 or 7 days after irradiation. The aortic rings were precontracted by phenylephrine and relaxation to acetylcholine and sodium nitroprusside were studied. RESULTS: The vasoconstrictor response to phenylephrine was significantly lower both acutely and 1 and 7 days after irradiation. Vasorelaxation to acetylcholine and sodium nitroprusside was not impaired acutely after irradiation. One and seven days after irradiation, vasorelaxation to acetylcholine and sodium nitroprusside was significantly enhanced. Treatment with INO-1001 reversed vascular dysfunction after irradiation. CONCLUSION: Vascular dysfunction was observed 1 and 7 days after irradiation, as evidenced by reduced vasoconstriction, coupled with endothelium-dependent and -independent hyperrelaxation. PARP inhibition restored vascular function and may, therefore, be suitable to reverse vascular dysfunction after irradiation.

Acetylcholine↗

[The rate of maternal complications in 107 pregnancies complicated with HELLP syndrome].

INTRODUCTION: HELLP syndrome (Haemolysis, Elevated Liver enzymes, Low platelet count) is a grave, life threatening form of preeclampsia, which was named by Weinstein in 1982, on the basis of characteristic changes in laboratory findings (haemolysis, elevated level of liver enzymes and thrombocytopenia). OBJECTIVE OF THE STUDY: To assess the rate of maternal complications in HELLP syndrome. MATERIAL AND METHODS: In the past ten years, 107 patients were treated for HELLP syndrome at the Intensive Care Unit (ICU) of the 1st Department of Obstetrics and Gynaecology, Semmelweis University. The authors summed up about their experience with the treatment of patients, with special regard to the typical symptoms of HELLP syndrome, the course of the disease, postpartum maternal complications. RESULTS: The frequency of HELLP syndrome in live births was found to be 0.37%. In 96% of the patients the pregnancy was terminated via Caesarean section. Pulmonary oedema was the most common cardiopulmonary complication (11%) and developed in Mississippi Group I in the majority of the cases (21%). Transfusions had to be given quite frequently; 62% of the patients in the study were transfused using erythrocyte preparations. In persistent or progressive cases in the postpartum period, the elimination (uterine curettage and lavage) of factors responsible for the persistence of the disease (toxic and vasoactive agents in the endometrium) resulted in the recovery of one third of the patients. Maternal thromboembolic complications developed in 11% of the patients, each of them was affected in Mississippi Group I, with the lowest platelet count. CONCLUSIONS: The immediate termination of a pregnancy in which HELLP syndrome emerges may save the patient's life. It is recommended to try and lift foci applying uterine curettage and lavage as the first step, if the mothers' condition persists or progresses after delivery. Its development is accompanied by a significant increase in maternal and fetal morbidity and mortality alike, therefore it is essential for the obstetricians to be familiar with the disease.

Adult↗

L-arginine improves endothelial and myocardial function after brain death.

BACKGROUND: Recently, we showed that brain death (BD) leads to a severe impairment of endothelial function. METHODS: To test the hypothesis, that nitric oxide supply improves endothelial function, we infused L-arginine (40 mg/kg) in 6 dogs after BD induction (subdural balloon). Six vehicle-treated BD animals served as controls. Coronary blood flow (CBF), preload recruitable stroke work (PRSW), and plasma L-arginine and nitrite/nitrate levels were measured before and 6 hr after BD induction. In addition, endothelium-dependent vasodilatation after intracoronary application of acetylcholine (ACH) and endothelium-independent vasodilation after sodium nitroprusside (SNP) were assessed. RESULTS: Six hours after BD, CBF decreased significantly in the control group (38.2+/-3.5 vs. 26.8+/-3.1 ml/min, P<0.05), whereas the decrease was less pronounced in the L-arginine group (41.8+/-6.9 vs. 36.0+/-1.2 ml/min, P<0.05 vs. control). Before BD, ACH led to a similar vasodilative response in both groups (81+/-6 vs. 75+/-7%). After BD, a paradox vasoconstriction occurred after ACH in the control group, while the vasodilative response did not change in the L-Arginine group (36+/-6 vs. 69+/-7%, P<0.05). The response to SNP did not differ between the groups and over the time. After BD PRSW decreased in both groups, however, it was still significantly higher in the L-arginine group (56+/-7 vs. 71+/-7 kerg, P<0.05). L-arginine (711+/-144 vs. 234+/-54 microM P<0.05) and nitrite/nitrate (39+/-3 vs. 27+/-3 microM P<0.05) levels were significantly higher in the L-arginine group. CONCLUSION: L-arginine treatment prevents endothelial dysfunction and improves myocardial performance after BD via enhancement of endogenous nitric oxide synthesis.

Animals↗

Effects of inosine on reperfusion injury after heart transplantation.

OBJECTIVE: Inosine, a break-down product of adenosine, has been recently shown to exert inodilatory and anti-inflammatory properties. We investigated the effects of inosine on ischemia/reperfusion injury in a rat heart transplantation model. METHODS: Intraabdominal heterotopic transplantation was performed in Lewis rats. After 1h of ischemic preservation, reperfusion was started after application of either saline vehicle (control, n=12) or inosine (100 mg/kg, n=12). Coronary blood flow, left ventricular function, endothelium-dependent vasodilatation to acetylcholine and endothelium-independent vasodilatation to sodium nitroprusside, and high energy phosphate content were measured after 1 and 24h of reperfusion. In addition, the activation of the poly(ADP-ribose) polymerase was detected by immunhistology. RESULTS: After 1h, coronary blood flow (4.1+/-0.3 ml/(ming) vs 2.9+/-0.3 ml/(ming), p<0.05), left ventricular systolic pressure (102+/-9 mmHg vs 83+/-4 mmHg, p<0.05) and dP/dt (2765+/-609 mmHg/s vs 1740+/-116 mmHg/s, p<0.05) were significantly higher in the inosine group in comparison to control. Vasodilatatory response to sodium nitroprusside was similar in both groups. Acetylcholine resulted in a significantly higher increase in coronary blood flow in the inosine group (76+/-5% vs 48+/-9%, p<0.05). Energy charge potential was significantly higher in the inosine group (1.69+/-0.10 micromol/g vs 0.74+/-0.27 micromol/g, p<0.05). After 24h, there was no difference between the groups in basal coronary blood flow, left ventricular systolic pressure, dP/dt, and the response to sodium nitroprusside. However, acetylcholine led to a still significantly higher response in the inosine group (112+/-13% vs 88+/-7%, p<0.05). Immunhistologic stainings revealed activation of poly(ADP-ribose) polymerase in control animals which was abolished by inosine. CONCLUSIONS: Thus, inosine improves myocardial and endothelial function during early reperfusion after heart transplantation with a persisting beneficial effect against reperfusion induced graft coronary endothelial dysfunction. The effects of inosine are mediated at least partly by modulation of the peroxynitrite-poly(ADP-ribose) polymerase pathway.

Animals↗

A protein-protein interaction network for human inherited ataxias and disorders of Purkinje cell degeneration.

Many human inherited neurodegenerative disorders are characterized by loss of balance due to cerebellar Purkinje cell (PC) degeneration. Although the disease-causing mutations have been identified for a number of these disorders, the normal functions of the proteins involved remain, in many cases, unknown. To gain insight into the function of proteins involved in PC degeneration, we developed an interaction network for 54 proteins involved in 23 inherited ataxias and expanded the network by incorporating literature-curated and evolutionarily conserved interactions. We identified 770 mostly novel protein-protein interactions using a stringent yeast two-hybrid screen; of 75 pairs tested, 83% of the interactions were verified in mammalian cells. Many ataxia-causing proteins share interacting partners, a subset of which have been found to modify neurodegeneration in animal models. This interactome thus provides a tool for understanding pathogenic mechanisms common for this class of neurodegenerative disorders and for identifying candidate genes for inherited ataxias.

Animals↗

Paclitaxel modifies the accumulation of tumor-diagnostic tracers in different ways in P-glycoprotein-positive and negative cancer cells.

AIM: To study how paclitaxel treatment modifies the accumulation of tumor-diagnostic radiotracers in P-glycoprotein (P-gp) positive and negative cancer cells. METHODS: The accumulations of different P-gp substrates, including rhodamine 123, daunorubicin and [(99m)Tc]hexakis-2-methoxybutyl isonitrile ((99m)Tc-MIBI), were measured in P-gp-positive (A2780AD) and P-gp-negative human ovarian carcinoma cells (A2780) and JY human lymphoid B cells. The uptakes of the tumor-diagnostic tracers (11)C-choline and 2-[(18)F]fluoro-2-deoxy-d-glucose ((18)FDG) were measured in the same cell lines. The P-gp expression and function were demonstrated by flow-cytometry. RESULTS: The (18)FDG measurements revealed that the glucose metabolic rate was significantly higher (p<0.01) in the P-gp-positive A2780AD cells than in the P-gp-negative cells. Paclitaxel (1-70microM) increased the (18)FDG uptake (up to 200%) of both P-gp-positive and P-gp-negative cells, whereas it did not modulate their (11)C-choline uptake. Paclitaxel reinstated the (99m)Tc-MIBI accumulation of the A2780AD cells (to 1500% of the control) in a concentration-dependent manner, while it increased the uptake of the P-gp-negative cells to a lesser extent (to a maximum of 200% of the control). CONCLUSION: Paclitaxel modifies the uptake of tumor-diagnostic tracers in both P-gp-dependent and independent manners. Interpretation of the multifactorial effects of paclitaxel may promote a correct in vivo diagnosis of P-gp-positive and P-gp-negative tumors.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

The zinc finger transcription factor Sp8 regulates the generation and diversity of olfactory bulb interneurons.

The molecular mechanisms that regulate the production and diversity of olfactory bulb interneurons remain poorly understood. With the exception of the GABAergic/dopaminergic subtype in the glomerular layer, no information exists concerning the generation of the other subtypes. Here we show that the recently identified zinc finger transcription factor Sp8 is expressed in neurogenic regions, which give rise to olfactory bulb interneurons at embryonic and postnatal time points and remains expressed in the calretinin-expressing and GABAergic/nondopaminergic interneurons of the glomerular layer. Conditional inactivation of Sp8 in the embryonic ventral telencephalon reveals a requirement for the normal generation of these interneuron subtypes. Sp8 conditional mutants exhibit an increase in cell death within the lateral ganglionic eminence and rostral migratory stream. Moreover, mutant neuroblasts/interneurons are misspecified and display abnormal migration patterns in the olfactory bulb, indicating that Sp8 contributes to olfactory bulb interneuron diversity by regulating the survival, migration, and molecular specification of neuroblasts/interneurons.

Animals↗

Adjunct brachytherapy: a new concept to prevent intimal hyperplasia after surgical endarterectomy?

OBJECTIVE: Endarterectomy represents a therapeutical option for patients with advanced coronary artery disease. The mid-term results are compromised by restenosis due to neointima formation. The aim of this study was to evaluate a new treatment concept - endarterectomy with consecutive gamma-irradiation - in a rat model. METHODS: Male Sprague-Dawley rats underwent left carotid endarterectomy with removal of intima: control (n=10) or were irradiated with 15 Gray (Gy) (n=13) or 20 Gy (n=10) postoperatively and compared with sham-operated rats (n=10). After 3 weeks, carotid arteries were perfusion-fixed and vessel compartment areas were measured. Transmission electron microscopy and immunohistochemical staining were used to confirm neointima formation. RESULTS: Three weeks after endarterectomy, neointimal hyperplasia was found in the control group (0.07+/-0.04 mm(2)). After irradiation, a dose-dependent reduction of neointima was observed (0.003 mm(2) at 15 Gy and 0.0007 mm(2) at 20 Gy, P<0.0001). However, immunohistochemical staining revealed that thin re-endothelialization after irradiation was not inhibited. CONCLUSIONS: Gamma-irradiation significantly suppressed neointimal hyperplasia in a rat model of surgical endarterectomy. Despite inhibition of intimal hyperplasia, re-endothelialization after adjuvant brachytherapy was present. Adjuvant brachytherapy may be therefore a new concept to prevent restenosis after endarterectomy in patients.

Animals↗

Adaptation of the right ventricle to an increased afterload in the chronically volume overloaded heart.

BACKGROUND: Increased right ventricular afterload is a common problem after correction of various heart diseases with chronic volume overload. We determined the effects of an acute increase of right ventricular afterload in normal and chronically volume overloaded hearts. METHODS: In 6 dogs, volume overload was induced by chronic arteriovenous shunts for 3 months. Six sham-operated animals served as controls. After closing the shunts, right ventricular systolic and end-diastolic pressure as well as end-diastolic volume were measured by conductance catheter. In addition, pressure-volume loops were recorded. Myocardial contractility was described by the slope of the end-systolic pressure-volume relationship. Afterload was increased to right ventricular systolic pressure to 35 mm Hg and to 50 mm Hg by pulmonary banding. RESULTS: Chronic volume overload resulted in a significant increase of right ventricular systolic pressure (34 +/- 2 versus 25 +/- 2 mm Hg, p < 0.05), end-diastolic pressure (10.4 +/- 1.7 versus 6.8 +/- 0.4 mm Hg, p < 0.05), and end-diastolic volume (39 +/- 2 versus 33 +/- 3 mL, p < 0.05). Baseline contractility (1.47 +/- 0.24 versus 1.53 +/- 0.32 mm Hg/mL) did not differ. While afterload increase to 35 and 50 mm Hg led to stepwise increase in contractility (2.73 +/- 0.30 mm Hg/mL and 4.15 +/- 0.30 mm Hg/mL, p < 0.05 versus baseline, respectively) at unchanged end-diastolic pressure and volume in controls, it showed only a slight increase (2.11 +/- 0.38 mm Hg/mL and 2.99 +/- 0.29 mm Hg/mL, p < 0.05 versus sham) with concomitant increase in end-diastolic pressure (12.4 +/- 2.2 mm Hg/mL and 16.3 +/- 1.9 mm Hg, p < 0.05) and volume (42 +/- 4 mL and 48 +/- 8 mL, p < 0.05) in the chronically volume overloaded group. CONCLUSIONS: Chronic volume overload per se does not impair right ventricular contractility. However, the inotropic adaptation (homeometric autoregulation) to an increased afterload is limited, which is partly compensated by the Frank-Starling mechanism (heterometric autoregulation).

Adaptation, Physiological↗

Immunomodulatory effects of poly(ADP-ribose) polymerase inhibition contribute to improved cardiac function and survival during acute cardiac rejection.

BACKGROUND: Recent studies have suggested that the peroxynitrite-poly(ADP-ribose) polymerase (PARP) pathway is activated during acute allograft rejection. Therefore, we investigated whether PARP inhibition improves transplant outcome and the extent to which immunologic factors contribute to the effects of PARP inhibition. METHODS: Isogeneic Lewis-to-Lewis and allogeneic Dark Agouti (DA)-to-Lewis rat cardiac transplants were studied under treatment with placebo, the PARP inhibitor INO-1001 (1 mg/kg/day), cyclosporine (2.5 or 5 mg/kg/day) or the combination of INO-1001 and low-dose cyclosporine. Functional, biochemical and histologic analyses were performed 3 and 5 days after transplantation in control and INO-1001-treated animals. In addition, stimulated T cells and endothelial cells were treated with INO-1001 to evaluate the potential immunosuppressive effects of PARP inhibition. RESULTS: PARP inhibition alone and in combination with cyclosporine significantly prolonged graft survival. Acute rejection led to a typical sequence of initial endothelial dysfunction and reduced contractile reserve followed by progressive systolic and diastolic dysfunction, which were reduced by PARP inhibition. PARP inhibition led to reduced antigen-specific and non-specific proliferation in stimulated T cells and dose-dependently inhibited intracellular adhesion molecule-1 (ICAM-1) up-regulation in stimulated endothelial cells. CONCLUSIONS: PARP inhibition was found to prolong graft survival and improve cardiac function during acute cardiac rejection. Direct immunosuppressive properties contribute at least partially to the beneficial effects of PARP inhibitors in graft rejection.

Animals↗