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1.
Am J Transplant ; 17(7): 1802-1812, 2017 Jul.
Article in English | MEDLINE | ID: mdl-28117941

ABSTRACT

Heart transplantation is the therapy of choice for end-stage heart failure. However, hemodynamic instability, which has been demonstrated in brain-dead donors (BDD), could also affect the posttransplant graft function. We tested the hypothesis that treatment of the BDD with the dopamine derivate n-octanoyl-dopamine (NOD) improves donor cardiac and graft function after transplantation. Donor rats were given a continuous intravenous infusion of either NOD (0.882 mg/kg/h, BDD+NOD, n = 6) or a physiological saline vehicle (BDD, n = 9) for 5 h after the induction of brain death by inflation of a subdural balloon catheter. Controls were sham-operated (n = 9). In BDD, decreased left-ventricular contractility (ejection fraction; maximum rate of rise of left-ventricular pressure; preload recruitable stroke work), relaxation (maximum rate of fall of left-ventricular pressure; Tau), and increased end-diastolic stiffness were significantly improved after the NOD treatment. Following the transplantation, the NOD-treatment of BDD improved impaired systolic function and ventricular relaxation. Additionally, after transplantation increased interleukin-6, tumor necrosis factor TNF-α, NF-kappaB-p65, and nuclear factor (NF)-kappaB-p105 gene expression, and increased caspase-3, TNF-α and NF-kappaB protein expression could be significantly downregulated by the NOD treatment compared to BDD. BDD postconditioning with NOD through downregulation of the pro-apoptotic factor caspase-3, pro-inflammatory cytokines, and NF-kappaB may protect the heart against the myocardial injuries associated with brain death and ischemia/reperfusion.


Subject(s)
Brain Death , Dopamine/analogs & derivatives , Heart Transplantation/methods , Ischemic Preconditioning , Reperfusion Injury/prevention & control , Tissue Donors , Ventricular Function, Left/physiology , Animals , Caspase 3/metabolism , Dopamine/pharmacology , Interleukin-6/metabolism , Male , NF-kappa B/metabolism , Rats , Rats, Inbred Lew , Tumor Necrosis Factor-alpha/metabolism , Ventricular Function, Left/drug effects
2.
Transl Psychiatry ; 6: e807, 2016 05 10.
Article in English | MEDLINE | ID: mdl-27163208

ABSTRACT

Genetic studies have linked the primate-specific gene locus G72 to the development of schizophrenia and bipolar disorder. Transgenic mice carrying the entire gene locus express G72 mRNA in dentate gyrus (DG) and entorhinal cortex, causing altered electrophysiological properties of their connections. These transgenic mice exhibit behavioral alterations related to psychiatric diseases, including cognitive deficits that can be reversed by treatment with N-acetylcysteine, which was also found to be effective in human patients. Here, we show that G72 transgenic mice have larger excitatory synapses with an increased amount of N-methyl-d-aspartate (NMDA) receptors in the molecular layer of DG, compared with wild-type littermates. Furthermore, transgenic animals have lower number of dentate granule cells with a parallel, but an even stronger decrease in the number of excitatory synapses in the molecular layer. Importantly, we also show that treatment with N-acetylcysteine can effectively normalize all these changes in transgenic animals, resulting in a state similar to wild-type mice. Our results show that G72 transcripts induce robust alterations in the glutamatergic system at the synaptic level that can be rescued with N-acetylcysteine treatment.


Subject(s)
Carrier Proteins/genetics , Dentate Gyrus/metabolism , Entorhinal Cortex/metabolism , Schizophrenia/genetics , Acetylcysteine/pharmacology , Animals , Dentate Gyrus/drug effects , Dentate Gyrus/physiopathology , Entorhinal Cortex/drug effects , Entorhinal Cortex/physiopathology , Free Radical Scavengers/pharmacology , Humans , Intracellular Signaling Peptides and Proteins , Mice , Mice, Transgenic , RNA, Messenger/metabolism , Receptors, N-Methyl-D-Aspartate/metabolism , Schizophrenia/metabolism , Synapses/metabolism
3.
Eur J Vasc Endovasc Surg ; 46(2): 242-8, 2013 Aug.
Article in English | MEDLINE | ID: mdl-23751217

ABSTRACT

OBJECTIVE: Based upon the well known protective effect of intracellular cyclic guanosine monophosphate (cGMP) accumulation, we tested the hypothesis that storage solution enriched with optimal concentration of the phosphodiestherase-5 inhibitor vardenafil could provide better protection of vascular grafts against reperfusion injury after long-term cold ischaemic storage. METHODS: Isolated thoracic aorta obtained from rats underwent 24-h cold ischaemic preservation in physiological saline or vardenafil (10(-11) M)-supplemented saline solution. Reperfusion injury was simulated by hypochlorite (200 µM) exposure for 30 minutes. Endothelium-dependent vasorelaxation was assessed, and histopathological and molecular-biological examination of the aortic tissue were performed. RESULTS: Compared with the control group, the saline group showed significantly attenuated endothelium-dependent maximal relaxation (Rmax) to acetylcholine after hypoxia-reoxygenation, which was significantly improved by vardenafil supplementation (Rmax control: 98 ± 1%; saline: 48 ± 6%; vardenafil: 75 ± 4%; p < .05). Vardenafil treatment significantly reduced DNA strand breaks (control: 10.6 ± 6.2%; saline: 72.5 ± 4.0%; vardenafil: 14.2 ± 5.2%; p < .05) and increased cGMP score in the aortic wall (control: 8.2 ± 0.6; saline: 4.5 ± 0.3; vardenafil: 6.7 ± 0.6; p < .05). CONCLUSIONS: Our results support the view that impairment of intracellular cGMP signalling plays a role in the pathogenesis of the endothelial dysfunction induced by cold storage warm reperfusion, which can be effectively reversed by pharmacological phosphodiesterase-5 inhibition.


Subject(s)
Aorta, Thoracic/drug effects , Endothelium, Vascular/drug effects , Imidazoles/pharmacology , Organ Preservation Solutions/pharmacology , Organ Preservation/methods , Phosphodiesterase 5 Inhibitors/pharmacology , Piperazines/pharmacology , Reperfusion Injury/prevention & control , Vascular Grafting , Vascular System Injuries/prevention & control , Animals , Aorta, Thoracic/metabolism , Aorta, Thoracic/pathology , Aorta, Thoracic/physiopathology , Aorta, Thoracic/transplantation , Apoptosis/drug effects , Cold Ischemia , Cyclic GMP/metabolism , Cytoprotection , DNA Damage , Dose-Response Relationship, Drug , Endothelium, Vascular/metabolism , Endothelium, Vascular/pathology , Endothelium, Vascular/physiopathology , Endothelium, Vascular/transplantation , Gene Expression Regulation/drug effects , Male , Rats , Rats, Sprague-Dawley , Reperfusion Injury/etiology , Reperfusion Injury/metabolism , Reperfusion Injury/pathology , Reperfusion Injury/physiopathology , Sulfones/pharmacology , Time Factors , Triazines/pharmacology , Vardenafil Dihydrochloride , Vascular Grafting/adverse effects , Vascular System Injuries/etiology , Vascular System Injuries/metabolism , Vascular System Injuries/pathology , Vascular System Injuries/physiopathology , Vasoconstriction/drug effects , Vasoconstrictor Agents/pharmacology , Vasodilation/drug effects , Vasodilator Agents/pharmacology
4.
Phys Rev Lett ; 85(5): 932-5, 2000 Jul 31.
Article in English | MEDLINE | ID: mdl-10991442

ABSTRACT

Lattice results show no standard model (SM) electroweak phase transition (EWPT) for Higgs masses approximately 72 GeV, which is below the present experimental limit. Perturbation theory and 3-dimensional simulations indicate an EWPT in the minimal supersymmetric SM (MSSM) that is strong enough for baryogenesis up to m(h) approximately 105 GeV. In this Letter we present the results of our large scale 4-dimensional MSSM EWPT simulations. We carried out infinite volume and continuum limits and found a transition whose strength agrees well with perturbation theory, allowing MSSM electroweak baryogenesis at least up to m(h) = 103+/-4 GeV. We determined the properties of the bubble wall.

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