Donor Preconditioning After the Onset of Brain Death With Dopamine Derivate n-Octanoyl Dopamine Improves Early Posttransplant Graft Function in the Rat.

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.

Addition of vardenafil into storage solution protects the endothelium in a hypoxia-reoxygenation model.

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.

Combined superoxide dismutase mimetic and peroxynitrite scavenger protects against neointima formation after endarterectomy in association with decreased proliferation and nitro-oxidative stress.

OBJECTIVE: Reactive oxygen and nitrogen species (e.g., peroxynitrite) may trigger neointima formation leading to restenosis. In a rat carotid endarterectomy (CEA) model, we investigated the effects of the manganese(III)tetrakis(4-benzoic acid)porphyrin (MnTBAP), a superoxide dismutase (SOD) mimetic and peroxynitrite scavenger on neointima formation. METHODS: CEA was performed in male Sprague-Dawley rats. Animals received either vehicle (control group; n=15) or 15 mg kg(-1) day(-1) MnTBAP intraperitoneally for 3 weeks (treatment group; n=13). Four groups of carotids were analysed: the left, uninjured carotids (sham) and the right, injured carotids (control CEA) from the control group, the right, injured carotids from the treatment group (CEA+MnTBAP) and an additional group of carotids that were harvested 1h following endarterectomy. The analysis of carotid arteries was performed by histology, immunohistochemistry and real-time polymerase chain reaction (PCR). Plasma malondialdehyde (MDA) levels were measured by lipid hydroperoxidase assay. RESULTS: Stenosis rate (10.5+/-8.1% vs. 45.4+/-28.3%), the percentage of proliferating cell nuclear antigen-positive cells (13.4+/-7.1% vs. 23.3+/-11.0%) and nitrotyrosine immunoreactivity (5.8+/-1.9 vs. 8.0+/-2.0) were significantly reduced in the vascular wall of the CEA+MnTBAP group compared with control CEA group. Ratio of Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labelling (TUNEL)-positive nuclei was significantly lower after antioxidant therapy (41.7+/-26.7% vs. 64.9+/-18.5%). Plasma MDA levels increased after endarterectomy (11.7+/-4.8 vs. 4.1+/-2.0 micromol l(-1)) and reduced in the treatment group (3.2+/-2.1 micromol l(-1)). No significant gene regulation after MnTBAP treatment could be noted. CONCLUSIONS: MnTBAP decreased neointima formation, which was associated with reduced vascular smooth muscle cell proliferation and attenuated local and systemic nitro-oxidative stress.

Efficacy of the non-adenosine analogue A1 adenosine receptor agonist (BR-4935) on cardiovascular function after cardiopulmonary bypass.

BACKGROUND: We tested the hypothesis that pharmacological preconditioning with a newly developed, potent non-adenosine analogue A1AdoR agonist (BR-4935) improves biventricular cardiac and endothelial function after cardiopulmonary bypass. METHODS: Twelve anesthetized dogs underwent cardiopulmonary bypass. Dogs were divided into two groups: group 1 (n = 6) received saline vehicle, group 2 (n = 6) received BR-4935 before cardiopulmonary bypass. Biventricular hemodynamic variables were measured using a combined pressure-volume conductance catheter. Coronary blood flow, ATP content, malondialdehyde and myeloperoxidase levels and vasodilatative responses to acetylcholine and sodium nitroprusside were also determined. RESULTS: Administration of the A1AdoR agonist led to a significantly better recovery of left and right ventricular systolic function after 60 minutes of reperfusion. Although the vasodilatative response to sodium nitroprusside was similar in both groups, acetylcholine resulted in a significantly greater increase in coronary blood flow in the BR-4935 group. In addition, the ATP content was significantly higher in the same group. Furthermore, malondialdehyde and myeloperoxidase levels significantly decreased in the A1AdoR group. CONCLUSION: Pharmacological preconditioning with a new, potent non-adenosine analogue A1AdoR agonist improves biventricular function recovery and endothelial function after hypothermic cardiac arrest.

Myocardial protection with the use of L-arginine and N-alpha-acetyl-histidine.

OBJECTIVE: Effective myocardial preservation is an important condition for cardiac surgery, especially in heart transplantation with long ischemia times. During ischemia and reperfusion, myocardial function is altered by cold-induced ischemic injury. Cold-induced ischemic injury is triggered by cold storage and the amino acid histidine, a main component of the storage solution histidine-tryptophan-ketoglutarate (HTK). Cold-induced ischemic injury generates free oxygen radicals in an iron-dependent way. We investigated the efficacy of new modifications with the addition of L-arginine and N-alpha-acetyl-histidine to the well-established HTK solution (Custodiol) using a rat heart transplant model. MATERIALS AND METHODS: Heterotopic transplantation was performed in Lewis rats (n = 20). After 1 hour of ischemic preservation and 1 hour of reperfusion, we assessed myocardial function and energy charge potential. The modifications of HTK solution included the addition of L-arginine, partial replacement of histidine with acetyl-histidine, and reduction of chloride concentration (HTK-1). In a second group, Custodiol served as the control. RESULTS: After 1 hour of reperfusion, left ventricular systolic pressure (106 +/- 33 vs 69 +/- 9 mm Hg; P < .05) and minimum rate of pressure development (dP/dt) (-1388 +/- 627 vs -735 +/- 219 mm Hg/s; P < .05) were significantly higher among the HTK-1 group compared with the control group. Energy charge potential did not differ significantly between the groups. CONCLUSION: This study showed that the novel modified HTK-1 solution improved myocardial contractility and relaxation after heart transplantation.