We investigated the hypothesis that a cardioprotective, antiarrhythmic effect might be obtained by brief ischemia of a remote part of the body before ischemia of the heart. Regional ischemia (RI) was induced in isolated Langendorff-perfused rat hearts: group I, 30-min RI and reperfusion (control hearts; n = 18); group II, 5-min RI before 30-min RI (a reference group of “classic” ischemic preconditioning; n = 12); and group III, ischemic preconditioning with in vivo 10-min limb ischemia (LI) before 30-min RI in the perfused heart ( n = 20). A significant decrease in reperfusion arrhythmia was found in groups II and III compared with group I ( P < 0.02). Release of norepinephrine (NE) and prostacyclin was higher in hearts from animals pretreated with LI ( P < 0.05). Prostacyclin increased in all groups at minute 1 of reperfusion, but there was no correlation to the antiarrhythmic effect. NE increased at the beginning of reperfusion after 30 min of ischemia; this release was significantly diminished after preconditioning with LI ( P < 0.05). We further investigated the role of NE in preconditioning with LI using drug interventions. Pretreatment with exogenous NE protected against tachyarrhythmia. Reserpine given 24 h before LI partially abolished the antiarrhythmic effect of LI preconditioning. However, the α1-adrenoreceptor blocker prazosin did not prevent the effect of LI preconditioning on either ischemic or reperfusion tachyarrhythmia. Therefore, brief ischemia of an extremity protects against reperfusion tachyarrhythmia. One of the humoral mediators involved in this response appears to be NE; others remain to be identified.
PolyADP-ribosylation is a transient posttranslational modification of proteins, mainly catalyzed by poly(ADP-ribose)polymerase-1 (PARP-1). This highly conserved nuclear protein is activated rapidly in response to DNA nick formation and promotes a fast DNA repair. Here, we examine a possible association between polyADP-ribosylation and the activity of neurotrophins and neuroprotective peptides taking part in life-or-death decisions in mammalian neurons. The presented results indicate an alternative mode of PARP-1 activation in the absence of DNA damage by neurotrophin-induced signaling mechanisms. PARP-1 was activated in rat cerebral cortical neurons briefly exposed to NGF-related nerve growth factors and to the neuroprotective peptides NAP (the peptide NAPVSIPQ, derived from the activity-dependent neuroprotective protein ADNP) and ADNF-9 (the peptide SALLRSIPA, derived from the activity-dependent neurotrophic factor ADNF) In addition, polyADP-ribosylation was involved in the neurotrophic activity of NGF-induced and NAP-induced neurite outgrowthindifferentiatingpheochromocytoma12cellsaswellasintheneuroprotectiveactivityofNAPinneuronstreatedwiththeAlzheimer's disease neurotoxin -amyloid. A fast loosening of the highly condensed chromatin structure by polyADP-ribosylation of histone H1, which renders DNA accessible to transcription and repair, may underlie the role of polyADP-ribosylation in neurotrophic activity.
Potential long-term cardioprotection was investigated in an extensive experimental study. Lactobacillus cultivation components (LCC) were administered intravenously in anesthetized rats 1, 7, and 21 days before global ischemia (GI). GI was produced by full stop flow in isolated Langendorff-perfused hearts for 20 min and was followed by reperfusion. Control animals were injected with saline. LCC reduced reperfusion tachyarrhythmia significantly and improved functional recovery of the ischemized rat heart. These beneficial effects were associated with reduction of release of norepinephrine (NE) and prostacyclin at the first minute of reperfusion, activation of myocardial catalase, and overexpression of 70-kDa heat stress protein (HSP-70) at ischemia and reperfusion (P < 0.05). This cardioprotection was documented up to 21 days after a single injection of LCC. Thus Lactobacillus cultivation components are new nontoxic materials that produce marked long-term cardioprotection against ischemia-reperfusion damage. This effect is attributed to an activation of the cellular defense system, manifested by activation of the antioxidant pathway and by expression of protective proteins. NE is involved in this process, and the data also suggest a role for prostacyclin in this model of cardioprotection. The potential of LCC and related compounds working through similar mechanisms in the prevention and therapy of various ischemic heart syndromes should be explored.
Oral administration of Lactobacillus produces marked cardioprotection against ischemia-reperfusion injury. This effect is attributed to activation of the cellular defense system, manifested by activation of the antioxidant pathway, and by expression of protective proteins. Norepinephrine is involved in this process. The results of this study suggest that Lactobacillus, which is generally considered safe, could serve as a basis for the development of a new agent for preventive therapy of various ischemic heart syndromes.
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