Browsing by Subject "cardioprotection"
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Item INTERMITTENT HYPOXIA CONDITIONING REDUCES INOS AND ENOS EXPRESSION IN RAT MYOCARDIUM: A MECHANISM FOR PROTECTION FROM ISCHEMIA AND REPERFUSION INJURY(2014-03) Downey, H. Fred; Manukhina, Eugenia B.; Goryacheva, Anna V.; Belkina, Ludmila M.; Terekhina, Olga L.; Mallet, Robert T.During a heart attack, the heart produces excessive amounts of harmful chemicals. This study showed that prior exposure of rats to short cycles of a low oxygen atmosphere reduced production of these chemicals and lessened the damage to muscle and blood vessels of the heart. This procedure may benefit humans at risk of heart attack. Purpose (a): Recently we demonstrated that intermittent, normobaric hypoxia conditioning (IHC) prevented injuries of myocardium and coronary blood vessels induced by myocardial ischemia and reperfusion (IR). This cardio- and vasoprotection of was associated with alleviation of nitric oxide overproduction. The aim of this study was to identify specific NO synthases responsible for the IR-induced NO overproduction and to determine the effects of IHC on these NO synthases. Methods (b): This research was approved by the Animal Care and Use Committee of the Institute of General Pathology and Pathology. IHC of rats was performed in a normobaric chamber (5-8 cycles/d for 20 d, FIO2 9.5 - 10% for 5 - 10 min/cycle, with intervening 4-min normoxia). IR was produced by ligation of the left anterior descending coronary artery for 30 min followed by 60-min reperfusion. The protein nitration marker, nitrotyrosine (3-NT) and neuronal (nNOS), inducible (iNOS), and endothelial (eNOS) nitric oxide synthases were measured by immunoblot. Results (c): IR induced appreciable 3-NT accumulation in the left ventricular free wall, increasing the 3-NT content by 42% (p<0.01), but not in septum. In IHC rats, 3-NT after IR was similar to that of control rats without IR. IHC decreased iNOS by 71% (p<0.05) and eNOS by 41% (p<0.05) in the left ventricular myocardium; the myocardial content of nNOS remained unchanged. Conclusions (d): IHC prevents IR-induced NO overproduction in myocardium by restricting myocardial expression of iNOS and eNOS.Item Intermittent hypoxia induced opioidergic protection of the heart(2015-08-01) Estrada, Juan A.; Robert T. Mallet; Steve W. Mifflin; J. Thomas CunninghamNormobaric intermittent hypoxia conditioning (IHC) induces a robust cardioprotected phenotype in dogs that is remarkably resistant to ischemia and reperfusion induced myocardial infarction and lethal arrhythmias. Previous studies demonstrated that IHC induced cardioprotection requires β1-adrenergic receptor activity. Cardiac opioid systems are stimulated by, and counteract the harmful effects of, excessive stressors such as sympathetic activity. Additional modes of hypoxic conditioning have been shown to induce synthesis of cardiac enkephalins and delta opioid receptors (DOR). The hypothesis that DOR mediates IHC cardioprotection was examined in two studies conducted in intermittent hypoxia conditioned and non-hypoxic sham dogs. For the first study dogs were assigned to groups subjected to non-hypoxic sham conditioning, IHC, IHC plus the aminothiol antioxidant N-acetylcysteine (NAC), and IHC plus the DOR antagonist naltrindole. After IHC or sham conditioning, the dogs were subjected to an left anterior descending coronary artery occlusion/reperfusion protocol and incidence of reperfusion arrhythmias and myocardial infarct size were measured and adjusted for coronary collateral flow. Naltrindole and NAC abolished the anti-infarct and anti-arrhythmia effects of IHC, in a manner independent of collateral blood flow. Intermittent hypoxia conditioning is thus dependent on DOR activity as well as formation of reactive oxygen species (ROS) during cylic hypoxia-reoxygenation. Whether ROS are generated upstream, downstream, or in parallel to DOR activation remains to be determined. DORs are abundant on dog parasympathetic nerves and therefore are ideally positioned to stimulate cardioprotective cholinergic activity. However it is unknown in what direction IHC modulates bimodal DORs, i.e. modulation of synaptic inhibitory or excitatory activity. In the second study dogs were assigned to sham conditioned, IHC, and IHC plus naltrindole groups. IHC resulted in a profound enhancement of vagal bradycardia, in the absence and presence of increasingly vagolytic doses of the DOR agonist MEAP. This result demonstrated that IHC shifts DOR signaling in favor of the vagotonic DOR-1 receptor subtype. However, the fate of the vagolytic DOR-2 receptors was unknown. Immunolabeling of atrial tissue revealed that IHC increased content of the monosialoganglioside GM1 in autonomic nerve fibers associated with parasympathetic fibers, an effect which may shift DOR signaling in favor of the DOR-1 subtype. In addition, IHC increased the number of fibers containing the vesicular acetylcholine transporter within the sinoatrial node. However, DOR positive fibers in both the atria and SAN were decreased after IHC, perhaps reflecting redistribution or intracellular trafficking of DOR1 and/or DOR2 receptors. Immunoblotting revealed decreased content of adrenergic protein tyrosine hydroxylase in the left ventricle following IHC. Collectively, these results indicate IHC is dependent on opioidergic activity to induce cardioprotection by enhancing cholinergic signaling components at the expense of adrenergic proteins, suggesting IHC-induced shifting of autonomic balance in favor of parasympathetic control of the heart.Item Potential Therapeutic Benefits of Cyclical Blood Flow Restriction Exercise: A Novel Adaptation of Remote Ischemic Preconditioning(2018-05) Sprick, Justin D.; Rickards, Caroline A.; Cunningham, J. Thomas; Mallet, Robert T.; Goulopoulou, StylianiMyocardial infarction and stroke are two major causes of death and disability. As such, novel interventions are needed to reduce the incidence and severity of these events, and improve post-event rehabilitation. I have developed a potentially novel therapy by combining two interventions that independently exert neuro- and cardio-protective effects - exercise and remote ischemic preconditioning (RIPC) - in the form of a unique exercise paradigm, cyclical blood flow restriction exercise (cyclical BFRE). I hypothesized that an acute bout of cyclical BFRE would augment the release of factors that mediate the protection associated with exercise and RIPC when performed independently (nitric oxide and cytokines). A concern about clinical application of BFRE is the potential amplification of the exercise pressor reflex, causing an unsafe rise in arterial pressure. To address this, I further hypothesized that exercise-induced elevations in plasma norepinephrine, arterial pressure, and cerebral blood flow would be 1) attenuated with cyclical blood flow restriction resistance exercise, due to the use of lower workloads, but 2) augmented with cyclical blood flow restriction aerobic exercise, due to increased exercise pressor reflex activation. Fifteen healthy human subjects completed 5 experiments: RIPC, aerobic exercise with and without cyclical blood flow restriction, and resistance exercise with and without cyclical blood flow restriction. A standard thigh cuff pressure of 220 mmHg was used for all restriction protocols. The major findings from these studies are: 1) an acute bout of cyclical BFRE does not increase release of nitric oxide and key anti- and pro-inflammatory cytokines when blood sampling is performed immediately post-exercise, 2) there is high inter-subject variability in the degree of blood flow restriction achieved with a standardized cuff pressure, 3) cyclical blood flow restriction resistance exercise elicits an attenuated increase in sympathetic activity compared to conventional resistance exercise, 4) cyclical blood flow restriction aerobic exercise elicits an exaggerated increase in sympathetic activity compared to conventional aerobic exercise, but the cyclical reperfusions resulted in lower arterial pressures. This work has laid the groundwork for future studies utilizing individualized cuff pressures in both healthy and clinical populations, as well as training studies to assess the long term adaptations that may result from cyclical BFRE.