Toshio Obata*School of Nursing, Faculty of Health Sciences, Osaka Aoyama University, 2-11-1 Niina, Mino City, Japan
*Address for Correspondence: Toshio Obata, Ph.D. School of Nursing, Faculty of Health Sciences, Osaka Aoyama University, 2-11-1 Niina, Mino City, Japan, Tel & Fax: +81-72-737-6754; Email: firstname.lastname@example.org
Dates:Submitted: 25 July 2018; Approved: 03 August 2018; Published: 06 August 2018
How to cite this article: Obata T. Microdialysis technique for in-vivo monitoring of •OH generation on myocardial injury in the rat. J Cardiol Cardiovasc Med. 2018; 3: 035-048. DOI: 10.29328/journal.jccm.1001025
Copyright: © 2018 Obata T. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Keywords: Hydroxyl radical; Monoamine Oxidase; Noradrenaline; KATP Channel; Microdialysis
Abbreviations: ROS: Reactive Oxygen Species; EPR: Paramagnetic Response; DHBA: Dihydroxybenzoic Acid; HPLC: High-Performance Liquid Chromatography; EPR: Electron Paramagnetic Response; XO: Xanthine Oxidase; MAO: Monoamine Oxidase; NA: Noradrenaline; ACE: Angiotensin-Converting Enzyme; [K+]o: Extracellular Potassium-ion Concentration; KATP: ATP sensitive K+; 5-HD, 5-Hydroxydecanoate; NO: Nitric oxide; NOS: NO synthase; ONOO-: peroxiniterite; L-NAME: NG-nitro-L-arginine Methyl Ester; LDL: Low-density Lipoprotein; HMG-CoA: 3-hydroxy-3-methylglutaryl coenzyme A; 1O2; singlet oxygen; ECG, Electrocardiogram; DOPGAL, 3,4-dihydroxyphenylglycol-aldehyde
The micro dialysis procedure is a technique that has been established for some years. Although free radical reaction is a part of normal metabolism, sustained elevation of noradrenaline (NA) in the extracellular fluid can be autoxidized, which in turn leads (possibly by an in direct mechanism) to the formation of cytotoxic free radicals. Reactive oxygen causes excessive Na+ entry through the fast Ca2+ channel, leading to intracellular Ca2+ overload through the Na+-Ca2+ exchange system. However, the interaction between intracellular Ca2+ overload and oxygen free radicals in myocardium is not clear. Angiotensin converting enzyme (ACE) inhibitor is associated with cardioprotective effect due to suppression of NA-induced hydroxyl radical (•OH) generation in the heart. Low-density lipoprotein (LDL) oxidation may be related to NA induced •OH generation. Although the neuroprotective effects of nitric oxide (NO) is discussed, NO contributes to the extracellular potassium concentration ([K+]o)-induced •OH generation via NO synthase (NOS) activation. Opening of ATP sensitive K+ channel (KATP) channel may cause •OH generation. These finding may be useful in elucidating the actual mechanism of free radical formation in the pathogenesis of heart disorders.
Ischaemia-reperfusion tissue injury is a major pathophysiological process responsible for severe organ damage in human health problems [1-3]. Oxygen-derived free radicals play an important role in several models of experimentally induced reperfusion injury . The deleterious effects of reperfusion of the ischaemic myocardium have been linked to the production of oxygen-derived free radicals . Although free radical reactions are a part of normal metabolism, overproduction or reduced efficiency of defense system towards reactive oxygen species (ROS), such as superoxide anion (O2-), hydrogen peroxide (H2O2) and hydroxyl radical (•OH) may contribute to ischaemia-reperfusion injury [6,7]. An oxygen-derived free radicals such as O2- itself is somewhat poorly reactive in aqueous solution, but does it participates in reactions with iron ions, generating the more damaging •OH . The •OH radicals are extremely reactive and rapidly react with a number of compounds, including lipids, proteins and nuclei acid . It is important to explain the role played by free radicals in some disease states. We developed the flexibly mounted microdialysis technique . This technique has made to it possible not only to collect dialysis samples from interstitial fluid with minimum injury to the cardiac muscles located the probe of the microdialysis system. Therefore, we will demonstrate and discusse the effects of the several drugs of the role of played by radicals in some disease state.
Detection of •OH generation
Although improved colorimetric  and fluorescence based [11,12] assays for measurement of hydroxylated products have been described, complete determination of hydroxylated product formation can be achieved only by use of gas chromatography [10,13] or high-performance liquid chromatography (HPLC) with or UV-or electrochemical (EC) detection, or both .
The •OH react with salicylate and generates 2,3- and 2,5-dihydroxybenzoic acid (DHBA), which can be measured electrochemically in picomoles quantity by an HPLC-EC procedure [15,16]. The in vivo generation of •OH free radicals in myocardium can be measured by in vivo microdialysis perfusion of salicylate, avoiding many of the pitfalls inherent in the systemic administration of salicylate. After minimizing the contribution of enzyme and/or blood-borne 2,5-DHBA, the present data demonstrate the validity of the use of 2,3-DHBA as an index of •OH formation in the heart. Therefore, we focused on the possible use of salicylate hydroxylation as an in vivo trapping procedure for monitoring the time course of 2,3-DHBA generation in the myocardium. However, 2,3-DHBA can be non-enzymatically formed by aromatic hydroxylation [17,18].
Microdialysis technique was recently introduced for in vivo heart experiments to measure interstitial biological substances, such as catecholamine, •OH and purine metabolites . We measured •OH in rat hearts by use of a microdialysis technique. With this technique it was feasible to make stable long-term measurements of •OH. The concentration profile of the administered dialysate is unknown; in general given through the probe would never reach the concentration in the dialysis probe . This is an unavoidable limitation of the microdialysis technique that should be kept in mind when interpreting the experimental data.
We designed a system for holding the microdialysis probe  which includes loose fixation of the tube and synchronization of the probe with that of the heart (Figure 1). Details of the technique necessary for manipulation of the flexibly mounted microdialysis probe in in vivo rat hearts (to measure the 2,3-DHBA) were described previously . We created a suitable microdialysis probe. In brief, the tip of the microdialysis probe (3 mm in length and 220 µm o.d. with the distal end closed) was made a of dialysis membrane (cellulose membrane 10 µm thick, blocking components with molecular weights >50 kDa). Two fine silica tubes (75 µm i.d.) were inserted into the tip of the cylinder shape dialysis probe and one of these served as the inlet for the perfusate and the other as the outlet for the dialysate. The inlet tube was connected to a micro-injection pump, and the outlet tube was led to the dialysate reservoir. These tubes of the dialysis probe (∼15cm long) were supported loosely at the mid-point on a semi-rotatable stainless-steel wire, so that their movement fully synchronized with the rapid up-and-down motion of the tip caused by the heart beats.
The probe was implanted from the epicardial surface into the left ventricular myocardium and was perfused through the inlet tube. For trapping •OH radicals in the myocardium, sodium salicylate in Ringer’s solution was perfused by a micro-injection pump, and the basal level of 2,3-DHBA during a definite time period was determined. In the preparation of ischemic rat heart, after the microdialysis probe implantation in the ischemic zone, the left anterior descending coronary artery (LAD) branch was clamped by a thread through a tube surrounding the coronary artery. The heart was subjected to regional ischemia for 15 min by the occlusion of the LAD coronary artery followed by reperfusion for 60 min. In order to ascertain the protective effect of myocardial infarction and reperfusion damage, the serum creatine phosphokinase (CPK) assay was measured .
Oxygen-derived free radical in post ischaemic tissue injury
It appears likely that free radical production may make a major contribution at certainly stages in the progression of the ischaemic and reperfusion injury . The primary source of superoxide in reperfused reoxygenated tissues appears to be the enzyme xanthine oxidase (XO), released during ischaemia by a calcium-triggered proteolytic attack on xanthine dehydrogenase . Dysfunction induced by free radicals may be a major component of ischaemic disease of the heart. The XO is also thought to be a source of O2-. The O2- itself is somewhat poorly reactive in aqueous solution, but also participate in the reaction in which the iron ions are involved, leading to the generation of more damaging •OH species. Theoretically, •OH may be formed in vivo during non-enzymatic oxidation [23,24] and/or enzymatic oxidation. According to the reaction pathway in Figure 2. •OH was generated by the presence of oxygen. The •OH can be also arise from an interaction between H2O2 and O2- (Haber-Weiss reaction). On the other hand, iron (II) in the presence of H2O2 results in further formation of •OH [25,26]. These results suggest that iron (III) may reduce •OH formation by Fenton reaction in the heart. The suppression of •OH formation by iron (III) may play a key role in the cardioprotective effect of iron (III) on the rat heart . There are other sources of •OH generation. The effect of pargyline, a monoamine oxidase (MAO) inhibitor, on the generation of •OH was confirmed in the rat hearts. The accumulation of noradrenaline (NA) in the extracellular fluid by pargyline can be autoxidized, which in turn, leads (possibly by an indirect mechanism) to the formation of cytotoxic •OH . Based on the mass-action principle, an increase of iron (III) should reverse the Fenton reaction and reduce the •OH production.
Although the mechanism of •OH generation in the ischaemic heart is obscure, a concomitant increase of NA and •OH takes place in myocardial injury. In case of ischaemic arrhythmia appeared, the presence of NA and free radicals was observed in ischaemia-reperfused rat heart . The accumulation of NA in the extracellular fluid by ischaemia-reperfusion can be autoxidized, which in turn leads (possibly by an indirect mechanism) to the formation of •OH radicals . In the presence of iron (III), ischaemia-reperfusion failed to increase in •OH production . The suppression of •OH formation by iron (III) may play a key role in the cardioprotective effect of iron (II) in the heart.
Effect of angiotensin-converting enzyme (ACE) inhibitor
Angiotensin-converting enzyme (ACE) inhibitor is known to have a cardio protective effect by reducing reperfusion arrhythmia [31,32]. It is well known that antihypertensive action of the ACE inhibitor is associated with an inhibition of NA release from peripheral sympathetic neuron . ACE inhibitors cardioprotective effects are associated with suppression of •OH generation [29,34]. It is well known that angiotensin II causes an increase of NA release from peripheral sympathetic neuron . The accumulation of NA may cause cytotoxic •OH generation. The free radical scavenging action of ACE inhibitor (i.e. captopril) is believed to be due to the presence of an SH-group in its structure . Numerous investigators have reported that myocardial ischaemia also increases catecholamine levels [36-38].
The accumulation of NA in the extracellular fluid elicited by ischaemia/reperfusion can be autoxidized, which in turn, leads (possibly by an indirect mechanism) to the formation of cytotoxic •OH radicals. NA release by ischaemia/reperfusion of the myocardium may be associated with oxidant damage in •OH generation. Endogenous angiotensin II may facilitate NA release via presynaptic angiotensin II receptors [39,40] or inhibit NA uptake at synaptic nerve terminals . Rona  documented that catecholamines play an important role in reperfusion and ischaemic myocardial injury, and proposed a common pathway in the pathogenesis of catecholamine-induced and reperfusion myocardial injuries. It is possible that ACE inhibitors may reduce catecholamine release and hence ameliorate myocardial injury. ACE inhibitors have been shown to potentiate the effects of endogenous bradykinin in animal models and in humans . However, the role of bradykinin in therapeutic effects of ACE inhibitors has remained controversial, mainly due to the lack of potent and specific bradykinin-blocking agents with which to test this hypothesis experimentally.
Potassium depolarization induce •OH generation
The interaction between depolarization and oxygen free radicals are not clear. It is well known that in the case of acute myocardial infarction or ischaemia, there is a marked increase in the extracellular potassium-ion concentration, [K+]o, and the resulting membrane potential of the ventricular muscle in the infarcted area is remarkably depolarized . In the heart, the release of NA was induced by nerve depolarization [45,46]. Catecholamine release contributes to the formation of cytotoxic free radicals. K+ depolarization enhances calcium ions (Ca2+) overload by [K+]o-induced depolarization and may generate •OH radicals in the myocardium. Although the precise mechanism of •OH generation in the ischaemic heart is obscure, we previously found concomitant increase of NA and •OH generation in myocardiac injury .
This data are in agreement with the data that K+ depolarization evokes •OH radicals . However, the release of NA was induced by nerve depolarization . NA may also have a deleterious effect on the myocardium by serving as a source of free radicals . It has been suggested that free radical production may mainly contribute to certain stages in the progression of the injury . Oxygen-derived free radicals are thought to be responsible for post ischaemic reperfusion injury [4,48]. Although controversial, a considerable effect on ischaemia/reperfusion exists  to support the notion that oxygen radicals play a role in ischaemia/reperfusion injury.
Calcium overload and •OH generation
Calcium ions (Ca2+) might have be a very important factor in the induction of irreversible ischaemic injury . Intracellular Ca2+ overload is then considered to lead to cell death under physiological conditions such as ischaemia and reperfusion injury . Several experimental studies have shown that oxygen-derived free radicals contribute to myocardial damage induced by ischaemic and reperfusion injury . The occurrence of intracellular Ca2+ plays a key role in cardiac dysfunction. Intracellular Ca2+ level builds and catalyzes the conversion of xanthine dehydrogenase to XO , which produces superoxide. Ca2+ may be a very important factor in the induction of irreversible ischaemic injury . However, the interaction between intracellular Ca2+ overload and oxygen free radicals in myocardium is not clear. Intracellular Ca2+ level has been proposed as a source of oxidative toxicity .
Elevation of intracellular Ca2+ levels causes the conversion of xanthine dehydrogenase to XO [53,56], which produces superoxide. Superoxide, either directly or after conversion to •OH , damages the biological membranes  and other cellular components, including DNA , resulting in cell death. The ischaemia is attributed to the occurrence of intracellular Ca2+ overload . Intracellular Ca2+ overload has been reported to be one of the causes of ischaemia reperfusion injury . Although the participation of Na+-Ca2+ exchange in the mechanism of intracellular Ca2+ elevation has been suggested , detailed information about the relationship between the status of Na+-Ca2+ exchange and oxygen free radical formation has not been available. Free radical formation may be attributed to the free radical formation by Ca2+ .
Effect of activation of ATP sensitive K+ (KATP) channels on hydroxyl radical production
Numerous mechanisms have been proposed to explain the cardioprotective action of the activation of KATP channels, including vasodilatation of coronary arteries and collateral vessels, inhibition of platelet aggregation, and inhibition of the release of oxygen free radicals. Glibenclamide has been used as a pharmacological tool to block selectively the KATP channels . Qian et al. , demonstrated that glibenclamide blocked cardioprotection conferred by ischaemic preconditioning in the heart. However, Thornton et al. , found that glibenclamide, given intravenously to rabbits did not abolish myocardial preconditioning. Thus it appears that controversy exists as to the role of KATP channels in mediating cardioprotection. Tokube et al. reported , that opening of cardiac KATP channels is induced by oxygen free radicals produced via xanthine oxidase reaction. However, the relationship between the opening of cardiac KATP channels and oxygen free radicals in myocardium is not clear. It is well known that myocardial ischaemia increases interstitial K+ concentrations of compromised ventricular muscles and decreases the resting membrane potential, leading to the slow conduction and ventricular tachyarrhythmias . Although interaction between KATP channels and oxygen free radicals in the myocardium is discussed, increased intracellular Ca2+ concentrations cause superoxide production . It is known that Ca2+ overload by K+ induced depolarization may generate •OH radicals. Although the mechanism of the action of K+ channel activators in subsequent •OH production is obscure, K+ channel activators were assessed by recording •OH formation in in vivo hearts. Rat hearts, cromakalim and nicorandil both increased ROS, measured with microdialysis probe perfused with sodium salicylate, which reacts with •OH radicals produced in the muscle to yield a production of 2,3-DHBA . EC50 of cromakalim and nicorandil were approximately 10 µM and 1 mM, respectively . Therefore, cromakalim may be a more potent K+ channel activator. Opening KATP channels significantly increased the level of 2,3-DHBA.
KATP channel openers can cause release of catecholamine, irrespective of their ability to open KATP [71,72]. The sustained elevation of NE in the extracellular fluid by KATP channel opener can be auto-xidized, which in turn, leads (possibly by an indirect mechanism) to the formation of cytotoxic •OH radicals. Activating KATP channel on nerve terminal may facilitate NA release. Activation of KATP channels was proposed to offer a protective effect on the ischaemia reperfused myocardium . It is likely that KATP channels play, at least, in part a role to protect the heart during episodes of ischcemia. Although the relationship between KATP channels and cardioprotective effect was obscure, glibenclamide decreased the production of •OH by preventing the opening of KATP channels. The •OH generation by cromakalim was suppressed by subsequent treatment with glibenclamide. Glibenclamide decreases the level of 2,3-DHBA . Cardioprotection mediated by attenuated free radical generation may be mitigated or abolished in the presence of KATP channel blockers. 5-Hydroxydecanoate (5-HD), a selective type of KATP channel blocker  also decreased cromakalim-induced 2,3-DHBA formation. Moreover, another KATP channel activator, nicorandil, also enhanced •OH formation. Both glibenclamide and 5-HD also decreased nicorandil-induced 2,3-DHBA formation .
Several experimental studies have shown that oxygen radicals contribute to myocardial damage induced by the ischcemia-reperfusion [6,75]. When the ischaemic arrhythmia appeared, the presence of free radicals was observed in the ischaemic-reperfused rat heart . Activation of KATP channel on ischcemia-reperfusion of myocardium may be cause release of NA. However, in the presence of glibenclamide or 5-HD, the elevation of 2,3-DHBA was not observed in ischaemic-reperfused rat heart. Glibenclamide is associated with a cardioprotective effect due to suppression of ischcemia-reperfusion-induced •OH generation. It is possible that opening of KATP in the cardiac nerve terminals facilitates the release of catecholamines, which the increase ROS production to trigger the protection . Cardioprotection mediated by these mechanisms may be mitigated or abolished in the presence of glibenclamide or 5-HD. Although it is well established that high levels of ROS are detrimental , moderate levels of H2O2 and O2- have been shown to elicit a cardioprotective effect similar to that observed with ischaemic preconditioning [78,79]. Forbes et al. , proposed that cardioprotective actions of diazoxide, a selective opener of the mitochondrial KATP channel, are mediated by generation of pro-oxidant environment. Pain et al. , also reported that the dioxide-induced reduction infarct size is attenuated by addition of antioxidants. These findings are agreement with that the assumption that both mitochondrial and sarcolemmal channels induced •OH formation .
Prazosin attenuate •OH generation
Prazosin has been demonstrated to exibit a protective effect on myocardial ischaemic injury . It is known that prazosin has a Na+ channel blocking action as well as an αI-adrenoceptor blocking action . Reactive oxygen causes excessive Na+ entry through the fast Ca2+ channel, leading to intracellular Ca2+ overload through the Na+-Ca2+ exchange system, and hence myocardial damage . Ca2+ overload is then mediated via activation of Na+-Ca2+ exchange due to increased cytosolic Na+ content. Na+ channel blocking drugs have been demonstrated to provide protection in ischaemia/reperfusion model . Although the role of catecholamines in the myocardial cellular injury is unclear, NA was induced by ischcemia/reperfusion [6,86]. NA released is thought to play a significant role in the etiology of various cardiac pathophysiological disorders . Accumulation of endogenous NA can leads to the formation of cytotoxic •OH radicals. Radical scavengers or anti-oxidant substances have been shown to attenuate myocardial dysfunction [88,89]. Theoretically, •OH may be formed in vivo during non-enzymatic oxidation  and/or enzymatic oxidation of NA . We demonstrated that tyramine (a catecholamine releaser)-induced •OH formation was attenuated by prazosin . It is possible that Na+ accumulation triggers Na+-Ca2+ exchange leading to Ca2+ overload. It is well known that Ca2+ overload may involve the formation of free radicals [26,92].
According to recent studies , prazosin has a Na+ channel blocking action as well as the α1-adrenoceptor blocking action. Su et al. , have found that prazosin inhibits inward Na+ current in the rat, guinea-pig and human myocardium and that this action of prazosin is unrelated to the blockade of α1-adrenoceptors. On the other hand, the reactive oxygen causes excessive Na+ entry through the fast Na+ channel, leading to intracellular Ca2+ overload through the Na+-Ca2+ exchange system, and hence myocardial damage . The beneficial effect of prazosin on the H2O2-induced derangements, therefore, may be due to its blocking effect on the Na+ channel of the cardiac cells. This notion is in agreement with the data from a recent study, in which α1-adrenoceptor antagonistic action of prazosin may not contribute to its action to attenuate the free radical induced damage, although the possibility of contribution of1-adrenoceptor blockade cannot be completely excluded .
Intracellular extracellular Ca2+ overload is considered to be the pathway leading to cell death in several pathological condition. Increases in intracellular Na+ levels could be caused by modified Na+ channel function [94,96]. Contribution of the Na+ channel blocking activity of prazosin to attenuate the ischaemia/reperfusion induced damage remain to be studied. During myocardial ischaemia, reduced ATP production generates disturbances in intracellular ion homeostasis, which ultimately lead to cellular Ca2+ overload and contractile failure. Ca2+ overload is then considered to be maintained via activation of Na+-Ca2+ exchange due to increased cytosolic Na+ content under ischaemic conditions. Intracellular Ca2+ overload is then considered to contribute to cell death under pathological conditions such as ischaemia/reperfusion injury . These results suggest that Na+-mediated Ca2+ overload may be relevant to ischcemia/reperfusion Ca2+ overload . This is a new cardioprotective principle.
Nitric oxide induces •OH generation
Nitric oxide (NO) is responsible for tissue damage during ischaemia. NO is a free radical which regulates a variety of biological function and pathogenesis of cellular injury. NO is synthesized from L-arginine by NO synthase (NOS) . It is known that O2- and NO rapidly to form the stable peroxiniterite (ONOO-) and then its decomposition generates •OH [99,100]. However, this theory is under consideration . NO may mediate •OH-induced ischaemia/reperfusion via depolarization of the ventricular muscle. Cytotoxic free radicals such as ONOO- and •OH may also be implicated in NO-mediated cell injury . It is known that NOS inhibition may inhibit depolarization-induced NOS activation by Ca2+ influx through blockade of Na+ and Ca2+ channels . The reactive oxygen species causes excessive Na+ entry through the fast Na+ channel, leading to intracellular Ca2+ overload through the Na+-Ca2+ exchange system . However, NG-nitro-L-arginine methyl ester (L-NAME), a NOS inhibitor, attenuate •OH generation by ischaemia/reperfusion . It is possible that NO mediates ischaemia/reperfusion induced •OH generation via depolarization in ventricular muscle. Accordingly to the reaction pathway in (Figure 3). •OH was generated by the presence of NOS and O2-. NO may possibility induce •OH generation after reaction with O2- and NO. NO mediates •OH generation via NOS inhibition.
Controversy exist concerning possible neurotoxity and/or neuroprotective roles of NO, which may prevent •OH-induced oxidative injury [103,104]. Moreover, iron complex-induced •OH generation and associated oxidative cellular injury was blocked by the co-administration of NO and dihydrolipoic acid (a potent antioxidant compound). Some NO donor (e.g., sodium nitroprusside) stimulated, while others (nitroglycerin, diethylamine/NO, NO in Ringer's solution) suppressed •OH generation in vivo . Exogenous NO can act as •OH scavenger and protect neurons from oxidative injury .
LDL oxidation and •OH generation
Several experimental studies have shown that oxygen radical contributes to myocardial damage induced by ischaemia/reperfusion [6,107]. It is well known that ischaemia induces depolarization [108,109]. NO may mediate ischaemia/reperfusion-induced •OH generation via depolarization in ventricular muscle. NO is responsible for tissue damage during ischcemia. L-NAME (NG-nitro-L-arginine methyl ester, a NOS inhibitor) attenuated •OH generation by ischcemia/reperfusion of rat heart . It is known that NOS inhibition is prevents depolarization induced NOS activation by affecting Ca2+ influx through blockade by Na+-Ca2+ channel . Oxidative modification of low-density lipoprotein (LDL) is thought to contribute to the production of oxygen derived-free radicals . Oxidative LDL (Ox-LDL) may be important in neurotoxicity in the brain . It is well known that 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor reduce the oxidizability of LDL . The inhibitory effect on the oxidizability of LDL oxidation can reduced •OH formation. The blockage of LDL oxidation by fluvastatin (an inhibitor of LDL oxidation) can reduce •OH generation. However, L-NAME did not affect NA-induced •OH formation. Fluvastatin is associated with a cardioprotective effect due to the suppression of NA-induced •OH formation by inhibiting LDL oxidation . LDL oxidation may be related to NA-induced •OH generation, but LDL oxidation may be related to NA-induced •OH generation, but LDL oxidation may be unrelated •OH generation K+ depolarization-induced •OH generation .
Effect of histidine on the formation of •OH in ischaemic injury
Histidine, a free amino acids, has been demonstrated to have an antioxidative action [113,114]. Although histidine is known to scavenger singlet oxygen (1O2) scavenger [115,116], the effect of histidine on ischaemic reperfusion injury still remains uncertain. Histidine is also a chelator of metal ions. Therefore, histidine could remove transition metals from the reactive site, resulting in a markedly decreased rate of •OH formation .
Ischaemia-reperfusion increased the level of NA. However, in the presence of histidine, ischcemia-reperfusion failed to increase the level of NA. Moreover, when the ischaemic arrhymia appeared, the presence of free radicals were observed in the ischaemic-reperfused rat heart . However, neither typical changes in Electrocardiogram (ECG) nor •OH generation in the ischaemic-reperfused rat heart was observed after administration of histidine . Histidine is a poor scavenger of •OH. Unfortunately, it is difficult to separate •OH radical from that by 1O2 because of the nonspecificity of histidine in scavenging both of the oxidant species. In addition, most of the 1O2 scavengers react with •OH radical, often with a greater rate constant than the reaction with 1O2. Histidine appears to scavenge most O2 species, as indicated by the present and previous studies . More, Feix and Kalyanaraman  reported that 1O2 could also attack salicylic acid to form 2,3-DHBA and 2,5-DHBA, which implies that salicylic acid is not a specific trapping agent for •OH, but can also trap 1O2. Histidine is thus an excellent scavenger of reactive O2 species in vivo conditions. Histidine protects myocardium against ischaemia-reperfusion induced •OH generation.
In vivo microdialysis techniques enable monitoring of generation of free radicals in myocardial tissues and could answer fundamental questions about the clinical implications of ROS. Data obtained in human are needed with the conduction of clinical studies investigating the effects of medications in physiological in vivo coditions. Although the cardioprotective effect of NO is discussed, NO also has a role in the pathogenesis of cellular injury. These experiments with cardiac microdialysis technique have versatile applications and offer new possibilities for the in vivo study of cardiac physiology.
- Souidi N, Stolk M, Seifert M. Ischemia-reperfusion injury: beneficial effects of mesenchymal stromal cells. Curr Opin Organ Transplant. 2013; 18: 34-43. Ref.: https://tinyurl.com/y9zkqw7r
- Yoshida M, Honma S. Regeneration of injured renal tubules. J Pharmacol Sci. 2014; 124: 117-122. Ref.: https://tinyurl.com/y7cg63p6
- Lekli I, Haines DD, Balla G, Tosaki A. Autophagy: an adaptive physiological countermeasure to cellular senescence and ischaemia/reperfusion-associated cardiac arrhythmias. J Cell Mol Med. 2017; 21: 1058-1072. Ref.: https://tinyurl.com/ybokkzbb
- McCord JM. Oxygen-derived free radicals in postischemic tissue injury. N Engl J Med. 1985; 312: 159-163. Ref.: https://tinyurl.com/y9su3xjz
- Gozal Y, Chevion M, Elami A, Berenshtein E, Kitrossky N, et al. Ischaemic preconditioning but not isoflurane prevents post-ischaemic production of hydroxyl radicals in a canine model of ischaemia-reperfusion. Eur J Anaesthesiol. 2005; 22: 49-55. Ref.: https://tinyurl.com/y7exate9
- Obata T, Hosokawa H, Yamanaka Y. In vivo monitoring of norepinephrine and •OH generation on myocardial ischemic injury by dialysis technique. Am J Physiol. 1994; 266; 903-908. Ref.: https://tinyurl.com/y95gpyqp
- Chen YR, Zweier JL. Cardiac mitochondria and reactive oxygen species generation. Circ Res. 2014; 114: 524-537. Ref.: https://tinyurl.com/y8hfjypu
- Hitchler MJ, Domann FE. Regulation of CuZnSOD and its redox signaling potential: implications for amyotrophic lateral sclerosis. Antioxid Redox Signal. 2014; 20: 1590-1598. Ref.: https://tinyurl.com/y88ubw4m
- Newcomb M, Hollenberg PF, Coon MJ. Multiple mechanisms and multiple oxidants in P450-catalyzed hydroxylations. Arch Biochem Biophys. 2003; 409: 72-79. Ref.: https://tinyurl.com/yazqzv4x
- Richmond R, Halliwell B, Chauhan J, Darbre A. Superoxide-dependent formation of hydroxyl radicals: detection of hydroxyl radicals by the hydroxylation of aromatic compounds. Anal Biochem. 1981; 118: 328-335. Ref.: https://tinyurl.com/ybh4rc6u
- Baker MS, Gebicki JM. The effect of pH on yields of hydroxyl radicals produced from superoxide by potential biological iron chelators. Arch Biochem Biophys. 1986; 246: 581-588. Ref.: https://tinyurl.com/y86ou7v9
- Gutteridge JM. Ferrous-salt-promoted damage to deoxyribose and benzoate. The increased effectiveness of hydroxyl-radical scavengers in the presence of EDTA. Biochem J. 1987; 243: 709-714. Ref.: https://tinyurl.com/yap6z47d
- Karam LR, Simic MG. Detecting irradiated foods: use of hydroxyl radical biomarkers. Anal Chem. 1988; 60: 1117-1119. Ref.: https://tinyurl.com/y7mnpwlh
- Radzik DM, Roston DA, Kissinger PT. Determination of hydroxylated aromatic compounds produced via superoxide-dependent formation of hydroxyl radicals by liquid chromatography/electrochemistry. Anal Biochem. 1983; 131: 458-464. Ref.: https://tinyurl.com/y9x4tgpo
- Floyd RA, Watson JJ, Wong PK. Sensitive assay of hydroxyl free radical formation utilizing high pressure liquid chromatography with electrochemical detection of phenol and salicylate hydroxylation products. J Biochem Biophys. 1984; 10: 221-235. Ref.: https://tinyurl.com/ybzn7kw4
- Obata T. Blocking cardiac ATP-sensitive K+ channels reduces hydroxyl radicals caused by potassium chloride-induced depolarization in the rat myocardium. Anal Biochem. 2006; 356: 59-65. Ref.: https://tinyurl.com/yadqgu57
- Halliwell B, Kaur H, Ingleman-Sundberg M. Hydroxylation of salicylate as an assay for hydroxyl radicals: a cautionary note. Free Radic Biol Med. 1991; 10: 439-441. Ref.: https://tinyurl.com/ydham33f
- Kostrzewa RM, Kostrzewa JP, Brus R. Dopaminergic denervation enhances susceptibility to hydroxyl radicals in rat neostriatum. Amino Acids. 2000; 19: 183-199. Ref.: https://tinyurl.com/y99bwqza
- Van Wylen DGL, Schmit TJ, Lasley RD, Gingell RL, Mentzer Jr RM. Cardiac microdialysis in isolated rat hearts: interstitial adenosine purine metabolites during ischemia. Am J Physiol. 1992; 262, 1934-1938. Ref.: https://tinyurl.com/y82rw64s
- Benveniste H. Brain microdialysis. J Neurochem. 1989; 52: 1667-1679. Ref.: https://tinyurl.com/yakzo3x8
- Sarapultsev P, Chupakhin O, Sarapultsev A, Rantsev M, Sidorova L, et al. New insights in to the treatment of myocardial infarction. Int J Exp Pathol. 2012; 93: 18-23. Ref.: https://tinyurl.com/y8y9p4bh
- Madamanchi NR, Runge MS. Redox signaling in cardiovascular health and disease. Free Radic Biol Med. 2013; 61: 473-501. Ref.: https://tinyurl.com/yc7sozec
- Ben-Shachar D, Youdim MBH. Intranigral iron injection induces behavioral and biochemical "parkinsonism" in rats. J Neurochem. 1991; 57: 2133-2135. https://tinyurl.com/y9gwuhzp
- Ashraf MZ, Kar NS, Podrez EA. Oxidized phospholipids: biomarker for cardiovascular diseases. Int J Biochem Cell Biol. 2009; 41: 1241-1244. Ref.: https://tinyurl.com/y9uny5ye
- Obata T, Yamanaka Y. Effect of iron (II) on the generation of hydroxyl free radicals in rat myocardium. Biochem Pharmacol. 1996; 51: 1411-1413. Ref.: https://tinyurl.com/yd33zsvb
- Obata T, Tamura M, Yamanaka Y. Evidence of hydroxyl free radical generation by calcium overload in rat myocardium. J Pharm Pharmacol. 1997; 49: 787-790. Ref.: https://tinyurl.com/y9qdskdu
- Obata T, Yamanaka Y. Nitric oxide induce hydroxyl radical generation in rat hearts via depolarization-induced nitric oxide synthase activation. Naunyn-Schmiedeberg's Arch Pharmacol. 2001; 364: 59-65. Ref.: https://tinyurl.com/y9ydpr6q
- Obata T. Use of microdialysis for in-vivo monitoring of hydroxyl free-radical generation in the rat. J Pharm Pharmacol. 1997; 49: 724-730. Ref.: https://tinyurl.com/yaadlsst
- Obata T, Yamanaka Y. Protective effect of imidaprilat, an angiotensin-converting enzyme inhibitor on •OH generation in rat myocardium. Biochim Biophys Acta. 1999; 1472: 62-70. Ref.: https://tinyurl.com/yasmp43f
- Obata T, Yamanaka Y. Iron (III) attenuates hydroxyl radical generation accompanying non-enzymatic oxidation of noradrenaline in the rat heart. Naunyn Schmiedebergs Arch Pharmacol. 2002; 365: 158-163. Ref.: https://tinyurl.com/y74t2vw2
- Wang LX, Ideishi M, Yahiro E, Urata H, Arakawa K, Saku K. Mechanism of the cardioprotective effect of inhibition of the renin-angiotensin system on ischemia/reperfusion-induced myocardial injury. Hypertens Res. 2001; 24: 179-187. Ref.: https://tinyurl.com/ydf5ayal
- Mangieri A. Renin-angiotensin system blockers in cardiac surgery. J Crit Care. 2015; 30: 613-618. Ref.: https://tinyurl.com/yc3yue69
- Herring N, Lee CW, Sunderland N, Wright K, Paterson DJ. Pravastatin normalises peripheral cardiac sympathetic hyperactivity in the spontaneously hypertensive rat. J Mol Cell Cardiol. 2011; 50: 99-106. Ref.: https://tinyurl.com/y6v3kxf8
- Obata T, Yamanaka Y. Effect of OH scavenging action by non-SH-containing angiotensin converting enzyme inhibitor imidaprilat using microdialysis. J Physiol. 1998; 92: 1-4. Ref.: https://tinyurl.com/ycssn6wa
- Sobotka PA, Krum H, Böhm M, Francis DP, Schlaich MP. The role of renal denervation in the treatment of heart failure. Curr Cardiol Rep. 2012; 14: 285-292. Ref.: https://tinyurl.com/y9x2kod7
- Bagchi D, Prasad R, Das DK. Direct scavenging of free radicals by captopril, an angiotensin converting enzyme inhibitor. Biochem Biophys Res Commun. 1989; 158: 52-57. Ref.: https://tinyurl.com/ya3wrxpz
- Laughlin MH, Bowles DK, Duncker DJ. The coronary circulation in exercise training. Am J Physiol Heart Circ Physiol. 2012; 302: 10-23. Ref.: https://tinyurl.com/ybwv9xs4
- Rana OA, Byrne CD, Greaves K. Intensive glucose control and hypoglycaemia: a new cardiovascular risk factor? Heart. 2014; 100: 21-27. Ref.: https://tinyurl.com/ydcvfv5x
- Isaacson JS, Reid IA. Importance of endogenous angiotensin II in the cardiovascular responses to sympathetic stimulation in conscious rabbits. Circ Res. 1990; 66: 662-671. Ref.: https://tinyurl.com/ya9l6uat
- Stegbauer J, Oberhauser V, Vonend O, Rump LC. Angiotensin-(1-7) modulates vascular resistance and sympathetic neurotransmission in kidneys of spontaneously hypertensive rats. Cardiovasc Res. 2004; 61: 352-359. Ref.: https://tinyurl.com/ycqrerv2
- Naito M, Yang XP, Chiba S. Modification of transmitter release from periarterial nerve terminals by dipyridamole in canine isolated splenic artery. Clin Exp Pharmacol Physiol. 2004; 31: 185-189. Ref.: https://tinyurl.com/y7syz23g
- Rona G. Catecholamine cardiotoxicity. J Mol Cell Cardiol. 1985; 17: 291-306. Ref.: https://tinyurl.com/y8uapmgs
- Erdös EG, Jackman HL, Brovkovych V, Tan F, Deddish PA. Products of angiotensin I hydrolysis by human cardiac enzymes potentiate bradykinin. J Mol Cell Cardiol. 2002; 34: 1569-1576. Ref.: https://tinyurl.com/yalf344q
- Knorr AM. Why is nisoldipine a specific agent in ischemic left ventricular dysfunction? Am J Cardiol. 1995; 75: 36-40. Ref.: https://tinyurl.com/ybroh5fg
- Malik KU, Sehic E. Prostaglandins and the release of the adrenergic transmitter. Ann NY Acad Sci. 1990; 604: 222-236. Ref.: https://tinyurl.com/y7gxcjj2
- Fern R, Ransom BR. Ischemic injury of optic nerve axons: the nuts and bolts. Clin Neurosci. 1997; 4: 246-250. Ref.: https://tinyurl.com/ybwfc922
- Liu T, O'Rourke B. Regulation of mitochondrial Ca2+ and its effects on energetics and redox balance in normal and failing heart. J Bioenerg Biomembr. 2009; 41: 127-132. Ref.: https://tinyurl.com/yamqyc93
- Williams MW, Taft CS, Ramnauth S, Zhao ZQ, Vinten-Johansen J. Endogenous nitric oxide (NO) protects against ischaemia-reperfusion injury in the rabbit. Cardiovasc Res. 1995; 30: 79-86. Ref.: https://tinyurl.com/y97enf34
- Hearse DJ, Bolli R. Reperfusion-induced injury: manifestation, mechanisms and clinical relevance. Cardiovasc Res. 1992; 26: 101-108. Ref.: https://tinyurl.com/yclp5hfk
- Goldhaber JI, Qayyum MS. Oxygen free radicals and excitation-contraction coupling. Antioxid Redox Signal. 2000; 2: 55-64. Ref.: https://tinyurl.com/y7u7fwcc
- Barba I, Chavarria L, Ruiz-Meana M, Mirabet M, Agulló E, et al. Effect of intracellular lipid droplets on cytosolic Ca2+ and cell death during ischaemia-reperfusion injury in cardiomyocytes. J Physiol. 2009; 587: 1331-1341. Ref.: https://tinyurl.com/yccea9ag
- Boucher FR, Jouan MG, Moro C, Rakotovao AN, Tanguy S, et al. Does selenium exert cardioprotective effects against oxidative stress in myocardial ischemia? Acta Physiol Hung. 2008; 95: 187-194. Ref.: https://tinyurl.com/ydd2tecx
- Vannucci RC. Experimental biology of cerebral hypoxia-ischemia: relation to perinatal brain damage. Pediatr Res. 1990; 27: 317-326. Ref.: https://tinyurl.com/yak34pdx
- Pepe S. Effect of dietary polyunsaturated fatty acids on age-related changes in cardiac mitochondrial membranes. Exp Gerontol. 2005; 40: 751-758. Ref.: https://tinyurl.com/ycsn9gb8
- An J, Zou W, Zhong Y, Zhang X, Wu M, et al. The toxic effects of Aroclor 1254 exposure on the osteoblastic cell line MC3T3-E1 and its molecular mechanism. Toxicology. 2012; 295: 8-14. Ref.: https://tinyurl.com/yau7tyeo
- Zhang Y, Hu S, Chen Y. Hepatocyte growth factor suppresses hypoxia/reoxygenation-induced XO activation in cardiac microvascular endothelial cells. Heart Vessels. 2015; 30: 534-544. Ref.: https://tinyurl.com/ybb4qr9j
- Deby C, Goutier R. New perspectives on the biochemistry of superoxide anion and the efficiency of superoxide dismutases. Biochem Pharmacol. 1990; 39: 399-405. Ref.: https://tinyurl.com/ybyen82o
- Minyailenko TD, Pozharov VP, Seredenko MM. Severe hypoxia activates lipid peroxidation in the rat brain. Chem Phys Lipids. 1990; 55: 25-28. Ref.: https://tinyurl.com/yb8fcckt
- Andreoli SP. Mechanisms of endothelial cell ATP depletion after oxidant injury. Pediatr Res. 1989; 25: 97-101. Ref.: https://tinyurl.com/y9mf4shk
- Demaison L, Moreau D, Martine L, Chaudron I, Grynberg A. Myocardial ischemia and in vitro mitochondrial metabolic efficiency. Mol Cell Biochem. 1996; 158: 161-169. Ref.: https://tinyurl.com/ydcaedvm
- Hoffman JW Jr, Gilbert TB, Poston RS, Silldorff EP. Myocardial reperfusion injury: etiology, mechanisms, and therapies. J Extra Corpor Technol. 2004; 36: 391-411. Ref.: https://tinyurl.com/y7vjgqxg
- Murphy E, Jacob R, Lieberman M. Cytosolic free calcium in chick heart cells. Its role in cell injury. J Mol Cell Cardiol. 1985; 17: 221-231. Ref.: https://tinyurl.com/ycs548zw
- Obata T, Yamanaka Y. Cardiac microdialysis of salicylic acid .OH generation on nonenzymatic oxidation by norepinephrine in rat heart. Biochem Pharmacol. 1997; 53: 1375-1378. Ref.: https://tinyurl.com/ycl9fqxo
- Edwards G, Weston AH. The pharmacology of ATP-sensitive potassium channels. Annu Rev Pharmacol Toxicol. 1993; 33: 597-637. Ref.: https://tinyurl.com/y778dbcp
- Qian YZ, Levasseur JE, Yoshida K, Kukreja RC. KATP channels in rat heart: blockade of ischemic and acetylcholine-mediated preconditioning by glibenclamide. Am J Physiol. 1996; 271: 23-28. Ref.: https://tinyurl.com/yc5jfxss
- Thornton JD, Liu GS, Olsson RA, Downey JM. Intravenous pre-treatment with A1-selective adenosine analogues protects the heart against infarction. Circulation. 1992; 85: 659-665.
- Tokube KA, Kiyosue T, Arita M. Openings of cardiac KATP channel by oxygen free radicals produced by xanthine oxidase reaction. Am J Physiol. 1996; 271: 478-489. Ref.: https://tinyurl.com/y9fbnv6c
- Hirche HJ, Franz CH, Bös L, Bissig R, Scharmann M. Myocardial extracellular K+ and H+ increase and noradrenaline release as possible cause of early arrhythmias following acute coronary artery occlusion. J Mol Cell Cardiol. 1980; 12: 579-593. Ref.: https://tinyurl.com/ya7fue52
- Chacon E, Acosta D. Mitochondrial regulation of superoxide by Ca2+: an alternate mechanism for the cardiotoxicity of doxorubicin. Toxicol Appl Pharmacol. 1991; 107: 117-128. Ref.: https://tinyurl.com/yc6fbcrx
- Obata T, Yamanaka Y. Block of cardiac ATP-sensitive K+ channels reduces hydroxyl radicals in the rat myocardium. Arch Biochem Biophys. 2000; 378: 195-200. Ref.: https://tinyurl.com/y9t8ev79
- Fabiani ME, Story DF. Prejunctional effects of cromakalim, nicorandil and pinacidil on noradrenergic transmission in rat isolated mesenteric artery. J Auton Pharmacol. 1994; 14: 87-98. Ref.: https://tinyurl.com/y7pxkfks
- D'Alonzo AJ, Zhu JL, Darbenzio RB, Dorso CR, Grover GJ. Proarrhythmic effects of pinacidil are partially mediated through enhancement of catecholamine release in isolated perfused guinea-pig hearts. J Mol Cell Cardiol. 1998; 30: 415-423. Ref.: https://tinyurl.com/y8rzz4og
- Shigematsu S, Sato T, Abe T, Saikawa T, Sakata T, Arita M. Pharmacological evidence for the persistent activation of ATP-sensitive K+ channels in early phase of reperfusion and its protective role against myocardial stunning. Circulation. 1995; 92: 2266-2275. Ref.: https://tinyurl.com/yanue7nx
- Notsu T, Tanaka I, Takano M, Noma A. Blockade of the ATP-sensitive K+ channel by 5-hydroxydecanoate in guinea pig ventricular myocytes. J Pharmacol Exp Ther. 1992; 260: 702-708. Ref.: https://tinyurl.com/yceeyez2
- Ripoll C, Lederer WJ, Nichols CG. On the mechanism of inhibition of KATP channels by glibenclamide in rat ventricular myocytes. J Cardiovasc Electrophysiol. 1993; 4: 38-47. Ref.: https://tinyurl.com/ydh77ozl
- Liu Y, O'Rourke B. Opening of mitochondrial KATP channels triggers cardioprotection: are reactive oxygen species involved? Circ Res. 2001; 88: 750-752. Ref.: https://tinyurl.com/y9e4yj22
- Jeroudi MO, Hartley CJ, Bolli R. Myocardial reperfusion injury: role of oxygen radicals and potential therapy with antioxidants. Am J Cardiol. 1994; 73: 2-7. Ref.: https://tinyurl.com/yapvme2b
- Baines CP, Goto M, Downey JM. Oxygen radicals released during ischemic preconditioning contribute to cardioprotection in the rabbit myocardium. J Mol Cell Cardiol. 1997; 29: 207-216. Ref.: https://tinyurl.com/ybttuhhe
- Tritto I, D'Andrea D, Eramo N, Scognamiglio A, De Simone C, et al. Oxygen radicals can induce preconditioning in rabbit hearts. Circ Res. 1997; 80: 743-748. Ref.: https://tinyurl.com/y9hkuf3d
- Forbes RA, Steenbergen C, Murphy E. Diazoxide-induced cardioprotection requires signaling through a redox-sensitive mechanism. Circ Res. 2001; 88: 802-809. Ref.: https://tinyurl.com/y8s65bst
- Pain T, Yang XM, Critz SD, Yue Y, Nakano A, et al. Opening of mitochondrial K (ATP) channels triggers the preconditioned state by generating free radicals. Circ Res. 2000; 87: 460-466. Ref.: https://tinyurl.com/y9e8l3lv
- Billman GE. Effect of alpha 1-adrenergic receptor antagonists on susceptibility to malignant arrhythmias: protection from ventricular fibrillation. J Cardiovasc Pharmacol. 1994; 24: 394-402. Ref.: https://tinyurl.com/yaypu6bx
- Pèrez O, Valenzuela C, Delpón E, Tamargo J. Class I and III antiarrhythmic actions of prazosin in guinea-pig papillary muscles. Br J Pharmacol. 1994; 111: 717-722. Ref.: https://tinyurl.com/yat6tetm
- Donck LV, Borgers M. Myocardial protection by R 56865: a new principle based on prevention of ion channel pathology. Am J Physiol. 1991; 261: 1828-1835. Ref.: https://tinyurl.com/ybnoq2ef
- Tosaki A, Koltai M, Paubert-Braquet M. Effect of iloprost on reperfusion-induced arrhythmias and myocardial ion shifts in isolated rat hearts. Eur J Pharmacol. 1990; 191, 69-81. Ref.: https://tinyurl.com/ycf5ldmj
- Toombs, CF, Wiltse AL, Shebuski RJ. Ischemic preconditioning fails to limit infarct size in reserpinized rabbit myocardium. Implication of norepinephrine release in the preconditioning effect. Circulation. 1993; 88: 2351-2358. Ref.: https://tinyurl.com/yax6kw7x
- Akiyama T, Yamazaki T, Ninomiya I. In vivo monitoring of myocardial interstitial norepinephrine by dialysis technique. Am J Physiol. 1991; 261: 1643-1647. Ref.: https://tinyurl.com/yaxo7dbz
- Slezak J, Tribulova N, Pristacova J, Uhrik B, Thomas T, et al. Hydrogen peroxide changes in ischemic and reperfused heart. Cytochemistry and biochemical and X-ray microanalysis. Am J Pathol. 1995; 147: 772-781. Ref.: https://tinyurl.com/yah8nf2w
- Vaage J, Antonelli M, Bufi M, Irtun O, DeBlasi RA, et al. Exogenous reactive oxygen species deplete the isolated rat heart of antioxidants. Free Rad Biol Med. 1997; 22: 85-92. Ref.: https://tinyurl.com/ybsrnbw7
- Obata T, Yamanaka Y. Cardiac microdialysis of salicylic acid to detect hydroxyl radical generation associated with sympathetic nerve stimulation. Neurosci Lett. 1996; 211: 216-218. Ref.: https://tinyurl.com/y8guzy6s
- Obata T, Aomine M, Yamanaka Y. Protective effect of histidine on iron (II)-induced hydroxyl radical generation in rat hearts. J Physiol Paris. 1999; 93: 213-218. Ref.: https://tinyurl.com/ybvv6oqa
- Hoffmann P, Richards D, Heinroth-Hoffmann I, Mathias P, Wey H, et al. Arachidonic acid disrupts calcium dynamics in neonatal rat cardiac myocytes. Cardiovasc Res. 1995; 30: 889-898. Ref.: https://tinyurl.com/yckva8x2
- Su MJ, Chi JF, Chu SH. Effects of prazosin on rat, guinea pig and human cardiac tissues. Chin J Physiol. 1995; 38: 159-169. Ref.: https://tinyurl.com/ycfruq8l
- Ver Donck L, Borgers M. Myocardial protection by R 56865: a new principle based on prevention of ion channel pathology. Am J Physiol. 1991; 266: 903-908. Ref.: https://tinyurl.com/ybnoq2ef
- Akahira M, Hara A, Hashizume H, Nakamura M, Abiko Y. Protective effect of prazosin on the hydrogen peroxide-induced derangements in the isolated perfused rat heart. Life Sci. 1998; 62: 1755-1766. Ref.: https://tinyurl.com/ycuqy536
- Wermelskirchen D, Wilffert B, Nebel U, Wirth A, Peters T. Veratridine-induced intoxication in the isolated left atrium of the rat: effects of some anti-ischemic compounds. Naunyn-Schmiedeberg's Arch Pharm. 1991; 344: 101-106. Ref.: https://tinyurl.com/yb4o59vn
- Tani, M., 1990. Mechanisms of Ca2+ overload in reperfused ischemic myocardium. Annu. Rev. Physiol. 52, 543-559.
- Comini L, Bachetti T, Gaia G, Pasini E, Agnoletti L, Pepi P, et al. Aorta and skeletal muscle NO synthase expression in experimental heart failure. J Mol Cell Cardiol. 1996; 28: 2241-2248. Ref.: https://tinyurl.com/y7sg5so7
- Beckman JS, Beckman TW, Chen J, Marshall PA, Freeman BA. Apparent hydroxyl radical production by peroxynitrite: implications for endothelial injury from nitric oxide and superoxide. Proc Natl Acad Sci. 1990; 87: 1620-1624. Ref.: https://tinyurl.com/yax9xts7
- Pietri S, Maurelli E, Drieu K, Culcasi M. Cardioprotective and anti-oxidant effects of the terpenoid constituents of Ginkgo biloba extract (EGb 761). J Mol Cell Cardiol. 1997; 29: 733-742. Ref.: https://tinyurl.com/y7jk9aes
- Darley-Usmar V, Wiseman H, Halliwell B. Nitric oxide and oxygen radicals: a question of balance. FEBS Lett. 1995; 369: 131-315. Ref.: https://tinyurl.com/yajufm9a
- Tatsumi S, Itoh Y, Ma FH, Higashira H, Ukai Y, et al. Inhibition of depolarization-induced nitric oxide synthase activation by NS-7, a phenylpyrimidine derivative, in primary neuronal culture. J Neurochem. 1998; 70: 59-65. Ref.: https://tinyurl.com/y73wkwyc
- Chiueh CC, Wu RM, Mohanakumar KP, Sternberger LM, Krishna G, et al. In vivo generation of hydroxyl radicals and MPTP-induced dopaminergic toxicity in the basal ganglia. Ann NY Acad Sci. 1994; 738: 25-36. Ref.: https://tinyurl.com/ycxr2jmy
- Mohanakumar KP, Steinbusch HW. Hydroxyl radicals and nitric oxide in neurotoxicity and neuroprotection. J Chem Neuroanat. 1998; 14: 125-127. Ref.: https://tinyurl.com/y9ze37ox
- Mohanakumar KP, Hanbauer I, Chiueh CC. Neuroprotection by nitric oxide against hydroxyl radical-induced nigral neurotoxicity. J Chem Neuroanat. 1998; 14: 195-205. Ref.: https://tinyurl.com/ya343dph
- Rauhala P, Mohanakumar KP, Sziraki I, Lin AM, Chiueh CC. S-nitrosothiols and nitric oxide, but not sodium nitroprusside, protect nigrostriatal dopamine neurons against iron-induced oxidative stress in vivo. Synapse. 1996; 23: 58-60. Ref.: https://tinyurl.com/y8sktwz4
- Kalogeris T, Bao Y, Korthuis RJ. Mitochondrial reactive oxygen species: a double edged sword in ischemia/reperfusion vs preconditioning. Redox Biol. 2014; 2: 702-714. Ref.: https://tinyurl.com/y82pcp29
- Seyedi N, Win T, Lander HM, Levi R. Bradykinin B2-receptor activation augments norepinephrine exocytosis from cardiac sympathetic nerve endings. Mediation by autocrine/paracrine mechanisms. Circ Res. 1997; 81: 774-784. Ref.: https://tinyurl.com/y8txxbvs
- Snabaitis AK, Shattock MJ, Chambers DJ. Comparison of polarized and depolarized arrest in the isolated rat heart for long-term preservation. Circulation. 1997; 96: 3148-3156. Ref.: https://tinyurl.com/yc78lrma
- Sugawa M, Ikeda S, Kushima Y, Takashima Y, Cynshi O. Oxidized low density lipoprotein caused CNS neuron cell death. Brain Res. 1997; 761: 165-172. Ref.: https://tinyurl.com/y9by4vro
- Shie FS, Neely MD, Maezawa I, Wu H, Olson SJ, et al. Oxidized low-density lipoprotein is present in astrocytes surrounding cerebral infarcts and stimulates astrocyte interleukin-6 secretion. Am J Pathol. 2004; 164: 1173-1181. Ref.: https://tinyurl.com/y9zj58rl
- Suzumura K, Tanaka K, Yasuhara M, Narita H. Inhibitory effects of fluvastatin and its metabolites on hydrogen peroxide-induced oxidative destruction of hemin and low-density lipoprotein. Biol Pharm Bull. 2000; 23: 873-878. Ref.: https://tinyurl.com/yafroc3g
- Kukreja RC, Hess ML. The oxygen free radical system from equations through membrane-protein interactions to cardiovascular injury and protection. Cardiovasc Res. 1992; 26: 641-655. Ref.: https://tinyurl.com/y6v3t4bv
- Grimsrud PA, Xie H, Griffin TJ, Bernlohr DA. Oxidative stress and covalent modification of protein with bioactive aldehydes. J Biol Chem. 2008; 283: 21837-21841. Ref.: https://tinyurl.com/y9fb9l4e
- Zhai X, Ashraf M. Direct detection and quantification of singlet oxygen during ischemia and reperfusion in rat hearts. Am J Physiol. 1995; 269: 1229-1236. Ref.: https://tinyurl.com/y7xmudw3
- Telfer A. Singlet oxygen production by PSII under light stress: mechanism, detection and the protective role of β-carotene. Plant Cell Physiol. 2014; 55: 1216-1223. Ref.: https://tinyurl.com/y9ddkhdm
- Joshi S, Husain MM, Chandra R, Hasan SK, Srivastava RC. Hydroxyl radical formation resulting from the interaction of nickel complexes of L-histidine, glutathione or L-cysteine and hydrogen peroxide. Hum Exp Toxicol. 2005; 24: 13-17. Ref.: https://tinyurl.com/y78k36v8
- Suzuki Y, Sudo J. Lipid peroxidation and generations of oxygen radicals induced by cephaloridine in renal cortical microsomes of rats. Jpn J Pharmacol. 1990; 52: 233-243. Ref.: https://tinyurl.com/y8zq8456
- Feix JB, Kalyanaraman B. Production of singlet oxygen-derived hydroxyl radical adducts during merocyanine-540-mediated photosensitization: analysis by ESR-spin trapping and HPLC with electrochemical detection. Arch Biochem Biophys. 1991; 291: 43-51. Ref.: https://tinyurl.com/y7ffdfxz
- Gerlach M, B en-Shachar D, Riederer P, Youdim MBH. Altered brain metabolism of iron as a cause of neurodegenerative diseases? J Neurochem. 1994; 63: 793-807. Ref.: https://tinyurl.com/y6u9rx74
- Obata T, Yamanaka Y, Chiueh CC. In vivo release of dopamine by perfusion of 1-methyl-4-phenylpyridinium ion in the striatum with a microdialysis technique. Jpn J Pharmacol. 1992; 60: 311-313. Ref.: https://tinyurl.com/yd2fwztu
- Schömig A, Dart AM, Dietz R, Mayer E, Kübler W. Release of endogenous catecholamines in the ischemic myocardium of the rat. Part A: locally mediated release. Circ Res. 1984; 55: 689-701. Ref.: https://tinyurl.com/y98ta23e