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Ferenc Domoki

Publications and source records attributed to Ferenc Domoki.

18 recordsLinked to original sources
PubMed2006

The effect of pre- and posttreatment with diazoxide on the early phase of chronic cerebral hypoperfusion in the rat.

Diazoxide has been identified as a mitochondrial, ATP-dependent K(+) channel opener, and a potentially neuroprotective compound under ischemic conditions. We set out to characterize the consequences of various treatment strategies with diazoxide in a rat model of chronic cerebral hypoperfusion. Cerebral hypoperfusion was induced by permanent, bilateral occlusion of the common carotid arteries (2VO, n = 36), sham-operated rats serving as controls (SHAM, n = 29). Diazoxide or its vehicle was administered i.p. daily (5 x 0.5 mg/kg/0.25 ml) or as a bolus injection (5 mg/kg/0.25 ml) before surgery or daily after surgery (5 x 0.5 mg/kg/0.25 ml). Spatial learning performance was assessed 1 week after 2VO in the Morris maze. Hippocampal pyramidal cell loss was assessed on cresyl violet-stained sections, while glial reactivity was labeled immunocytochemically. Daily or bolus pretreatment with diazoxide significantly improved 2VO-related learning impairment, whereas posttreatment was ineffective. The number of CA1 pyramidal neurons was reduced by 2VO, which was prevented by repeated or bolus pretreatment with diazoxide. Astrocyte proliferation and microglial activation were enhanced by posttreatment with diazoxide in the hippocampus CA1 area of 2VO animals as compared with SHAM. These data demonstrate that the neuroprotective effect exerted by diazoxide depends on the time of administration with respect to the onset of ischemia; pretreatment but not posttreatment with the compound has proved to be neuroprotective in chronic cerebral hypoperfusion. Thus, pretreatment with diazoxide offers therapeutical prospects for the treatment of cerebral ischemia.

Animals↗
PubMed2006

Kynurenic acid attenuates NMDA-induced pial arteriolar dilation in newborn pigs.

The excitatory amino acid glutamate is a potent vasodilator in the central nervous system. Glutamate-induced vasodilation is mediated primarily by N-methyl-D-aspartate (NMDA) and AMPA/kainate (KAIN) receptors. We have now tested whether two metabolites of the kynurenine pathway of tryptophan degradation acting at the NMDA receptor, the antagonist kynurenic acid (KYNA) and the agonist quinolinic acid (QUIN), are capable of modulating the dilation of pial arterioles. The closed cranial window technique was used, and changes in vessel diameter ( approximately 100 microm) were analyzed in anesthetized newborn piglets. Topical application of NMDA (10(-4) M) or KAIN (5 x 10(-5) M) resulted in marked vasodilation (44 +/- 5% and 39 +/- 4%, respectively). Neither KYNA nor QUIN (both at 10(-5) to 10(-3) M) affected the vessel diameter when applied alone. Co-application of KYNA dose-dependently reduced the vasodilation caused by 10(-4) M NMDA and also attenuated the KAIN-induced response. Ten minutes of global cerebral ischemia did not modify the interaction between KAIN and KYNA. In contrast, KYNA did not affect vasodilation to hypercapnia, elicited by the inhalation of 10% CO2. Moreover, endogenous levels of KYNA and QUIN in the cerebral cortex, hippocampus and thalamus were found to be essentially unchanged during the early reperfusion period (0.5-2 h) following an episode of cerebral ischemia. Our data are relevant for the use of drugs that target the kynurenine pathway for therapeutic interventions in cerebrovascular diseases.

Analysis of Variance↗
PubMed2006

Reventilation with room air or 100% oxygen after asphyxia differentially affects cerebral neuropathology in newborn pigs.

AIM: To test if reventilation with room air (RA) or 100% oxygen (O2) after asphyxia would differentially affect neuronal damage in different brain areas of newborn pigs. METHODS: Anaesthetized piglets were subjected to 10 min asphyxia (n=27) or served as time controls (n=7). Reventilation started with either RA or O2 for 1 h, and was continued with RA for an additional 1-3 h. Cortical or cerebellar blood flow was assessed with laser-Doppler flowmetry (LDF). Haematoxylin/eosin-stained sections from six brain regions were prepared for blinded neuropathological examination and scoring. RESULTS: Asphyxia resulted in significant neuronal damage compared to time controls in all areas examined except the pons. O2 ventilation elicited greater neuronal lesions in the hippocampus and the cerebellum but smaller damage in the basal ganglia compared to RA. The assessed physiological parameters including the LDF signals were similar in both ventilation groups, except for PaO2 in the first hour of reventilation (RA 75+/-5 mmHg, O2 348+/-57 mmHg; p<0.05). Interestingly, however, reactive hyperaemia was much higher in the O2-sensitive cerebellum as compared with the cortex (1101+/-227 vs 571+/-73; p<0.05, area under the curve). CONCLUSION: O2 toxicity after asphyxia was demonstrated in the piglet hippocampus and cerebellum but not in the cerebral cortex or basal ganglia. The observed regional differences may be associated with local haemodynamic factors.

Air↗
PubMed2005

Post-ischemic administration of diazoxide attenuates long-term microglial activation in the rat brain after permanent carotid artery occlusion.

Diazoxide is a putative mitochondrial, ATP-sensitive potassium channel opener that has been implicated in neuroprotection in cerebral ischemia. Administered as pretreatment, diazoxide can attenuate ischemia-related neuronal injury, but little is known about the potential neuroprotective properties of the drug when it is given after the onset of an ischemic insult. In a previous study, we applied diazoxide after imposing chronic cerebral hypoperfusion by means of permanent, bilateral occlusion of the common carotid arteries (2VO) in rats. We observed that ischemia-induced learning impairment assessed in the Morris water maze, and microglial activation visualized by immunocytochemistry, were prevented by diazoxide as determined at 13 weeks after 2VO. However, dimethyl sulfoxide, the organic solvent of diazoxide also prevented memory deficits, without any effect on microglial activity. Therefore, we have repeated our experiments with the use of an inorganic solvent, aqueous NaOH solution in order to clarify the effect of diazoxide independent of dimethyl sulfoxide. The present results demonstrated that diazoxide alone did not improve learning performance, but it prevented microglial activation in the hippocampus 13 weeks after the onset of 2VO. These data provide evidence that post-treatment with diazoxide is not effective in impeding a long-term memory deficiency, but it can attenuate ischemia-induced microglial activation, independently of the solvent used.

Animals↗
PubMed2005

Flow motion pattern differences in the forehead and forearm skin: Age-dependent alterations are not specific for Alzheimer's disease.

Oscillations in laser Doppler signals derived from the forehead and forearm skin were analyzed in 77 healthy probands from 4 various age groups (ranging between 15 and 77 years) and 22 late-onset sporadic Alzheimer's disease (AD) patients. A characteristic pattern of oscillations in the microcirculatory blood flux ( approximately 8 cycles/min, 0.13 Hz) was observed in the forehead skin, the occurrence of which correlated inversely with age (r = 0.80). The occurrence of forehead vasomotion pattern was 100% in the teenagers, whereas it was significantly less in the elderly control subjects (32%) and in the AD patients (18%). Forearm reactive hyperemia was provoked by 1-min occlusion of the brachial artery, and the vascular reactivity was calculated. This phenomenon also proved to be age-dependent, but the process was not related to AD. Our results indicate that the lack of forehead vasomotion reflects aging better than does the forearm vasomotion. Both of these functions are preserved in AD.

Adolescent↗
PubMed2005

[Ischemic preconditioning in the brain].

Stroke-related death is the third most common cause of mortality in Hungary after cardiovascular diseases and cancer. In addition to the unfavourable mortality figures, the consequent development of neurological and psychiatric disorders in stroke patients imposes an enormous burden on the health care system and on the families. Numerous studies are being conducted world wide on the prevention of stroke and other cerebrovascular disorders like chronic hypoperfusion, as well as on acute stroke management and patient rehabilitation issues. As a result, our understanding of the mechanism of hypoxic brain damage steadily increased over the past years and decades which brought along promising achievements both in the field of stroke prevention and therapy. However, these broad-spectrum approaches also made clear that preventing neuronal death and thus reducing neurological damage are complex tasks that cannot be successfully resolved by targeting single mechanisms. Therefore, the development of alternative new drugs and clinically applicable complex neuroprotective strategies is warranted. One of the most promising approaches is to create ischemic tolerance in the brain by using pharmacological preconditioning paradigms. These drugs trigger similar events to those initiated by brief ischemic insults that later can make the cerebral tissue resistant to subsequent otherwise lethal stress (ischemic preconditioning).

Animals↗
PubMed2005

Effects of ATP-sensitive potassium channel activators diazoxide and BMS-191095 on membrane potential and reactive oxygen species production in isolated piglet mitochondria.

Mitochondrial ATP-sensitive potassium (mitoK(ATP)) channel openers protect the piglet brain against ischemic stress. Effects of mitoK(ATP) channel agonists on isolated mitochondria, however, have not been directly examined. We investigated the effects of K(ATP) channel openers and blockers on membrane potential and on the production of reactive oxygen species (ROS) in isolated piglet mitochondria. Diazoxide and BMS-191095, putative selective openers of mitoK(ATP), decreased the mitochondrial membrane potential (delta psi(m)). On a molar basis, diazoxide was less effective than BMS-191095. In contrast, diazoxide but not BMS-191095 increased ROS production by mitochondria. Since diazoxide also inhibits succinate dehydrogenase (SDH), we examined the effects of 3-nitropropionic acid (3-NPA), an inhibitor of SDH. 3-NPA failed to change the delta psi(m) but increased ROS production. Inhibitors of K(ATP) channels did not affect resting delta psi(m) or ROS production, but glibenclamide and 5-hydroxydecanoate (5-HD) blocked effects of diazoxide and BMS-191095 on delta psi(m) and diazoxide effects on ROS production. We conclude that BMS-191095 has selective effects on mitoK(ATP) channels while diazoxide also increases ROS production probably via inhibition of SDH.

Adenosine Triphosphate↗
PubMed2005

Selective inhibitors differentially affect cyclooxygenase-dependent pial arteriolar responses in newborn pigs.

Cyclooxygenase (COX)-derived prostanoids play an important role in the cerebrovascular control of newborns. In humans and in the widely accepted model of piglets, both the COX-1 and the COX-2 isoforms are expressed in cerebral arteries. However, the involvement of these isoforms in cerebrovascular control is unknown. Therefore we tested if specific inhibitors of COX-1 and/or COX-2 would differentially affect pial arteriolar responses to COX-dependent stimuli in piglets. Anesthetized, ventilated piglets (n = 35) were equipped with a closed cranial window, and changes in pial arteriolar diameters (baseline approximately 100 microm) to hypercapnia (ventilation with 5-10% CO(2), 21% O(2), balance N(2)), arterial hypotension (40 mm Hg MABP achieved by blood withdrawal), and Ach (Ach, 10-100 microM) were determined via intravital microscopy. Arteriolar responses were repeatedly tested 15 min after IV administration of selective COX-1 and COX-2 inhibitors SC-560 and NS-398 (1-1 mg/kg), and nonselective inhibitors indomethacin (0.3-1 mg/kg), acetaminophen (30 mg/kg), and ibuprofen (30 mg/kg). Hypercapnia resulted in concentration-dependent, reversible, (approximately 20-40%) increases in pial arteriolar diameters that were unaffected by NS-398, SC-560, acetaminophen and ibuprofen. In contrast, 0.3 mg/kg indomethacin significantly reduced, 1 mg/kg virtually abolished the vasodilation. Arterial hypotension elicited (approximately 15-20%) vasodilation that was similarly reduced by NS-398 and indomethacin but was unaltered by SC-560. Ach dose-dependently constricted pial arterioles. This response was similarly attenuated by NS-398, indomethacin, and ibuprofen, but left intact by SC-560. We conclude that the assessed COX-dependent vascular reactions appear to depend largely on COX-2 activity. However, hypercapnia-induced vasodilation was found indomethacin-sensitive instead of a COX-dependent response in the piglet.

Acetaminophen↗
PubMed2005

Diazoxide preserves hypercapnia-induced arteriolar vasodilation after global cerebral ischemia in piglets.

Diazoxide (Diaz), an activator of mitochondrial ATP-sensitive K+ (mitoKATP) channels, is neuroprotective, but the mechanism of action is unclear. We tested whether Diaz preserves endothelium-dependent (hypercapnia) or -independent [iloprost (Ilo)] cerebrovascular dilator responses after ischemia-reperfusion (I/R) in newborn pigs and whether the effect of Diaz is sensitive to 5-hydroxydecanoate (5-HD), an inhibitor of mitoKATP channels. Anesthetized, ventilated piglets (n = 48) were equipped with closed cranial windows. Changes in diameter of pial arterioles were determined with intravital microscopy in response to graded hypercapnia (5-10% CO2 - 21% O2-balance N2, n = 25) or Ilo (0.1-1 microg/ml, n = 18) before and 1 h after 10 min of global I/R. Experimental groups were pretreated with vehicle, NS-398 (a selective cyclooxygenase-2 inhibitor, 1 mg/kg), Diaz (3 mg/kg), or 5-HD (20 mg/kg) + Diaz. Potential direct effects of Diaz and 5-HD on hypercapnic vasodilation were also tested in the absence of I/R (n = 5). To confirm the direct effect of Diaz on mitochondria, mitochondrial membrane potential in cultured piglet cerebrovascular endothelial cells was monitored using Mito Tracker Red. Hypercapnia resulted in dose-dependent pial arteriolar vasodilation, which was attenuated by approximately 70% after I/R in vehicle- and NS-398-treated animals. Diaz and 5-HD did not affect the CO2 response. Diaz significantly preserved the postischemic vasodilation response to hypercapnia, but not to Ilo. Diaz depolarized mitochondria in cultured piglet cerebrovascular endothelial cells, and 5-HD completely abolished the protective effect of Diaz, both findings indicate a role for mitoKATP channels. In summary, preservation of arteriolar dilator responsiveness by Diaz may contribute to neuroprotection.

Animals↗
PubMed2005

Regional cortical blood flow changes following sodium lactate infusion in Alzheimer's disease.

Bilateral temporoparietal hypoperfusion is a characteristic single photon emission computed tomography (SPECT) finding in Alzheimer's disease (AD). Lactate is a metabolic vasodilator and is known to provoke increased cerebral blood flow (CBF) in healthy adults. This work investigated whether lactate, which is present in high concentrations in AD cerebrospinal fluid, affects AD-specific perfusion abnormalities. Twenty mild-to-moderately demented AD probands participated in the self-controlled study. The regional CBF was examined utilizing (99m)Tc-HMPAO SPECT after sodium lactate infusion (0.5 M, 5 mL/kg body weight) and 0.9% NaCl infusion, one on each of two separate days. Despite the vasodilatator effects of sodium lactate, AD rCBF patterns did not show increase in temporo-parietal regions after its infusion. AD-specific bi-temporo-parietal reduction in CBF was accompanied by further hypoperfusion in the parieto-occipital areas after the sodium lactate infusion in seven patients, while no CBF changes were observed in the case of the remaining 13 probands. The pattern of the CBF abnormalities was not correlated with the apolipoprotein E genotype. The decreased vascular responsiveness to sodium lactate reflects disturbed vasoregulatory processes in AD and it is unlikely that lactate would have any relevance in the treatment of AD-related cerebral hypoperfusion, but could be used to improve the value of perfusion SPECT in the diagnosis of AD.

Aged↗
PubMed2004

Diazoxide prevents mitochondrial swelling and Ca2+ accumulation in CA1 pyramidal cells after cerebral ischemia in newborn pigs.

Diazoxide (DIAZ), an opener of mitochondrial ATP-sensitive K(+) channels (mK(ATP)), protects neurons against hypoxic/ischemic stress in vivo, however, direct evidence showing mitochondrial effects of DIAZ in postischemic neurons is lacking. We investigated if DIAZ affects mitochondrial alterations after global ischemia/reperfusion (I/R) in CA1 pyramidal neurons by using oxalate-pyroantimonate electron cytochemistry. Anesthetized piglets were either non-treated, or treated with DIAZ (3 mg/kg, iv), I/R, DIAZ+I/R, or 5-hydroxy-decanoate (5HD)+DIAZ+I/R (n=6, 6, 11, 5, 7, respectively). Ischemia (10 min) was induced by intracranial pressure (ICP) elevation. After 5-30 min of reperfusion, the brains were fixed for ultrastructural studies. Relative volumes of Ca(2+)-containing deposits and mitochondria in CA1 pyramidal cells were determined by point counting on electron micrographs. I/R resulted in maximal increases in mitochondrial volume (from 7.14+/-0.63% to 9.74+/-0.57%*), and Ca(2+) levels (from 5.86+/-1.11% to 11.39+/-1.35%*; mean+/-S.E.M., *p<0.05) at 10-15-min reperfusion time. In this interval, pretreatment with DIAZ virtually abolished mitochondrial swelling (6.88+/-0.49%) and Ca(2+) accumulation (5.15+/-0.82%) evoked by I/R. The protective effect of DIAZ was reduced by 5HD, an inhibitor of mK(ATP), resulting in a calcium accumulation similar to that after IR (10.44+/-1.98%). Thus, DIAZ might preserve mitochondrial integrity in CA1 pyramidal cells after I/R, at least in part mediated by mK(ATP).

Animals↗
PubMed2004

Diazoxide and dimethyl sulphoxide prevent cerebral hypoperfusion-related learning dysfunction and brain damage after carotid artery occlusion.

Chronic cerebral hypoperfusion, a mild ischemic condition is associated with advancing age and severity of dementia; however, no unanimous therapy has been established to alleviate related neurological symptoms. We imposed a permanent, bilateral occlusion of the common carotid arteries of rats (n=18) to create cerebral hypoperfusion. A mitochondrial ATP-sensitive K+ channel opener diazoxide (DZ, 5 mg/kg) or its solvent dimethyl sulphoxide (DMSO) were administered i.p. (0.25 ml) on five consecutive days after surgery. Sham-operated animals (n=18) served as control for the surgery, while nontreated rats were used as control for the treatments. Three months after the onset of cerebral hypoperfusion, the rats were tested in a hippocampus-related learning paradigm, the Morris water maze. Subsequently, the animals were sacrificed and neurons, astrocytes and microglia were labeled with immunocytochemistry in the dorsal hippocampus. DMSO and diazoxide dissolved in DMSO restored cerebral hypoperfusion-related learning dysfunction and prevented cyclooxygenase-2-positive neuron loss in the dentate gyrus. Cerebral hypoperfusion led to reduced astrocyte proliferation, which was not clearly affected by the treatment. Microglia activation was considerably enhanced by cerebral hypoperfusion, which was completely prevented by diazoxide dissolved in DMSO, but not by DMSO alone. We conclude that diazoxide can moderate ischemia-related neuroinflammation by suppressing microglial activation. Furthermore, we suggest that DMSO is a neuroprotective chemical in ischemic conditions, and it must be considerately used as a solvent for water-insoluble compounds in experimental animal models.

Animals↗
PubMed2004

Targeting mitochondrial ATP-sensitive potassium channels--a novel approach to neuroprotection.

Mitochondrial responses to ischemic stress play an important role in necrosis and apoptosis of brain cells. Recent studies using several different experimental preparations have shown that activation of ATP-sensitive potassium channels in mitochondria (mitoK(ATP) channels) is able to protect neurons and astroglia against injury and death. Thus, targeting of mitoK(ATP) channels appears to be a novel approach to neuroprotection. However, little is known about the mechanisms involved. The purpose of this review is to detail the current state of knowledge about this important, emerging area of investigation, and to provide suggestions for future studies.

Animals↗
PubMed2003

Perineural capsaicin treatment attenuates reactive hyperaemia in the rat skin.

The neural mechanisms of reactive cutaneous hyperaemia were studied by using a novel experimental approach: the simultaneous measurement of cutaneous blood flow by laser-Doppler flowmetry in adjacent innervated and chemodenervated skin regions of the rat hindpaw served by the same artery. Transient occlusion of the femoral artery (0.5-6 min) resulted in reactive hyperaemia that was greatly reduced in the chemodenervated region. After 3 min arterial occlusion, peak cutaneous blood flow was 109+/-13% vs. 53+/-7%* (% change from baseline, n=11, *P<0.05), and the total hyperaemic response was 110+/-21 vs. 52+/-12* (arbitrary perfusion units) in intact vs. chemodenervated skin regions, respectively. The findings provide clear evidence for the involvement of peptidergic capsaicin-sensitive afferent nerves in the mechanism of reactive cutaneous hyperaemia.

Animals↗
PubMed2003

Up-regulation of cerebral carbonic anhydrase by anoxic stress in piglets.

The resuscitation of asphyxiated babies is associated with changes in cerebral protein synthesis that can influence the neurological outcome. Insufficient gas exchange results in rapid shifts in extracellular and intracellular pH. Carbonic anhydrase (CA) plays an important role in buffering acute changes in pH in the brain. We investigated whether asphyxia/re-ventilation influences the expression of cerebral CA isoforms (CA-II, CA-III and CA-IV) in anaesthetized newborn pigs. The cerebral cortex, hippocampus, cerebellum and retina were sampled, and prepared for either CA immunohistochemistry or CA immunoblotting from piglets subjected to asphyxia (10 min) followed by 2-4 h of re-ventilation, and also from normoxic controls. The CA immunoreactivity (IR) of all the isoforms studied was weak in the controls, apart from staining of a few oligodendrocytes in the subcortical white matter, some astrocytes in the superficial layer of the cerebral cortex, the cerebellar Purkinje cells and the retinal Müller cells that possessed moderate CA-II IR. However, asphyxia induced a marked increase in the CA IR of all isoforms in all the cerebral regions investigated and the retina after 4 h of survival. The pyramidal cells of the frontal cortex and hippocampus displayed the most conspicuous increase in CA IR. Immunoblotting confirmed increased levels of all the CA isoenzymes. We conclude that raised CA levels after asphyxia may contribute to the compensatory mechanisms that protect against the pathological changes in the neonatal CNS.

Animals↗
PubMed2002

N-methyl-D-aspartate-induced vasodilation is mediated by endothelium-independent nitric oxide release in piglets.

N-methyl-D-aspartate (NMDA) elicits pial arteriolar dilation that has been associated with neuronal nitric oxide (NO) production. However, endothelial factors or glial P-450 epoxygenase products may play a role. We tested whether NMDA-induced pial vasodilation 1) primarily involves NO diffusion from the parenchyma to the surface arterioles, 2) involves intact endothelial function, and 3) involves a miconazole-sensitive component. Arteriolar diameters were determined using closed cranial window-intravital microscopy in anesthetized piglets. NMDA (10-100 microM) elicited virtually identical dose-dependent dilations in paired arterioles (r = 0.94, n = 15). However, NMDA- but not bradykinin (BK)-induced dilations of arteriolar sections over large veins were reduced by 31 +/- 1% (means +/- SE, P < 0.05, n = 4) compared with adjacent sections on the cortical surface. Also, 100 microM NMDA increased cerebrospinal fluid levels of NO metabolites from 3.7 +/- 1.0 to 5.3 +/- 1.2 microM (P < 0.05, n = 6). Endothelial stunning by intracarotid injection of phorbol 12,13-dibutyrate did not affect NMDA-induced vasodilation but attenuated vascular responses to hypercapnia and BK by approximately 70% (n = 7). Finally, miconazole (n = 6, 20 microM) pretreatment and coapplication with NMDA did not alter vascular responses to NMDA. In conclusion, NMDA appears to dilate pial arterioles exclusively through release and diffusion of NO from neurons to the pial surface in piglets.

Animals↗
PubMed2002

Effects of hypothermia on neuronal-vascular function after cerebral ischemia in piglets.

We determined whether cerebral arteriolar dilation to N-methyl-d-aspartate (NMDA), a response dependent on stimulation of cortical neurons and inhibited by anoxic stress, would be preserved by hypothermia during and following ischemia. Pial arteriolar diameters in anesthetized piglets were determined via intravital microscopy. Arteriolar responses to NMDA (10, 50, and 100 micromol/l) were measured before and 1 h after 10 min of global ischemia. Piglets were exposed to either total body or selective brain cooling (33-34 degrees C). Arteriolar dilation to lower doses or to 100 micromol/l NMDA was not affected by hypothermia alone (51 +/- 3 vs. 46 +/- 7%, normothermia vs. hypothermia; n = 7) in nonischemic animals. However, arteriolar responses to 100 micromol/l NMDA were clearly attenuated after ischemia despite body cooling during ischemia (53 +/- 3 vs. 32 +/- 6%; n = 8), hypothermia during ischemia and early reperfusion (49 +/- 10 vs. 20 +/- 3%; n = 8), or selective brain cooling (48 +/- 5 vs. 20 +/- 5%; n = 10). In contrast, pretreatment with indomethacin resulted in complete preservation of NMDA-induced vasodilation after ischemia. Thus, hypothermia fails to protect against neuronal dysfunction during ischemia.

Animals↗