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Time Course and Mechanism of Myocardial Catecholamine Release During Transient Ischemia In Vivo
Circulation Volume 101, Issue 226 June 2000

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Background—Elevated concentrations of norepinephrine (NE) have been observed in ischemic myocardium. We investigated the magnitude and mechanism of catecholamine release in the myocardial interstitial fluid (MIF) during ischemia and reperfusion in vivo through the use of microdialysis.Methods and Results—In 9 anesthetized pigs, interstitial catecholamine concentrations were measured in the perfusion areas of the left anterior descending coronary artery (LAD) and the left circumflex coronary artery. After stabilization, the LAD was occluded for 60 minutes and reperfused for 150 minutes. During the final 30 minutes, tyramine (154 nmol · kg⁻¹ · min⁻¹) was infused into the LAD. During LAD occlusion, MIF NE concentrations in the ischemic region increased progressively from 1.0±0.1 to 524±125 nmol/L. MIF concentrations of dopamine and epinephrine rose from 0.4±0.1 to 43.9±9.5 nmol/L and from <0.2 (detection limit) to 4.7±0.7 nmol/L, respectively. Local uptake-1 blockade attenuated release of all 3 catecholamines by >50%. During reperfusion, MIF catecholamine concentrations returned to baseline within 120 minutes. At that time, the tyramine-induced NE release was similar to that seen in nonischemic control animals despite massive infarction. Arterial and MIF catecholamine concentrations in the left circumflex coronary artery region remained unchanged.Conclusions—Myocardial ischemia is associated with a pronounced increase of MIF catecholamines, which is at least in part mediated by a reversed neuronal reuptake mechanism. The increase of MIF epinephrine implies a (probably neuronal) cardiac source, whereas the preserved catecholamine response to tyramine in postischemic necrotic myocardium indicates functional integrity of sympathetic nerve terminals.
Nitric Oxide in Renal Cortex and Medulla : An In Vivo Microdialysis Study
- Ai-Ping Zou and
- Allen W. Cowley
Hypertension Volume 29, Issue 11 January 1997

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This study examined the production of nitric oxide (NO) in the renal cortex and medulla through the use of an in vivo microdialysis technique. Oxyhemoglobin (OxyHb) at a concentration of 3 μmol/L was perfused through the dialysis system to trap tissue NO. Methemoglobin (MetHb), which was formed by NO oxidation of OxyHb in the dialysate, was spectrophotometrically assayed at 401 nm. Because the oxidation of OxyHb to produce MetHb is stoichiometric with NO, the production of NO can be determined by the rate of MetHb formation. We found that NO concentration was significantly higher (P<.05) in the medulla (57.1±5.57 nmol/L, n=10) than in the cortex (31.2±5.7 nmol/L, n=9). The minimal detectable NO level of this assay is ≈10 nmol/L. Intravenous infusion of l-arginine (3 mg/kg per minute) for 30 minutes produced a twofold to threefold increase in cortical and medullary NO; N^G-nitro-l-arginine methyl ester (L-NAME) (10 μg/kg per minute) decreased NO by 33% in the renal cortex and by 46.5% in the renal medulla. We have also compared under the same conditions the degradation products of NO, nitrite, and nitrate in the renal cortex and medulla using in vivo microdialysis combined with microtiter plate colorimetry. Nitrite/nitrate concentration was significantly higher (P<.05) in the medulla (2.7±0.6 μmol/L, n=4) than in the cortex (2.1±0.2 μmol/L, n=4). Infusion of l-arginine increased cortical and medullary nitrite/nitrate by 65% and 39%, respectively. L-NAME reduced cortical and medullary nitrite/nitrate by 18% and 23%, respectively. The results indicate that the OxyHb-NO microdialysis trapping technique is a highly sensitive in situ method for detecting regional tissue NO concentration and changes in the NO synthase activity in the kidney. These studies have shown that NO concentration is higher in medullary tissue than in the cortex.
Intrarenal Dopamine Production and Distribution in the Rat : Physiological Control of Sodium Excretion
- Zhi-Qin Wang,
- Helmy M. Siragy,
- Robin A. Felder and
- Robert M. Carey
Hypertension Volume 29, Issue 11 January 1997

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Dopamine (DA), produced by the renal proximal tubule, has been demonstrated as an intrarenal paracrine hormone mediating diuresis and natriuresis. The precise mechanism by which DA exerts its cell-to-cell action is not fully understood. In the present study, renal interstitial fluid (RIF) DA (by in vivo microdialysis) and urinary DA excretion (U_daV) were compared in anesthetized rats on either normal (0.28% NaCl, NS) or high (4.0% NaCl, HS) sodium balance and in response to acute γ-l-glutamyl-l-dopa (gludopa) administration. Urine flow (UV) and sodium excretion (U_naV) in HS were greater than in NS rats. U_daV was increased in HS compared with NS rats. RIF DA was significantly lower in HS than NS rats. Gludopa at 3, 5, and 7.5 nmol/kg (IV bolus) produced a larger increase in U_daV than RIF DA. Only the highest dose of gludopa (7.5 nmol/kg), which resulted in a 7.3-fold increase in U_daV and 1.7-fold increase in RIF DA, was associated with significant diuresis and natriuresis. Cortical and medullary blood flow remained unchanged after gludopa (7.5 nmol/kg) administration, while angiotensin II (100 ng·kg⁻¹·min⁻¹) induced significant reduction in cortical and medullary blood flow. Prior bilateral renal denervation did not have a significant effect on basal DA levels (RIF DA and U_daV) or gludopa-induced DA production or natriuresis and diuresis. These data demonstrated that both chronic sodium loading and acute gludopa administration stimulated renal DA production and release predominantly into the tubule lumen, where DA had a direct tubule action in the control of U_naV. Renal DA production and its renal effects were not significantly regulated by renal sympathetic nerve activity.
Bradykinin B₂ Receptor Modulates Renal Prostaglandin E₂ and Nitric Oxide
- Helmy M. Siragy,
- Ayad A. Jaffa and
- Harry S. Margolius
Hypertension Volume 29, Issue 31 March 1997

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Bradykinin and lys-bradykinin generated intrarenally appear to be important renal paracrine hormones. However, the renal effects of endogenously generated bradykinin are still not clearly defined. In this study, we measured acute changes in renal excretory and hemodynamic functions and renal cortical interstitial fluid levels of bradykinin, prostaglandin E₂, and cGMP in response to an acute intrarenal arterial infusion of the bradykinin B₂ receptor antagonist Hoe 140 (icatibant), cyclooxygenase inhibitor indomethacin, or nitric oxide synthase inhibitor N^G-monomethyl-l-arginine (L-NMMA) given individually or combined in uninephrectomized, conscious dogs (n=10) in low sodium balance. Icatibant caused a significant decrease in urine flow, urinary sodium excretion, and renal plasma flow rate (each P<.001). Glomerular filtration rate did not change during icatibant administration. Icatibant produced an unexpected large increase in renal interstitial fluid bradykinin (P<.0001) while decreasing renal interstitial fluid prostaglandin E₂ and cGMP (each P<.001). Both indomethacin and L-NMMA when given individually caused significant antidiuresis and antinatriuresis and decreased renal blood flow (each P<.001). Glomerular filtration rate decreased during L-NMMA administration (P<.001) and did not change during indomethacin administration. Combined administration of icatibant and indomethacin or L-NMMA caused significant decreases in renal excretory and hemodynamic functions, which were not different from changes observed with icatibant alone. The failure of icatibant to change renal function after inhibition of cyclooxygenase and nitric oxide synthase activity suggests that the effects of kinin B₂ receptor are mediated by intrarenal prostaglandin E₂ and nitric oxide generation. The increase in renal interstitial fluid bradykinin during icatibant requires further study of possible alterations in kinin synthesis, degradation, or clearance as a result of B₂ receptor blockade.
Systemic Administration of Lipopolysaccharide Induces Release of Nitric Oxide and Glutamate and c-fos Expression in the Nucleus Tractus Solitarii of Rats
- Hui-Ching Lin,
- Fang-Jung Wan,
- Bor-Hwang Kang,
- Chin-Chen Wu and
- Ching-Jiunn Tseng
Hypertension Volume 33, Issue 51 May 1999

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Abstract—There is increasing recognition that communication pathways exist between the immune system and brain, which allows bidirectional regulation of immune and brain responses to infection. The endotoxin lipopolysaccharide (LPS) has been reported to elicit release of cytokines and expression of inducible nitric oxide synthase (iNOS) in peripheral organs. Whereas LPS given systemically causes endotoxic shock, little is known about its central nervous system action, particularly the induction of iNOS. Nitric oxide (NO) and glutamate in the nucleus tractus solitarii (NTS) are important mediators of central cardiovascular regulation. We have previously demonstrated that intravenous injections of LPS increased the NO precursor l-arginine–induced depressor effect in the NTS. The present study investigated further the effects of LPS on the release of NO and glutamate in the NTS and the expression of c-fos, an immediate early response gene product, in neural substrates for central cardiovascular control. In vivo microdialysis coupled with chemiluminescence and electrochemical detection techniques were used to measure extracellular levels of NO and glutamate in the rat NTS. Immunohistochemistry was used for the examination of c-fos protein expression. We found that intravenous infusion of LPS (10 mg/kg) produced a biphasic depressor effect, with an early, sharp hypotension that partially recovered in 15 minutes and a secondary, more prolonged hypotension. In the NTS, a progressive increase of extracellular glutamate and NO levels occurred 3 and 4 hours after LPS was given, respectively. The effects of LPS on the induction of delayed hypotension and NO formation in the NTS were abolished by pretreatment with the iNOS inhibitor aminoguanidine. Finally, c-fos protein expression in the NTS and related structures for cardiovascular regulation was observed after LPS challenge. Taken together, these data suggest that an endotoxin given systemically can elicit delayed increases of glutamate release and iNOS-dependent NO production in the NTS and activate the central neural pathway for modulating cardiovascular function.
Intravascular Source of Adenosine During Forearm Ischemia in Humans : Implications for Reactive Hyperemia
- Fernando Costa,
- Paulgun Sulur,
- Mark Angel,
- José Cavalcante,
- Virginia Haile,
- Brian Christman and
- Italo Biaggioni
Hypertension Volume 33, Issue 61 June 1999

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Abstract—It is believed that adenosine is released in ischemic tissues and contributes to reactive hyperemia. We tested this hypothesis in the human forearm using microdialysis to estimate interstitial and intravascular levels of adenosine and caffeine withdrawal to potentiate endogenous adenosine and determine its effect on reactive hyperemia. Forearm blood flow response to ischemia was measured by air plethysmography before and 60 hours after the last dose of caffeine (250 mg TID for 7 days, n=6). Forearm blood flow increased by 274±66% and 467±97% after 3 minutes of forearm ischemia, before and during caffeine withdrawal, respectively (P<0.05). Thus, caffeine withdrawal enhances reactive hyperemia. To determine the source of adenosine, we measured interstitial adenosine with the use of a microdialysis probe inserted into the flexor digitorum superficialis muscle of the forearm, and we measured intravascular adenosine with the use of a microdialysis probe inserted retrogradely into the medial cubital vein. Dialysate samples were collected at 15-minute intervals during resting, forearm ischemia, and recovery periods. Forearm ischemia failed to increase muscle dialysate concentrations of adenosine but did increase intravascular dialysate adenosine 2.1-fold, from 0.61±0.12 to 1.28±0.39 μmol/L (P<0.01, n=8). Intravascular dialysate concentrations of thromboxane B₂ did not increase during ischemia, ruling out platelet aggregation as a source of adenosine. These results support the hypothesis that endogenous adenosine contributes to reactive hyperemia and indicate that the major source of adenosine in the human forearm is intravascular. We speculate that endothelial cells are the source of intravascular adenosine during ischemia.
Altered Pressure-Natriuresis in Obese Zucker Rats
- Keiji Fujiwara,
- Koichi Hayashi,
- Hiroto Matsuda,
- Eiji Kubota,
- Masanori Honda,
- Yuri Ozawa and
- Takao Saruta
Hypertension Volume 33, Issue 61 June 1999

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Abstract—It has not been examined whether the pressure-natriuresis response is altered in the insulin-resistant condition. Furthermore, despite an important role of nitric oxide (NO) in modulating pressure-natriuresis, no investigations have been conducted assessing the renal interstitial NO production in insulin resistance. The present study examined whether pressure-natriuresis was altered in insulin-resistant obese Zucker rats (OZ) and assessed the cortical and medullary nitrate/nitrite (NOx) levels with the use of the renal microdialysis technique. In OZ, serum insulin/glucose ratio (23.0±4.0×10⁻⁸, n=9) and blood pressure (119±3 mm Hg) were greater than those in lean Zucker rats (LZ; 7.0±1.9×10⁻⁸ and 103±4 mm Hg, n=9). The pressure-natriuresis curve in OZ was shifted to higher renal perfusion pressure (RPP), and the slope was blunted compared with that in LZ (0.073±0.015 vs 0.217±0.047 μEq/min kidney weight/mm Hg, P<0.05). The basal renal NOx level was reduced in OZ (cortex, 4.032±0.331 μmol/L; medulla, 4.329±0.515 μmol/L) compared with that in LZ (cortex, 7.315±1.102 μmol/L; medulla: 7.698±0.964 μmol/L). Furthermore, elevating RPP increased the medullary NOx in LZ, but this pressure-induced response was lost in OZ. Four-week treatment with troglitazone, an insulin-sensitizing agent, improved hyperinsulinemia, systemic hypertension, and basal renal NOx levels (cortex, 5.639±0.286 μmol/L; medulla, 5.978±0.284 μmol/L), and partially ameliorated the pressure-natriuresis curves; the slope of pressure-natriuresis curves and elevated RPP-induced NOx, however, were not corrected. In conclusion, our study suggests that insulin resistance is closely associated with abnormal pressure-natriuresis and hypertension. These deranged renal responses to insulin resistance are most likely attributed to impaired medullary NO production within the medulla.
Estimation of Skeletal Muscle Interstitial Adenosine During Forearm Dynamic Exercise in Humans
- Fernando Costa,
- John Heusinkveld,
- Robert Ballog,
- Stephen Davis and
- Italo Biaggioni
Hypertension Volume 35, Issue 51 May 2000

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Abstract—It has been proposed that adenosine is a metabolic signal that triggers activation of muscle afferents involved in the exercise pressor reflex. Furthermore, exogenous adenosine induces sympathetic activation that mimics the exercise pressor reflex, and blockade of adenosine receptors inhibits sympathetic activation induced by exercise. Thus, we hypothesize that adenosine is released locally by the muscle during exercise. We used microdialysis probes, placed in the flexor digitorium superficialis muscle, to estimate muscle interstitial adenosine levels in humans. We estimated resting in vivo muscle interstitial adenosine concentrations (0.292±0.058 μmol/L, n=4) by perfusing increasing concentrations of adenosine to determine the gradient produced in the dialysate. Muscle interstitial adenosine concentrations increased from 0.23±0.04 to 0.82±0.14 μmol/L (n=14, P<0.001) during intermittent dynamic exercise at 50% of maximal voluntary contraction. Lactate increased from 0.8±0.1 to 2.3±0.3 mmol/L (P<0.001). Lower intensity (15% maximal voluntary contraction) intermittent dynamic exercise increased adenosine concentrations from 0.104±0.02 to 0.42±0.16 μmol/L (n=7). The addition of ischemia to this low level of exercise produced a greater increase in adenosine (from 0.095±0.02 to 0.48±0.2 μmol/L) compared with nonischemic exercise (0.095±0.02 to 0.25±0.12 μmol/L). These results indicate that microdialysis is useful in estimating adenosine concentrations and in reflecting changes in muscle interstitial adenosine during dynamic exercise in humans.
Adenosine, a Metabolic Trigger of the Exercise Pressor Reflex in Humans
- Fernando Costa,
- Andre Diedrich,
- Benjamin Johnson,
- Paulgun Sulur,
- Ginnie Farley and
- Italo Biaggioni
Hypertension Volume 37, Issue 31 March 2001

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There is substantial evidence that adenosine activates muscle afferent nerve fibers leading to sympathetic stimulation, but the issue remains controversial. To further test this hypothesis, we used local injections of adenosine into the brachial artery while monitoring systemic muscle sympathetic nerve activity (MSNA) with peroneal microneurography. The increase in MSNA induced by 3 mg intrabrachial adenosine (106±32%) was abolished if forearm afferent traffic was interrupted by axillary ganglionic blockade (21±19%, n=5, P<0.05). Furthermore, the increase in MSNA induced by intravenous adenosine was 3.7-fold lower and later (onset latency 20.9±4.8 seconds versus 8.5±1 seconds) than intrabrachial adenosine. Finally, we used forearm exercise (dynamic handgrip at 50% and 15% maximal voluntary contraction, MVC), with or without superimposed ischemia, to modulate interstitial levels of adenosine (estimated with microdialysis) while monitoring MSNA. Fifteen minutes of intense (50% MVC) and moderate (15% MVC) exercise increased adenosine dialysate concentrations from 0.31±0.1 to 1.24±0.4 μmol/L (528±292%) and from 0.1±0.02 to 0.419±0.16 μmol/L (303±99%), respectively (n=7, P<0.01). MSNA increased 88±25% and 38±28%, respectively. Five minutes of moderate exercise increased adenosine from 0.095±0.02 to 0.25±0.12 μmol/L, and from 0.095±0.02 to 0.48±0.19 μmol/L when ischemia was superimposed on exercise (n=7, P=0.01). The percent increase in MSNA induced by the various interventions correlated with the percent increase in dialysate adenosine levels (r=0.96). We conclude that adenosine activates muscle afferent nerves, triggering reflex sympathetic activation.
ADP Acting on P2Y₁₃ Receptors Is a Negative Feedback Pathway for ATP Release From Human Red Blood Cells
- Lingwei Wang,
- Göran Olivecrona,
- Matthias Götberg,
- Martin L. Olsson,
- Maria Sörhede Winzell and
- David Erlinge
Circulation Research Volume 96, Issue 24 February 2005

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Red blood cells may regulate tissue circulation and O₂ delivery by releasing the vasodilator ATP in response to hypoxia. When released extracellularly, ATP is rapidly degraded to ADP in the circulation by ectonucleotidases. In this study, we show that ADP acting on P2Y₁₃ receptors on red blood cells serves as a negative feedback pathway for the inhibition of ATP release. mRNA of the ADP receptor P2Y₁₃ was highly expressed in human red blood cells and reticulocytes. The stable ADP analogue 2-MeSADP decreased ATP release from red blood cells by inhibition of cAMP. The P2Y₁₂ and P2Y₁₃ receptor antagonist AR-C67085 (30 μmol/L), but not the P2Y₁ blocker MRS2179, inhibited the effects of 2-MeSADP. At doses where AR-C67085 only blocks P2Y₁₂ (100 nmol/L), it had no effect. AR-C67085 and the nucleotidase apyrase increased cAMP per se, indicating a constant cAMP inhibitory effect of endogenous extracellular ADP. 2-MeSADP reduced plasma ATP concentrations in an in vivo pig model. Our results indicate that the ATP degradation product ADP inhibits ATP release by acting on the red blood cell P2Y₁₃ receptor. This negative feedback system could be important in the control of plasma ATP levels and tissue circulation.
Release of Fatty Acid Amides in a Patient With Hemispheric Stroke: A Microdialysis Study
- Wolf-R. Schäbitz,
- Andrea Giuffrida,
- Christian Berger,
- Alfred Aschoff,
- Markus Schwaninger,
- Stefan Schwab and
- Daniele Piomelli
Stroke Volume 33, Issue 81 August 2002

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Background— Excitotoxic insults such as stroke may induce release of fatty acid ethanolamides (FAEs), contributing to the downstream events in the ischemic cascade. We therefore studied release of FAEs such as anandamide, palmitylethanolamide (PEA), and oleylethanolamide (OEA) in the brain of a patient suffering from malignant hemispheric infarction treated with hypothermia.Case Description— A patient with life-threatening hemispheric stroke was treated with moderate hypothermia (33°C) that was maintained for 3 days, followed by a 3-day rewarming period. Microdialysis was applied to measure glutamate, lactate, and glycerol by using a microdialysis analyzer. FAEs were measured by microdialysis coupled with high-performance liquid chromatography/mass spectrometry. Release of neuroprotective fatty amides occurred within the first day after ischemia and reached high concentrations for all 3 substances in tissue surrounding the primary ischemic lesion: anandamide up to 42 pmol/mL, PEA up to 120 pmol/mL, and OEA up to 242 pmol/mL. There was a significant correlation with elevation of lactate as early marker for the hypoxic insult.Conclusions— This is the first report demonstrating release of FAEs in vivo during human stroke and may suggest contribution of the FAE signaling system to the pathophysiological events after ischemia.
Acute Focal Neurological Deficits in Aneurysmal Subarachnoid Hemorrhage: Relation of Clinical Course, CT Findings, and Metabolite Abnormalities Monitored With Bedside Microdialysis
- Asita Sarrafzadeh,
- Daniel Haux,
- Oliver Sakowitz,
- Goetz Benndorf,
- Harry Herzog,
- Ingeborg Kuechler and
- Andreas Unterberg
Stroke Volume 34, Issue 61 June 2003

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Background and Purpose— We sought (1) to identify early metabolic markers for the development of (ir)reversible neurological deficits and cerebral infarction in subarachnoid hemorrhage (SAH) patients by using the microdialysis technique and (2) to evaluate the influence of intracerebral hemorrhage (ICH) on microdialysis parameters.Methods— We performed a prospective study of 44 SAH patients with acute focal neurological deficits (AFND) occurring acutely with SAH (due to ICH) or directly after surgery (due to clip stenosis, thromboembolism, or early edema). Fifty-one nonischemic SAH patients served as a control group. A microdialysis catheter was inserted into the vascular territory of the aneurysm after clipping. The microdialysates were analyzed hourly for extracellular glucose, lactate, lactate/pyruvate ratio, glutamate, and glycerol with a bedside analyzer. Microdialysis-related CT findings were evaluated for the presence of ICH and cerebral infarction. Reversibility of neurological symptoms after 4 weeks and 6- and 12-month outcomes were assessed.Results— In patients with AFND, cerebral metabolism was severely disturbed when microdialysis started compared with controls (P<0.005). Infarction on CT was associated with pathological microdialysis parameters (P<0.002) and development of a fixed deficit (P<0.003), while the presence of ICH alone was not. A secondary neurological deterioration of AFND patients (n=11) was reflected by preceding (0 to 20 hours) changes of microdialysate concentrations.Conclusions— In the presence of ICH, pathological microdialysis values may indicate reversible tissue damage. Extreme microdialysis values and pathological microdialysis concentrations that further deteriorate 2-fold are highly indicative of the development of cerebral infarction and permanent neurological deficits. Therefore, the analysis of relative changes of microdialysis parameters is crucial for the detection of ischemia in SAH patients.
Prediction of Malignant Course in MCA Infarction by PET and Microdialysis
- Christian Dohmen,
- Bert Bosche,
- Rudolf Graf,
- Frank Staub,
- Lutz Kracht,
- Jan Sobesky,
- Michael Neveling,
- Gerit Brinker and
- Wolf-Dieter Heiss
Stroke Volume 34, Issue 91 September 2003

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Background and Purpose— To predict malignant course in patients with large middle cerebral artery (MCA) infarction, we combined PET imaging and neuromonitoring, including microdialysis.Methods— Thirty-four patients with stroke of >50% of the MCA territory in early cerebral CT scan were included. Probes for microdialysis and measurement of intracranial pressure and tissue oxygen pressure (Pto₂) were placed into the ipsilateral frontal lobe. PET was performed with ¹¹C-flumazenil to assess CBF and irreversible neuronal damage.Results— PET measurements within 24 hours after stroke showed larger volumes of ischemic core (mean, 144.5 versus 62.2 cm³) and larger volumes of irreversible neuronal damage (157.9 versus 47.0 cm³) in patients with malignant course (ie, edema formation with midline shift) than in patients with benign course. Mean cerebral blood flow values within the ischemic core were significantly lower and the volume of the ischemic penumbra was smaller in the malignant than in the benign group. In patients with malignant course, cerebral perfusion pressure dropped to <50 to 60 mm Hg 22 to 72 hours (mean, 52.0 hours) after onset of symptoms; subsequently, Pto₂ dropped and glutamate increased, indicating secondary ischemia. Maximal changes in the monitored variables reached significant levels for glutamate, aspartate, GABA, glycerol, lactate-to-pyruvate ratio, hypoxanthine, intracranial pressure, cerebral perfusion pressure, and Pto₂.Conclusions— PET allowed prediction of malignant MCA infarction within the time window suggested for hemicraniectomy. Neuromonitoring helped to classify the clinical courses by characterizing pathophysiological sequelae of malignant edema formation. In contrast to PET, however, it did not predict fatal outcome early enough for successful implementation of invasive therapies.
Cerebral Ischemia in Aneurysmal Subarachnoid Hemorrhage: A Correlative Microdialysis-PET Study
- Asita S. Sarrafzadeh,
- Daniel Haux,
- Lutz Lüdemann,
- Holger Amthauer,
- Michail Plotkin,
- Ingeborg Küchler and
- Andreas W. Unterberg
Stroke Volume 35, Issue 31 March 2004

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Background and Purpose— Cerebral microdialysis (MD) is discussed as a technique for detection of cerebral ischemia in subarachnoid hemorrhage; however, clinical data on cerebral blood flow (CBF) are limited in these patients. The main objective of this study was to investigate whether pathological MD parameters reflect a reduced regional CBF (rCBF) determined by ¹⁵O-H₂O PET.Methods— Thirteen subarachnoid hemorrhage patients (age, 48.7±15.0 years; World Federation of Neurological Surgeons grade 1 to 5) were studied. Extracellular glucose, lactate, lactate/pyruvate (L/P) ratio, glutamate, and glycerol levels were analyzed hourly. rCBF was determined in the volume of interest of the MD catheter and all vascular territories. MD values were correlated to rCBF on the day of PET. Then, MD concentrations of asymptomatic versus ischemic phases (3-day medians) were analyzed.Results— In symptomatic patients (n=10), rCBF was significantly lower compared with controls (n=3, P=0.048). Glutamate correlated best with rCBF (r=−0.66; P=0.014), followed by glycerol (r=−0.62; P=0.021). The L/P ratio was most sensitive (0.82) and specific (1.0) in indicating symptoms of ischemia, but only during longer periods of ischemia.Conclusions— rCBF correlates best with glutamate, followed by glycerol, whereas the L/P ratio is sensitive only after longer periods of ischemia. Clinically relevant regional metabolic derangements occur already above an rCBF of 20 mL·100 g⁻¹·min⁻¹. Future research should focus on identifying alternative causes of metabolic derangement in subarachnoid hemorrhage patients and optimal treatment management in these patients.
Identification and Clinical Impact of Impaired Cerebrovascular Autoregulation in Patients With Malignant Middle Cerebral Artery Infarction
- Christian Dohmen,
- Bert Bosche,
- Rudolf Graf,
- Thomas Reithmeier,
- Ralf-Ingo Ernestus,
- Gerrit Brinker,
- Jan Sobesky and
- Wolf-Dieter Heiss
Stroke Volume 38, Issue 11 January 2007

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Background and Purpose— To study cerebrovascular autoregulation and its impact on clinical course in patients with impending malignant middle cerebral artery infarction, we used invasive multimodal neuromonitoring, including measurement of cerebral perfusion pressure, tissue oxygen pressure, and microdialysis.Methods— Fifteen patients with a stroke that involved >50% of the middle cerebral artery territory were included. Probes were placed into the ipsilateral frontal lobe. Autoregulation was assessed by calculation of the cerebral perfusion pressure–oxygen reactivity index (COR) and the correlation coefficient (R) of cerebral perfusion pressure and tissue oxygen pressure at 24 and 72 hours after stroke.Results— COR and R at 24 hours after stroke were higher in the 8 patients with a malignant course (ie, massive edema formation) compared with the 7 patients with a benign course (COR, 1.99±1.46 versus 0.68±0.29; R, 0.49±0.28 versus 0.06±0.31; P<0.05), indicating impaired autoregulation in the malignant course group. At 72 hours, further increases in COR and R were observed in the malignant course group in contrast to the benign course group with stable values over time (COR, 3.31±2.38 versus 0.75±0.31; R, 0.75±011 versus 0.36±0.27; P<0.05). With a COR of 0.99, a cutoff value for prediction of a malignant course was found. The lactate-pyruvate ratio was higher in patients with a malignant compared with a benign course at both time points. COR, R, and the lactate-pyruvate ratio showed significant correlations with outcome parameters as a midline shift on cranial computed tomography and score on the modified Rankin scale after 3 months.Conclusions— We found early impairment of cerebrovascular autoregulation in peri-infarct tissue of patients who developed malignant brain edema, whereas autoregulation was preserved in patients with a benign course. Impaired cerebral autoregulation seems to play a key role for development of a malignant course and might serve as a predictive marker. Impaired cerebral autoregulation also accentuates the need for consequent adjustment of cerebral perfusion pressure in patients with impaired autoregulation.
Potent ς₁-Receptor Ligand 4-Phenyl-1-(4-Phenylbutyl) Piperidine Modulates Basal and N-Methyl-d-Aspartate–Evoked Nitric Oxide Production In Vivo
- Anish Bhardwaj,
- Masahiko Sawada,
- Edythe D. London,
- Raymond C. Koehler,
- Richard J. Traystman and
- Jeffrey R. Kirsch
Stroke Volume 29, Issue 111 November 1998

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Background and Purpose—ς-Receptor ligands ameliorate ischemic neuronal injury and modulate neuronal responses to N-methyl-d-aspartate (NMDA) receptor stimulation. Because NMDA-evoked synthesis of nitric oxide (NO) may play an important role in excitotoxic-mediated injury, we tested the hypothesis that ς-receptor ligands attenuate basal and NMDA-evoked NO production in the striatum in vivo.Methods—Microdialysis probes were placed bilaterally into the striatum of halothane-anesthetized adult Wistar rats. Rats were divided into 7 treatment groups and perfused with artificial cerebrospinal fluid (aCSF) containing 3 μmol/L [¹⁴C]l-arginine for 2 to 3 hours followed by NMDA in various combinations with the following drugs: l-nitroarginine (L-NNA); the ς₁-receptor ligand 4-phenyl-1-(4-phenylbutyl) piperidine (PPBP); the selective ς₁-receptor antagonist 1-(cyclopropylmethyl)-4-(2′-oxoethyl) piperidine hydrobromide (DuP 734); and the noncompetitive NMDA receptor blocker MK-801 in aCSF. Right-left differences between [¹⁴C]l-citrulline in the effluent from rats treated with different drug combinations were assumed to reflect differences in NO production.Results—After a 3-hour loading period with [¹⁴C]l-arginine, addition of 1 mmol/L NMDA increased [¹⁴C]l-citrulline recovery compared with aCSF alone. This NMDA-evoked increase was inhibited by 1 mmol/L of L-NNA and PPBP. Perfusion of 1 mmol/L of the ς₁-receptor antagonist DuP 734 with 1 mmol/L PPBP augmented NMDA-evoked [¹⁴C]l-citrulline recovery compared with perfusion with PPBP and NMDA. MK-801 attenuated the basal as well as NMDA-evoked [¹⁴C]l-citrulline recovery. PPBP did not cause any further attenuation in the basal and NMDA-evoked [¹⁴C]l-citrulline recovery in the presence of MK-801.Conclusions—These data indicate that a ς₁-receptor ligand attenuates basal as well as NMDA-evoked NO production. Because the attenuated NO production was reversed by DuP 734, PPBP appears to act as an agonist at the ς₁-receptor. Attenuated NO production by ς₁-receptor agonists provides one possible mechanism for focal ischemic neuroprotection.
Neurochemical Monitoring of Fatal Middle Cerebral Artery Infarction
- C. Berger,
- A. Annecke,
- A. Aschoff,
- M. Spranger and
- S. Schwab
Stroke Volume 30, Issue 21 February 1999

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Background—Microdialysis is a method for neurochemical monitoring that has been applied more frequently over the past few years in patients suffering from subarachnoid hemorrhage, acute brain injury, and stroke. It is used to study the course of extracellular molecules of low molecular weight, such as excitatory amino acids or metabolic end products.Case Description—We report the case of a 43-year-old patient suffering from left hemispheric stroke with a space-occupying postischemic edema leading to a considerable mass effect on the contralateral side. For treatment of severe edema, hypothermia was initiated. The microdialysis and intracranial pressure probe were placed into the noninfarcted hemisphere. A massive increase in levels of glutamate, glycerine, and the lactate-pyruvate ratio was measured 24 hours before intracranial pressure elevation was observed and brain death occurred.Conclusions—Monitoring excitatory amino acids, glycerine as a membrane component, and lactate-pyruvate ratio as an energy marker by microdialysis is a useful tool to increase our understanding of biochemical events in secondary brain damage. For future prevention of secondary ischemia in patients with massive stroke, close neurochemical monitoring might be valuable to improve therapy, particularly in the critically ill.
Nitric Oxide Production in the CA1 Field of the Gerbil Hippocampus After Transient Forebrain Ischemia : Effects of 7-Nitroindazole and N^G-Nitro-l-Arginine Methyl Ester
- Baiping Lei,
- Naoto Adachi,
- Takumi Nagaro and
- Tatsuru Arai
Stroke Volume 30, Issue 31 March 1999

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Background and Purpose—The present study was designed to examine the time course of nitric oxide (NO) production and the source of NO in the CA1 field of the gerbil hippocampus after transient forebrain ischemia.Methods—The production of NO in the CA1 field of the hippocampus after transient ischemia was monitored consecutively by measuring total NO metabolites (NO_x⁻, NO₂⁻ plus NO₃⁻) with the use of brain microdialysis. 7-Nitroindazole (7-NI) and N^G-nitro-l-arginine methyl ester were used to dissect the relative contributions of neuronal NO synthase and endothelial NO synthase to the NO production. The histological outcomes of 7-NI in 5- and 10-minute global ischemia were also evaluated.Results—The production of NO in the CA1 field of the hippocampus after ischemia was dependent on the severity of ischemia. Ischemia for 2 or 5 minutes did not induce a significant increase in NO_x⁻ levels in the CA1 field of the hippocampus after reperfusion, whereas the 10- and 15-minute ischemias produced significant and persistent increases in NO_x⁻ levels. 7-NI did not inhibit the basal NO_x⁻ levels and showed no effects on NO_x⁻ levels after 5 minutes of ischemia. However, it completely inhibited the increased NO_x⁻ levels after 10 or 15 minutes of ischemia. 7-NI provided minor neuroprotection in 5 minutes but not in 10 minutes of global ischemia.Conclusions—The increased NO level in the CA1 field of the hippocampus after ischemia is produced mostly by neuronal NO synthase, whereas the basal NO level mainly originates from endothelial NO synthase. The observed neuroprotective effect of 7-NI in 5-minute global ischemia in gerbils may not be due to neuronal NO synthase inhibition by this drug.
Neuroprotective FK506 Does Not Alter In Vivo Nitric Oxide Production During Ischemia and Early Reperfusion in Rats
- Thomas J. Toung,
- Anish Bhardwaj,
- Valina L. Dawson,
- Ted M. Dawson,
- Richard J. Traystman and
- Patricia D. Hurn
Stroke Volume 30, Issue 61 June 1999

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Background and Purpose—Previous studies have demonstrated that the immunosuppressant FK506 provides neuroprotection in experimental brain injury and suggest that this action may be mediated by suppression of neuronal nitric oxide synthase activation that occurs after ischemic depolarization. We sought to determine whether FK506 reduces histological injury after middle cerebral artery occlusion (MCAO) in the rat and whether the neuroprotective effect is mediated via suppression of in vivo nitric oxide (NO) production during ischemia or early reperfusion.Methods—Under controlled conditions of normoxia, normocarbia, and normothermia, halothane-anesthetized male Wistar rats were subjected to 2 hours of MCAO by the intraluminal occlusion technique in a blinded, randomized experimental trial. Ipsilateral parietal cortical laser-Doppler flowmetry was monitored throughout ischemia. Animals were randomly assigned to 4 pretreatment groups: intravenous FK506 0.3 mg/kg or 1.0 mg/kg, vehicle (cremaphor), or an equivalent volume of saline administered 30 minutes before MCAO. Infarction volume was assessed by a triphenyltetrazolium chloride staining at 22 hours of reperfusion. In separate experiments, microdialysis probes were placed bilaterally into the striatum. Rats were perfused with artificial cerebrospinal fluid containing 3 μmol/L [¹⁴C]- l-arginine for 3 hours and then subjected to 2 hours of right MCAO. Intravenous 0.3 mg/kg FK506 or cremaphor was given 30 minutes before right MCAO. Right-left differences between [¹⁴C]-l-citrulline in the effluent were assumed to reflect differences in NO production.Results—All values are mean±SE. FK506 at 0.3 mg/kg reduced infarction volume in cortex: 40±12 mm³ compared with saline (109±15 mm³) and cremaphor vehicle (148±23) (P<0.05). Striatal infarction was also reduced by low-dose FK506: 16±4 mm³ versus 36±4 mm³ and 34±4 mm³ in saline and vehicle groups, respectively (P<0.05). High-dose treatment reduced infarction volume in cortex (61±14 mm³, P<0.05 from saline and vehicle groups) and in striatum (22±5 mm³, P<0.05 from saline and vehicle groups). [¹⁴C]-l-citrulline recovery via microdialysis was markedly enhanced in ischemic compared with nonischemic striatum. However, ischemia-evoked [¹⁴C]-l-citrulline recovery was not different in FK506-treated rats compared with vehicle-treated animals.Conclusions—These data demonstrate that FK506 provides robust neuroprotection against transient focal cerebral ischemia in the rat. The mechanism of protection in vivo is not through attenuation of ischemia-evoked NO production during MCAO and early reperfusion.
Middle Cerebral Artery Occlusion and Reperfusion in Primates Monitored by Microdialysis and Sequential Positron Emission Tomography
- Per Enblad,
- Peter Frykholm,
- Johann Valtysson,
- Hans C:son Silander,
- Jesper Andersson,
- Karl-Johan Fasth,
- Yasuyoshi Watanabe,
- Bengt Långström,
- Lars Hillered and
- Lennart Persson
Stroke Volume 32, Issue 71 July 2001

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Background and Purpose—In a previous investigation concerning the hemodynamic and metabolic changes over time displayed by sequential positron emission tomography (PET) in a middle cerebral artery (MCA) occlusion/reperfusion primate model, a metabolic threshold for irreversible ischemia could be identified (reduction of metabolic rate of oxygen [CMRO₂] to ≈60% of the contralateral hemisphere). To evaluate the potential of microdialysis (MD) as an instrument for chemical brain monitoring, the aim of this subsequent study was to relate the chemical changes in MD levels directly to the regional metabolic status (CMRO₂ above or below the metabolic threshold) and the occurrence of reperfusion, as assessed by PET.Methods—Continuous MD (2 probes in each brain) and sequential PET measurements were performed during MCA occlusion (2 hours) and 18 hours (mean) of reperfusion in 8 monkeys (Macaca mulatta). Energy-related metabolites (lactate, pyruvate, and hypoxanthine) and glutamate were analyzed. The MD probe regions were divided into 3 categories on the basis of whether CMRO₂ was below or above 60% of the contralateral region (metabolic threshold level) during MCA occlusion and whether reperfusion was obtained: severe ischemia with reperfusion (n=4), severe ischemia without reperfusion (n=4), and penumbra with reperfusion (n=5).Results—The lactate/pyruvate ratio, hypoxanthine, and glutamate showed similar patterns. MD probe regions with severe ischemia and reperfusion and probe regions with severe ischemia and no reperfusion displayed high and broad peaks, respectively, during MCA occlusion, and the levels almost never decreased to baseline. Penumbra MD probe regions displayed only slight transient increases during MCA occlusion and returned to baseline.Conclusions—This experimental study of focal ischemia showed that the extracellular changes of energy-related metabolites and glutamate differed depending on the ischemic state of the brain during MCA occlusion and depending on whether reperfusion occurred. If MD proves to be beneficial in clinical practice, it appears important to observe relative changes over time.

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