Matthias Behrends

Signal transduction of ischemic preconditioning

Ischemic preconditioning is a phenomenon in which exposure of the heart to a brief period of ischemia causes it to quickly adapt itself to become resistant to infarction from a subsequent ischemic insult. The mechanism is not fully understood but, at least in the rabbit, it is known to be triggered by occupation of adenosine receptors, opioid receptors, bradykinin receptors and the generation of free radicals during the preconditioning ischemia. All of these are thought to converge on and activate protein kinase C (PKC), which in turn activates a tyrosine kinase. This kinase cascade eventually terminates on some unknown effector, possibly a potassium channel or a cytoskeletal protein, which makes the cells resistant to infarction. If this process can be understood, it should be possible to devise a method for conferring this protection to patients with acute myocardial infarction.

Infarct size reduction by AT1-receptor blockade through a signal cascade of AT2-receptor activation, bradykinin and prostaglandins in pigs ☆

OBJECTIVE We studied the effect of the angiotensin II type 1 (AT1)-receptor antagonist candesartan on infarct size resulting from regional myocardial ischemia in pigs. BACKGROUND The effects of AT1-receptor blockade on infarct size in different species remain controversial and its potential cardioprotective mechanisms are still unclear. In pigs, infarct development closely resembles that observed in humans. METHODS A total of 62 enflurane-anesthetized pigs underwent a protocol of 90-min low-flow ischemia and 120-min reperfusion. Systemic hemodynamics (micromanometer), regional myocardial function (sonomicrometry), regional myocardial blood flow (microspheres) and infarct size (TTC [triphenyl tetrazolium chloride]-staining) were determined. RESULTS Left ventricular peak pressure decreased with candesartan (1 mg/kg i.v.) from 97+/-2 standard error of the mean (SEM) to 86+/-5 mm Hg and was then readjusted by aortic banding. In placebo pigs (n=9), infarct size was 21.8+/-4.8% of the area at risk. Candesartan (n=7) reduced infarct size to 9.7+/-2.5% (p < 0.05). Pretreatment with the AT2-receptor antagonist PD123319 (3 microg/kg/min intracoronarily [i.c.]; n=8), the bradykinin B2-receptor antagonist HOE140 (0.01 microg/kg/min i.c.; n=8) or the cyclooxygenase inhibitor indomethacin (10 mg/kg i.v.; n= 8) per se did not affect infarct size but did abolish the reduction of infarct size achieved by candesartan (PD123319 + candesartan (n=7): 23.2+/-4.7%; HOE140 + candesartan (n=7): 18.2+/-4.0%; indomethacin + candesartan (n=8): 21.1+/-5.2%). Hemodynamics, regional myocardial blood flow during ischemia and the area at risk were comparable among all groups of pigs. CONCLUSIONS Reduction of infarct size by the AT1-receptor antagonist candesartan in pigs involves angiotensin II type 2 receptor (AT2) activation, bradykinin and prostaglandins.

Enhanced reduction of myocardial infarct size by combined ACE inhibition and AT1-receptor antagonism

The effects of the angiotensin‐converting‐enzyme inhibitor (ACEI) ramiprilat, the angiotensin II type 1 receptor antagonist (AT1A) candesartan, and the combination of both drugs on infarct size (IS) resulting from regional myocardial ischaemia were studied in pigs. Both ACEI and AT1A reduce myocardial IS by a bradykinin‐mediated process. It is unclear, however, whether the combination of ACEI and AT1A produces a more pronounced IS reduction than each of these drugs alone. Forty‐six enflurane‐anaesthetized pigs underwent 90 min low‐flow ischaemia and 120 min reperfusion. Systemic haemodynamics (micromanometer), subendocardial blood flow (ENDO, microspheres) and IS (TTC‐staining) were determined. The decreases in left ventricular peak pressure by ACEI (by 9±2 (s.e.mean) mmHg), AT1A (by 11±2 mmHg) or their combination (by 18±3 mmHg, P<0.05 vs ACEI and AT1A, respectively) were readjusted by aortic constriction prior to ischaemia. With placebo (n=10), IS averaged 20.0±3.3% of the area at risk. IS was reduced to 9.8±2.6% with ramiprilat (n=10) and 10.6±3.1% with candesartan (n=10). Combined ramiprilat and candesartan (n=10) reduced IS to 6.7±2.1%. Blockade of the bradykinin‐B2‐receptor with icatibant prior to ACEI and AT1A completely abolished the reduction of IS (n=6, 22.8±6.1%). The relationship between IS and ischaemic ENDO with placebo was shifted downwards by each ACEI and AT1A and further shifted downwards with their combination (P<0.05 vs all groups); icatibant again abolished such downward shift. The combination of ACEI and AT1A enhances the reduction of IS following ischaemia/reperfusion compared to a monotherapy by either drug alone; this effect is mediated by bradykinin.

Intraperitoneal and retroperitoneal carbon dioxide insufflation evoke different effects on caval vein pressure gradients in humans: evidence for the starling resistor concept of abdominal venous return.

Background The authors hypothesized that intraperitoneal and retroperitoneal carbon dioxide insufflation during surgical procedures evoke markedly different effects on the venous low-pressure system, induce different inferior caval vein pressure gradients at similar insufflation pressures, and may provide evidence for the Starling resistor concept of abdominal venous return. Methods Intra- and extrathoracic caval vein pressures were measured using micromanometers during carbon dioxide insufflation at six cavity pressures (baseline and 10, 15, 20, and 24 mmHg and desufflation) in 20 anesthetized patients undergoing laparoscopic (supine, n = 8) or left (n = 6) or right (n = 6) retroperitoneoscopic (prone position) surgery. Intracavital, esophageal, and gastric pressures also were assessed. Data were analyzed for insufflation pressure–dependent and group effects by one-way and two-way analysis of variance for repeated measurements, respectively, followed by the Newman–Keuls post hoc test (P < 0.05). Results Intraperitoneal, unlike retroperitoneal, insufflation markedly increased, in an insufflation pressure–dependent fashion, the inferior-to-superior caval vein pressure gradient (P < 0.00001) at the level of the diaphragm. In contrast to what was observed with retroperitoneal insufflation, transmural intrathoracic caval vein pressure increased at 10 mmHg insufflation pressure, but the increase flattened with an insufflation pressure of more than 10 mmHg, and pressure decreased with an inflation pressure of 20 mmHg (P = 0.0397). These data are consistent with a zone 2 or 3 abdominal vascular condition during intraperitoneal and a zone 3 abdominal vascular condition during retroperitoneal insufflation. Conclusions Intraperitoneal but not retroperitoneal carbon dioxide insufflation evokes a transition of the abdominal venous compartment from a zone 3 to a zone 2 condition, presumably impairing venous return, supporting the Starling resistor concept of abdominal venous return in humans.

Transient Hyperglycemia Affects the Extent of Ischemia-Reperfusion-induced Renal Injury in Rats

Background:Chronic hyperglycemia is known to increase renal injury, particularly during ischemia-reperfusion episodes. The goal of this study was to examine whether transient hyperglycemia during or after renal ischemia-reperfusion increased renal dysfunction. Methods:Male Lewis rats underwent sham operations or unilateral nephrectomies followed by contralateral renal ischemia-reperfusion. Hyperglycemic rats were given 25% dextrose to induce transient hyperglycemia lasting throughout the duration of ischemia (PI rats) or beginning 2 h after initiation of reperfusion (PR rats). Additional vehicle control rats received saline and underwent ischemia-reperfusion surgery as with PI and PR rats. Twenty-five minutes of mild renal ischemia followed by 24 h of reperfusion was induced by occluding the renal artery and vein. Results:Terminal serum creatinine concentrations were significantly higher in the PI rats when compared with the PR or vehicle control rats. Histology demonstrated significantly increased necrosis in the PI rats relative to PR and control animals. Tissue analyses demonstrated significantly higher heat shock protein 70, heat shock protein 32, and cleaved caspase-3 protein levels in the PI rats. Oxidative stress generated through the xanthine pathway in the PI group was significantly increased compared with the oxidative stress in the PR and vehicle control rats. In contrast, vascular endothelial growth factor and erythropoietin were significantly decreased in the PI rats compared with the PR rats and controls. Conclusions:Hyperglycemia that occurred during renal ischemia-reperfusion resulted in severe functional injury compared with normoglycemia or with hyperglycemia that occurred after reperfusion. Investigated molecular pathways are more profoundly affected by hyperglycemia that occurs before renal ischemia-reperfusion.

Increased severity of renal ischemia-reperfusion injury with venous clamping compared to arterial clamping in a rat model

BACKGROUND Arterial inflow occlusion is a well-known mechanism of renal injury during major vascular surgery. In contrast, renal injury from venous outflow obstruction is poorly understood. The goal of this study was to examine the injury pattern of renal venous outflow obstruction, compare this with the traditional model of arterial occlusion, and examine possible mechanisms. METHODS Male Fisher rats were used for the renal warm ischemia model. Twenty-five minutes of renal ischemia was induced by selectively occluding either the renal artery or vein. After 24 h of reperfusion, whole blood and kidney tissue were collected for further analysis. RESULTS Serum creatinine (SCr) concentrations taken 24 h after reperfusion were significantly greater in the venous occlusion group (V) when compared to the arterial group (A). While histology did not demonstrate significant differences in extent of necrosis between both groups, a stronger inflammatory response resulted from venous occlusion. Specifically, significantly greater MCP-1 mRNA and significantly greater MCP-1, TNF-alpha, and HO-1 protein levels were found in the venous group, while no differences in MIP-2, ICAM-1, and VCAM-1 mRNA expression existed between A and V. Further analysis demonstrated presence of increased cleaved caspase-3 protein in the artery group than in the venous group. CONCLUSIONS Venous renal outflow obstruction results in more severe functional renal injury when compared to arterial inflow occlusion. Macrophage activation and neutrophilic infiltration appear to be exaggerated during venous occlusion.

Portable infrared pupillometry: a review.

Portable infrared pupillometers provide an objective measure of pupil size and pupillary reflexes, which for most clinicians was previously only a visual impression. But despite the fact that pupillometry can uncover aspects of how the human pupil reacts to drugs and noxious stimulation, the use of pupillometry has not gained widespread use among anesthesiologists and critical care physicians. The present review is an introduction to the physiology of pupillary reflexes and the currently established clinical applications of infrared pupillometry, which will hopefully encourage physicians to use this diagnostic tool in their clinical practice. Portable infrared pupillometry was introduced in 1989. The technology involves flooding the eye with infrared light and then measuring the reflected image on an infrared sensor. Pupil size, along with variables of the pupillary light reflex and pupillary reflex dilation, is calculated by the instrument and displayed on a screen immediately after each time-stamped measurement. Use of these instruments has uncovered aspects of how the human pupil reacts to drugs and noxious stimulation. The primary clinical applications for portable pupillometry have been in the assessment of brainstem function. Portable pupillometry is useful in the management of pain because it allows for assessments of the effect of opioids and in the titration of combined regional–general anesthetics.

Attenuation of myocardial stunning by the AT1 receptor antagonist candesartan

Abstract The effect of AT1 receptor blockade on myocardial stunning is still somewhat ambiguous. In some prior studies, coronary occlusion was of too long duration such that the effects of infarction and stunning on the recovery of contractile function could not be distinguished. In others, blood pressure was decreased such that the improved wall excursion could be the consequence of reduced afterload and/or of attenuated stunning. The present study, therefore, investigated the effect of the AT1 receptor antagonist candesartan in a pure model of myocardial stunning with controlled systemic hemodynamics. Fourteen anesthetized open-chest dogs were subjected to 15 minutes occlusion of the left circumflex coronary artery (LCx) and 4 hours subsequent reperfusion. Systemic hemodynamics (micromanometer), regional myocardial blood flow (colored microspheres), and posterior wall thickening (PWT, sonomicrometry) were measured, and data were compared between 7 placebo controls (group 1) and 7 dogs receiving 1 mg/kg candesartan i.v. before LCx occlusion (group 2). Left ventricular peak pressure was kept constant by an intra-aortic balloon, and heart rate did not change throughout the protocol. Regional myocardial blood flow was not different between the groups under control conditions, increased in response to candesartan in group 2 (posterior subendocardial blood flow from 0.99 ± 0.18 to 1.57 ± 0.45; p < 0.05 vs. control conditions), but was not different during myocardial ischemia and at 4 hours of reperfusion between the groups. Under control conditions and during myocardial ischemia, PWT was also not different between the groups. At 4 hours of reperfusion, PWT was still depressed in group 1 (−1.5 ± 3.4 % vs. 17.7 ± 5.6 % during control conditions, p < 0.05), whereas PWT had recovered in group 2 (11.4 ± 3.7 % at 4 hours reperfusion vs. 18.3 ± 2.7 during control conditions, NS, p < 0.05 vs. group 1). In conclusion, pretreatment with the AT1 receptor antagonist candesartan improved the functional recovery of reperfused myocardium. This attenuation of myocardial stunning was not based on more favorable systemic hemodynamics or regional myocardial blood flow.

Infrared pupillometry to detect the light reflex during cardiopulmonary resuscitation: A case series ,

BACKGROUND The presence or absence of the pupillary light reflex following cardiopulmonary resuscitation has been shown to have prognostic value. We asked whether the light reflex could be objectively measured during cardiopulmonary resuscitation in humans and whether the quality of the reflex was associated with outcome. METHODS Sixty-seven in-hospital code blue alerts were attended of which 30 met our inclusion criteria. Portable infrared pupillometry was used to measure the light reflex during each code. The reliability of the presence of the light reflex during each code as a predictor of survival and neurological outcome was analyzed statistically using the Barnards Exact test. RESULTS In 25 patients (83%) the pupillary light reflex was detectable throughout or during a part of the resuscitation. Continuous presence of the light reflex or absence for less than 5 min during resuscitation was associated with early survival of the code and a good neurological outcome. In contrast, no patients without a light reflex or with a gradually deteriorating light reflex survived the code and absence of a pupillary light reflex for more than 5 min was associated with an unfavorable outcome. CONCLUSION Portable infrared pupillary measurements can reliably demonstrate the presence and quality of the pupillary light reflex after cardiac arrest and during resuscitation. In our limited case series, the presence of the pupillary light reflexes obtained in serial measurements during resuscitation was associated with early survival and a favorable neurological status in the recovery period.

Ischemic preconditioning improves energy state and transplantation survival in obese zucker rat livers

Livers from obese donors often have fatty infiltrates and are more susceptible to ischemia-reperfusion injury and subsequent graft dysfunction. This often leads to the exclusion of organs from obese donors. We investigated whether ischemic preconditioning (IP, 10 min ischemia, 10 min reperfusion) preserves cellular metabolism in livers from obese Zucker rats during cold ischemia. Liver samples (−IP and +IP) were collected from obese and control lean rats at different time points of cold ischemia (CI) and analyzed by magnetic resonance spectroscopy (1H- and 31P-MRS) to assess whether IP improves hepatic cellular metabolism. IP significantly improved high energy metabolism in IP livers from obese rats when compared with obese controls during the first hours of CI. At 4 h of cold storage, obese IP livers were not different from control lean non-IP livers. The beneficial metabolic effect of IP on livers form obese rats, however, was absent at 8 h of reperfusion. In contrast, in livers from lean rats, IP resulted in improved high-energy metabolism during the entire observation period of 8 h. In a later part of the study, IP of liver grafts from obese rats before 4 h of cold storage improved recipient survival after graft transplantation. IP of liver grafts from obese rats before 4 h of CI increases 24-h survival of recipient animals from 25% to 88%.