Can retrograde perfusion mitigate cerebral injury after particulate embolization? A study in a chronic porcine model

OBJECTIVE: We assessed the impact on histologic and behavioral outcome of an interval of retrograde cerebral perfusion after arterial embolization, comparing retrograde cerebral perfusion with and without inferior vena caval occlusion with continued antegrade perfusion. METHODS: Sixty Yorkshire pigs (27 to 30 kg) were randomly assigned to the following groups: antegrade cerebral perfusion control; antegrade cerebral perfusion after embolization; retrograde cerebral perfusion control; retrograde cerebral perfusion after embolization; retrograde cerebral perfusion with inferior vena cava occlusion, retrograde cerebral perfusion with inferior vena cava occlusion control, and retrograde cerebral perfusion with inferior vena cava occlusion after embolization. After cooling to 20 degrees C, a bolus of 200 mg of polystyrene microspheres 250 to 750 (microm diameter (or saline solution) was injected into the isolated aortic arch. After 5 minutes of antegrade cerebral perfusion, 25 minutes of antegrade cerebral perfusion, retrograde cerebral perfusion, or retrograde cerebral perfusion with inferior vena cava occlusion was instituted. After the operation, all animals underwent daily assessment of neurologic status until the time of death on day 7. RESULTS: Aortic arch return, cerebral vascular resistance, and oxygen extraction data during retrograde cerebral perfusion showed differences, suggesting that more effective flow occurs during retrograde cerebral perfusion with inferior vena cava occlusion, which also resulted in more pronounced fluid sequestration. Microsphere recovery from the brain revealed significantly fewer emboli after retrograde cerebral perfusion with inferior vena cava occlusion. Behavioral scores showed full recovery in all but one control animal (after retrograde cerebral perfusion with inferior vena cava occlusion) by day 7 but were considerably lower after embolization, with no significant differences between groups. The extent of histopathologic injury was not significantly different among embolized groups. Although no histopathologic lesions were present in either the antegrade cerebral perfusion control group or the retrograde cerebral perfusion control group, mild significant ischemic damage occurred after retrograde cerebral perfusion with inferior vena cava occlusion even in control animals. CONCLUSIONS: Although effective washout of particulate emboli from the brain can be achieved with retrograde cerebral perfusion with inferior vena cava occlusion, no advantage of retrograde cerebral perfusion with inferior vena cava occlusion after embolization is seen from behavioral scores, electroencephalographic recovery, or histopathologic examination; retrograde cerebral perfusion with inferior vena cava occlusion results in greater fluid sequestration and mild histopathologic injury even in control animals. Retrograde cerebral perfusion with inferior vena cava occlusion shows clear promise in the management of embolization, but further refinements must be sought to address its still worrisome potential for harm.     

Determination of optimum retrograde cerebral perfusion conditions

Retrograde cerebral perfusion through a superior vena caval cannula is a new technique used to protect the brain during operations on the aortic arch. We measured cerebral tissue blood flow, oxygen consumption, and cerebrospinal fluid pressure under various perfusion conditions in hypothermic (20 degrees C) mongrel dogs (n = 18, 12.8 +/- 0.6 kg) to determine the optimum conditions for retrograde cerebral perfusion. Retrograde cerebral perfusion was performed by infusion via the superior vena caval cannula and drainage via the ascending aortic cannula while the inferior vena cava and azygos vein were clamped. Retrograde cerebral perfusion was performed as the external jugular venous pressure was changed from 15 to 35 mm Hg in increments of 5 mm Hg. Cerebral tissue blood flow was measured by the hydrogen clearance method. Hypothermic retrograde cerebral perfusion with an external jugular venous pressure of 25 mm Hg provided about half the cerebral tissue blood flow of hypothermic (20 degrees C) cardiopulmonary bypass with a flow rate of 1000 ml/min (13.7 +/- 7.9 versus 32.7 +/- 8.5 ml/min per 100 gm). It decreased significantly as the external jugular venous pressure was decreased from 25 to 15 mm Hg but did not increase significantly as the external jugular venous pressure was increased from 25 to 35 mm Hg. Whole-body oxygen consumption during hypothermic retrograde cerebral perfusion with an external jugular venous pressure of 25 mm Hg was one quarter of that during hypothermic cardiopulmonary bypass (3.4 +/- 0.7 versus 12.7 +/- 5.6 ml/min) and varied in proportion to external jugular venous pressure. The cerebrospinal fluid pressure was a little lower than the external jugular venous pressure (19.2 +/- 4.5 mm Hg versus 24.8 +/- 2.4 mm Hg) but also varied with the external jugular venous pressure. The cerebrospinal fluid pressure remained lower than 25 mm Hg so long as the external jugular venous pressure remained lower than 25 mm Hg. High external jugular venous pressure was associated with high intracranial pressure, which restricts cerebral tissue blood flow and may cause brain edema. We believe that a venous pressure of 25 mm Hg is the optimum condition for retrograde cerebral perfusion.     

Three-fold effect of lovastatin treatment on low density lipoprotein metabolism in subjects with hyperlipidemia: increase in receptor activity, decrease in apoB production, and decrease in particle affinity for the receptor. Results from a novel triple-tracer approach

OBJECTIVE: This study was designed to determine whether simultaneous antegrade/retrograde cardioplegia improves myocardial perfusion in areas supplied by occluded vessels. METHODS: Isolated pig hearts placed in a Langendorff preparation were divided into two groups. The left anterior descending coronary artery was occluded at its origin. In group 1 (n = 7), simultaneous antegrade/retrograde cardioplegia was conducted with use of a single perfusion unit with tubing in a Y-shaped configuration at the end, joined to the aorta and the coronary sinus. In group 2 (n = 8) simultaneous antegrade/retrograde cardioplegia was performed with two separate units, one for antegrade delivery of cardioplegic solution and the other for retrograde cardioplegic solution delivery. Myocardial perfusion in the region supplied by the left anterior descending artery and the region not supplied by this artery was assessed by magnetic resonance imaging, with use of a magnetic resonance contrast agent. The contrast agent was introduced into the common perfusion line in group 1 and into the aortic line only in group 2. RESULTS: Magnetic resonance images showed that the myocardium in the region supported by the left anterior descending artery could not be perfused with antegrade cardioplegic solution because of occlusion of the artery. During simultaneous antegrade/retrograde cardioplegia, however, the myocardium in the left anterior descending region was perfused by approximately 40% to 50% (group 1) or 20% to 30% (group 2) of the degree of perfusion in the region not perfused by the left anterior descending artery (100%). Almost no cardioplegic solution was delivered to the heart through the coronary sinus route during simultaneous antegrade/retrograde cardioplegia in both groups of hearts. Myocardial perfusion in the region supported by the left anterior descending artery was heterogeneous during simultaneous antegrade/retrograde cardioplegia. CONCLUSIONS: Simultaneous antegrade/retrograde cardioplegia significantly improved myocardial perfusion in jeopardized areas of the myocardium. The jeopardized myocardium was mainly perfused by the solution drained from the adjacent normal tissue. Elevated pressure at the coronary sinus during simultaneous antegrade/retrograde cardioplegia is responsible for the redistribution of antegradely delivered cardioplegic solution.     

Traumatic brain contusions: a clinical role for the kinin antagonist CP-0127

Focal cerebral contusions can be dynamic and expansive, leading to delayed neurological deterioration. Due to the high mortality associated with such cerebral contusions, our standard practice had evolved into evacuating contusions in patients who had a deterioration in level of consciousness, lesions > 30 cc and CT suggestion of raised ICP. Experimental brain edema studies have implicated kinins in causing 2 degrees brain swelling. CP-0127 (Bradycor), a specific bradykinin antagonist, has been found to reduce cerebral edema in a cold lesion model in rats. In a randomized, single blind pilot study, a 7 day infusion of CP-0127 (3.0 micrograms/kg/min) was compared to placebo in patients with focal cerebral contusions presenting within 24-96 hours of closed head injury with an initial GCS 9-14. The ICP, GCS, and vital signs were monitored hourly. The total lesion burden (TLB) was measured on serial CT scans. There were no differences in age, baseline GCS, TLB, initial ICP, or laboratory findings between the two groups (n = 20). The mean (+/- s.d.) rise in peak ICP from baseline was greater in the placebo group than with CP-0127 (21.9 +/- 4.7 vs 9.5 +/- 2.0, P = 0.018). In addition, the mean reduction in GCS in the placebo group was significantly greater than in the CP-0127 group (4 +/- 1.0 vs 0.6 +/- 0.4, P = 0.002). Significantly raised ICP and clinically significant neurological deterioration occurred in 7/9 patients on placebo (77%) and only in 1 patient (9%; n = 11) on CP-0127, mandating surgery (P = 0.005). There were no adverse drug reactions, significant changes in vital signs or variations in the laboratory values. The cerebral perfusion pressure was adequately maintained in all patients irrespective of therapy. These preliminary results with CP-0127 provide supporting evidence that the kinin-kallikrein system could be involved in cerebral edema. In this study, treatment with CP-0127 appeared to alter the natural history of traumatic brain contusions by preventing the 2 degrees brain swelling. In addition, CP-0127 obviated the need for surgery in the majority of treated patients. CP-0127 could act on the cerebral vasculature to limit dys-autoregulation and brain swelling or on the blood brain barrier to reduce cerebral edema.     

Retrograde cerebral perfusion enhances cerebral protection during prolonged hypothermic circulatory arrest: a study in a chronic porcine model

BACKGROUND: This study was undertaken to confirm earlier findings that retrograde cerebral perfusion (RCP) can improve cerebral outcome after prolonged hypothermic circulatory arrest (HCA), and to determine whether RCP with inferior vena caval occlusion, which is more effective in removing particulate emboli, is superior to conventional RCP in enhancing cerebral protection. METHODS: Sixty-two pigs (27 to 30 kg) were randomly assigned to undergo one of the following for 90 minutes at 20 degrees C: antegrade cerebral perfusion (ACP); conventional RCP (RCP); RCP with occlusion of the inferior vena cava (RCP-O), or HCA with the head packed in ice. RCP flow was regulated to a sagittal sinus pressure of 20 mm Hg. Hemodynamic, electrophysiologic, and metabolic monitoring were carried out until 4 hours after rewarming, daily behavioral and neurologic assessments until elective sacrifice on day 7, and histologic analysis of the brain after death. RESULTS: Complete behavioral recovery was seen in all surviving animals by day 5 after ACP or RCP, but in only 83% after RCP-O and 50% after HCA (p = 0.001). A histopathologic score of 2 or more, indicating more than mild injury, was not found in any animal after ACP, in 27% after RCP, in 47% after HCA, and in 68% after RCP-O (p = 0.002). The median oxygen consumption was 6.66 mL/min after ACP, 1.37 mL/min with RCP, and 1.02 mL/min with RCP-O (p < 0.0001). The median amount of fluid sequestered was 2,450 mL after RCP-O, 760 mL after RCP, and -200 mL after ACP (p < 0.0001). CONCLUSIONS: Conventional RCP without inferior vena caval occlusion results in a significantly better outcome than RCP-O after prolonged HCA, despite more efficient cerebral perfusion during RCP-O, and also provides cerebral protection superior to prolonged HCA alone, but care must be taken during its implementation to minimize cerebral edema and other possible causes of retroperfusion-related cerebral injury.     

Delta-1 is a regulator of neurogenesis in the vertebrate retina

Controversy exists about the effect of tissue edema on cerebral microcirculation. High spatial resolution is required for observation of extravasation and microcirculation during focal vasogenic edema formation. To study the relationship between tissue edema and perfusion, we developed a technique for simultaneous visualization of extravasation and microvessel perfusion in rats. Focal intracortical microvascular injury was generated with a 1-sec Nd-YAG laser pulse. Evans blue albumin (EBA) was infused 30 min before decapitation to study extravasation and FITC-dextran was injected 30 sec prior to decapitation to examine microvessel perfusion. Computerized scanning laser-excited fluorescence microscopy followed by high resolution image analysis permitted quantitative assessment of both parameters on single fresh-frozen brain sections. Studied at 30 min (3.66 +/- 0.15 mm), 2 hr (4.14 +/- 0.08 mm, P < .05), and 8 hr (4.69 +/- 0.18 mm, P < .01) after injury, the diameter of the circular, sharply demarcated zone of EBA-extravasation increased progressively. At 30 min, microvessels at a zone surrounding the area of EBA-extravasation contained 69 +/- 14% (P < .05) more fluorescent FITC-filling than in the control hemisphere, but the density of perfused microvessels was unchanged. At 2 hr, secondary tissue changes had already occurred in a zone surrounding the initial laser lesion. While severe reduction in the density (-76 +/- 13%, P < .05) of perfused microvessels was observed within 400 to 240 microm inside the border of EBA extravasation, perfusion indexes were normal despite the presence of extravasated plasma constituents within 0-80 microm from the border. In a narrow zone (80 microm) outside the border of extravasation, individual microvessels contained 34 +/- 9% (P < .01) less FITC-fluorescence than those in a homologous area of the uninjured contralateral hemisphere. This report demonstrates the feasibility of simultaneous measurement and high-resolution mapping of indices of microvascular perfusion (density, filling) and extravasated plasma constituents in damaged and intact brain areas. In this model, the presence of extravasated plasma constituents the size of proteins did not immediately influence indices of cortical microcirculation. However, microvascular perfusion may be perturbed surrounding such an area of advancing vasogenic edema formation.     

Diaspirin cross-linked hemoglobin resuscitation improves cerebral perfusion after head injury and shock

BACKGROUND: Shock associated with traumatic brain injury (TBI) doubles the mortality of TBI alone by inducing a secondary ischemic injury. Rapid correction of cerebral perfusion pressure (CPP) is thought to be essential to improving outcome. Diaspirin cross-linked hemoglobin (DCLHb) has been shown to improve cerebral blood flow, increase mean arterial pressure (MAP), and reduce lesion size in models of occlusive cerebral ischemia but has not been evaluated in a model of TBI combined with hemorrhagic shock. METHODS: We studied the effects of DCLHb resuscitation in a porcine model of cryogenic TBI and hemorrhagic shock (MAP = 50 mmHg). After combined insults, animals were randomized to receive a bolus of 4 mliters/kg of either lactated Ringer's solution (n = 5) or DCLHb (n = 6). Lactated Ringer's solution was then infused in both groups to maintain MAP at baseline. Shed blood was returned 1 hour after the initiation of resuscitation (R1). Animals were studied for 24 hours. RESULTS: DCLHb infusion resulted in a significantly greater MAP at R1 and R24 (95 +/- 4 vs. 82 +/- 2 and 99 +/- 3 vs. 85 +/- 3 mm Hg, respectively) and a significantly greater CPP at R1 and R24 (83 +/- 10 vs. 68 +/- 5 and 89 +/- 6 vs. 71 +/- 11 mm Hg, respectively). Intracranial pressure was lower in the DCLHb group, but this difference was not significant. There was no significant difference between the groups in cerebral oxygen delivery. DCLHb animals required less fluid to maintain MAP (12,094 +/- 552 vs. 15,542 +/- 1094 mliters, p < 0.05). CONCLUSION: These data suggest that DCLHb is beneficial in the early resuscitation of head injury and shock and that further investigation is warranted. Key Words: Diaspirin cross-linked hemoglobin, Head injury, Shock, Cerebral perfusion pressure.     

Matrix metalloproteinases and TIMPs are associated with blood-brain barrier opening after reperfusion in rat brain

BACKGROUND and PURPOSE: Reperfusion disrupts cerebral capillaries, causing cerebral edema and hemorrhage. Middle cerebral artery occlusion (MCAO) induces the matrix-degrading metalloproteinases, but their role in capillary injury after reperfusion is unknown. Matrix metalloproteinases (MMPs) and tissue inhibitors to metalloproteinases (TIMPs) modulate capillary permeability. Therefore, we measured blood-brain barrier (BBB) permeability, brain water and electrolytes, MMPs, and TIMPs at multiple times after reperfusion. METHODS: Adult rats underwent MCAO for 2 hours by the suture method. Brain uptake of 14C-sucrose was measured from 3 hours to 14 days after reperfusion. Levels of MMPs and TIMPs were measured by zymography and reverse zymography, respectively, in contiguous tissues. Other rats had water and electrolytes measured at 3, 24, or 48 hours after reperfusion. Treatment with a synthetic MMP inhibitor, BB-1101, on BBB permeability and cerebral edema was studied. RESULTS: Brain sucrose uptake increased after 3 and 48 hours of reperfusion, with maximal opening at 48 hours and return to normal by 14 days. There was a correlation between the levels of gelatinase A at 3 hours and the sucrose uptake (P<0.05). Gelatinase A (MMP-2) was maximally increased at 5 days, and TIMP-2 was highest at 5 days. Gelatinase B and TIMP-1 were maximally elevated at 48 hours. The inhibitor of gelatinase B, TIMP-1, was also increased at 48 hours. Treatment with BB-1101 reduced BBB opening at 3 hours and brain edema at 24 hours, but neither was affected at 48 hours. CONCLUSIONS: The initial opening at 3 hours correlated with gelatinase A levels and was blocked by a synthetic MMP inhibitor. The delayed opening, which was associated with elevated levels of gelatinase B, failed to respond to the MMP inhibitor, suggesting different mechanisms of injury for the biphasic BBB injury.     

Effect of nimodipine on infectious brain edema in rabbits

AIM: To study the effect of nimodipine (Nim) on infectious brain edema (BE). METHODS: An infectious BE model was induced by injection of Bordetella pertussis suspension (BPS) into right internal carotid artery in rabbits. Eighteen rabbits were randomly divided into 3 groups (n = 6). Group BE: BPS (0.6 mL.kg-1) was given; group NS: normal saline was given as control; group Nim: 10 min after injection of BPS, Nim, 10 micrograms.kg-1, was injected i.v. as a bolus followed by continuous infusion of 0.75 microgram.kg-1.min-1. All the rabbits were kept under observation for 4 h. Evans blue staining was assessed; water, calcium, calmodulin (Cal), and sodium contents were determined in the right brain. RESULTS: Nim vs BE: water 82.2 +/- 1.0% vs 84.4 +/- 1.2 (P < 0.01); calcium 10.5 +/- 1.3 mmol.kg-1 dry tissue vs 17.5 +/- 1.4 (P < 0.01); Cal 15.9 +/- 1.8 mumol.kg-1 wet tissue vs 24.0 +/- 3.0 (P < 0.01); sodium 173 +/- 7 mmol.kg-1 dry tissue vs 275 +/- 38 (P < 0.05). No significant difference for Evans blue staining between the two groups. CONCLUSION: Nim had beneficial effect on the infectious BE.     

Effect of hyperosmotic solutions on human brain tumour vasculature

Reversible opening of the blood-brain barrier (BBB) has been used to increase delivery of chemotherapeutic agents into brain tumours, but it is complicated and requires general anaesthesia. Without affecting the normal BBB, and avoiding the complications of BBB modification by hyperosmotic solution, we tried an adequate minimal BBB disruption in brain tumours. Although the effect of BBB disruption on normal brain has been described, there are no reports of the effect of an impaired BBB on microcirculation. In this study, four patients underwent surgical resection of a glioblastoma multiforme (GM; n = 1), astrocytoma (n = 2), or metastatic brain tumour (n = 1). Epicerebral microcirculation was observed in the operative field. Serial fluorescein microangiograms of the tumour and peritumoural area were obtained before and after BBB disruption was introduced intra-operatively by retrograde infusion of mannitol introducing a catheter via the temporal superficial artery back to the carotid bifurcation. On the initial microangiogram, staining by the fluorescein dye was observed in the GM and metastatic tumour but not in the astrocytoma; no extravasation of fluorescein dye was observed in the peritumoural areas. After BBB disruption, fluorescein perfusion increased and extravasation of fluorescein dye from the venules was observed in the GM and the metastatic tumour and in the peritumoural area of both lesions; BBB disruption started from venules in the peritumoural area without affecting the normal brain. However, such effects were not observed in the astrocytomas after BBB disruption nor in normal brain tissue in any patient. It appears that the integrity of the BBB is less stable in the peritumoural area of GM and metastatic brain tumours than it is in astrocytomas or normal brain. Osmotic BBB disruption may offer a method for achieving global delivery of therapeutic agents to brain tumours and peritumoural areas.     

Effect of subarachnoid bupivacaine block on anesthetic requirements for thiopental in rats

BACKGROUND: Subarachnoid bupivacaine blockade has been reported to reduce thiopental and midazolam hypnotic requirements in patients. The purpose of this study was to examine if local anesthetically induced lumbar intrathecal blockade would reduce thiopental requirements for blockade of motor responses to noxious and nonnoxious stimuli in rats. METHODS: After intrathecal and external jugular catheter placement, rats were assigned randomly to two groups in a crossover design study, with each rat to receive either 10 microl of 0.75% bupivacaine or 10 microl of normal saline intrathecally. The doses of intravenously administered thiopental required to ablate the eyelid reflex, to block the withdrawal reflex of a front limb digit, and to block the corneal reflex were compared. In two separate groups of animals, hemodynamic parameters and concentrations of thiopental in the brain were compared between intrathecally administered bupivacaine and saline. RESULTS: The thiopental dose required to block the described responses was decreased with intrathecally administered bupivacaine versus intrathecally administered saline from (mean +/- SD) 40 +/- 5 to 24 +/- 4 mg/kg (P < 0.001) for the eyelid reflex, from 51 +/- 6 to 29 +/- 6 mg/kg (P < 0.005) for front limb withdrawal, and from 67 +/- 8 to 46 +/- 8 mg/kg (P < 0.01) for the corneal reflex. The concentration of thiopental in the brain at the time of corneal reflex blockade for the group given bupivacaine was significantly lower than in the group given saline (24.1 vs. 35.8 microg/g, P = 0.02). CONCLUSION: This study demonstrates that lumbar intrathecally administered local anesthetic blockade decreases anesthetic requirements for thiopental for a spectrum of end points tested. This effect is due neither to altered pharmacokinetics nor to a direct action of the local anesthetic on the brain; rather, it is most likely due to decreased afferent input.     

Increase in endocervical CD4 lymphocytes among women with nonulcerative sexually transmitted diseases

BACKGROUND AND PURPOSE: Stroke-prone spontaneously hypertensive rats (SHRSP) subjected to high sodium intake develop severe hypertension, cerebral edema, and proteinuria, culminating in organ damage and early death. MRI, which can be applied serially, provides the unique opportunity to study temporal and quantitative relations between these changes and whether diminution of sodium intake can attenuate established cerebral edema. METHODS: SHRSP were subjected to 1% NaCl in drinking water. Cerebral MRI, proteinuria and systolic blood pressure (SBP) were measured serially. After detection of cerebral edema (T2-weighted MRI), 6 rats were killed for histology, to confirm the diagnosis of cerebral edema. The others were followed up for 7 more days while salt loading was continued (n = 10, group 1) or after sodium intake was normalized (n = 7, group 2). RESULTS: SHRSP invariably developed cerebral edema in 30 days (range, 8 to 54 days). At this point neurological signs were absent in 16 of 23 rats. SBP rose until 1 week before detection of cerebral edema, and then stabilized at approximately 265 mm Hg. Proteinuria invariably preceded cerebral edema, with a concentration exceeding 40 mg/d predicting development of cerebral edema in 9 days (range, 3 to 15 days). There was linear correlation (R=.62, P<.0001) between proteinuria and cerebral edema (pixels with an intensity above a defined threshold). Rats in group 1 showed an increase in cerebral edema (from 5.8+/-1.1% to 12.5+/-2.8%; P<.05), and proteinuria remained high (from 305+/-44 to 338+/-29 mg/d); and 2 died spontaneously. Rats in group 2 showed no significant change in edema (from 4.9+/-0.5% to 6.9+/-1.3%) but a marked fall in proteinuria (from 294+/-24 to 119+/-10 mg/d; P<.05), both significantly different from group 1 (P<.05); all survived. SBP remained unaltered in both groups. CONCLUSIONS: Our data establish MRI as a sensitive method for detection of cerebral edema, often prior to neurological signs, in SHRSP. Proteinuria predicts cerebral edema, and these two variables, both obtained noninvasively, are quantitatively related. Moreover, in SHRSP normalizing sodium intake after salt loading attenuates development of cerebral edema and reduces proteinuria.     

Enalapril prevents imminent and reduces manifest cerebral edema in stroke-prone hypertensive rats

BACKGROUND AND PURPOSE: Stroke-prone spontaneously hypertensive rats (SHRSP), subjected to high NaCl intake, show severe hypertension, organ damage, and early death. Preventive treatment with an angiotensin-converting enzyme (ACE) inhibitor is known to reduce mortality. Previously we found that proteinuria always precedes cerebral edema in SHRSP. Hence, in this study ACE inhibition was started later, ie, directly after manifestation of either proteinuria or cerebral edema. METHODS: SHRSP were subjected to 1% NaCl intake. Group 1 served as a control. In group 2 early-onset treatment with the ACE inhibitor enalapril was initiated after proteinuria was >40 mg/d. In group 3 late-onset ACE inhibition was started after the first observation of cerebral edema with T2-weighted MRI. Cerebral edema was expressed as the percentage of pixels with an intensity above a defined threshold. RESULTS: In controls median survival was 54 days (range, 32 to 80 days) after start of salt loading. The terminal level of cerebral edema was 19.0+/-3.0%. Under early-onset enalapril, median survival increased to 320 days (range, 134 to 368 days; P<0.01 versus group 1). Cerebral edema was prevented in all but 1 rat. Systolic blood pressure was slightly and transiently reduced at day 14. Proteinuria was markedly reduced (52+/-7 versus 190+/-46 mg/d in group 1 at day 7; P<0.05). Under late-onset enalapril, median survival was 264 days (range, 154 to 319 days; P<0.01 versus group 1). Cerebral edema decreased to baseline levels (9.6+/-2.9 at day 0 to 3.4+/-0.5% at day 3; (P<0.05). Ultimately cerebral edema reoccurred in 6 of the 8 rats. SBP decreased slightly at day 7 only. Proteinuria decreased from 283+/-27 at day 0 to 116+/-22 mg/d at day 7 (P<0.05). Complete remission of the original locus of cerebral edema was confirmed histologically. CONCLUSIONS: In SHRSP with proteinuria, treatment with an ACE inhibitor both prevented the development of cerebral edema and reduced manifest cerebral edema and proteinuria. Survival was markedly prolonged. These findings support the use of ACE inhibition for treatment in hypertensive encephalopathy.     

Effects of MDL 72527, a specific inhibitor of polyamine oxidase, on brain edema, ischemic injury volume, and tissue polyamine levels in rats after temporary middle cerebral artery occlusion

The possible effects of the polyamine interconversion pathway on tissue polyamine levels, brain edema formation, and ischemic injury volume were studied by using a selective irreversible inhibitor, MDL 72527, of the interconversion pathway enzyme, polyamine oxidase. In an intraluminal suture occlusion model of middle cerebral artery in spontaneously hypertensive rats, 100 mg/kg MDL 72527 changed the brain edema formation from 85.7 +/- 0.3 to 84.5 +/- 0.9% in cortex (p < 0.05) and from 79.9 +/- 1.7 to 78.4 +/- 2.0% in subcortex (difference not significant). Ischemic injury volume was reduced by 22% in the cortex (p < 0.05) and 17% in the subcortex (p < 0.05) after inhibition of polyamine oxidase by MDL 72527. There was an increase in tissue putrescine levels together with a decrease in spermine and spermidine levels at the ischemic site compared with the nonischemic site after ischemia-reperfusion injury. The increase in putrescine levels at the ischemic cortical and subcortical region was reduced by a mean of 45% with MDL 72527 treatment. These results suggest that the polyamine interconversion pathway has an important role in the postischemic increase in putrescine levels and that blocking of this pathway can be neuroprotective against neuronal cell damage after temporary focal cerebral ischemia.     

Effect of anisodine on acute forebrain ischemia-reperfusion damage in rats

AIM: To study the protective effect of anisodine (Ani) on acute forebrain ischemia-reperfusion injury in rats. METHODS: Both vertebral arteries were occluded by electrocautery. Severe, but transient bilateral cerebral ischemia was produced by clamping both common carotid arteries in rats. Atomic absorption spectrophotometric and spectrophotometric methods were used to determine the contents of calcium and extravasated Evans blue (EB), respectively, remained in forebrain at 60-min recirculation after 30-min ischemia. RESULTS: At 60-min recirculation, the brain calcium contents were increased from 112 +/- 6 micrograms/g brain dry weight in control (sham operation) group to 165 +/- 7 micrograms/g brain dry weight with marked increase of EB extravasation. Ani (2.5 mg.kg-1, i.p.), and scopolamine (Sco, 0.25 mg.kg-1, i.p.) decreased the elevated calcium and extravasated EB contents. CONCLUSION: Ani prevented the brain from ischemia insults through reducing intracellular calcium accumulation resulted from ischemia and reperfusion.     

Antegrade or retrograde blood cardioplegic method: comparison of postsurgical right ventricular function and conduction disturbances

This study was undertaken to compare postsurgical right ventricular function and the occurrence of conduction disturbances after employing cold blood antegrade or retrograde cardioplegia during open heart surgery. Thirty-four patients were divided into AC (antegrade) and RC (retrograde) groups for the difference of route for delivery of cardioplegic solutions. Preoperative evaluation of cardiac and respiratory function revealed to be equal characteristics between the groups. Postoperatively, A-aDO2 and respiratory index (RI) as functional parameters of oxygenation capacity, LVSWI, RVSWI, dosage of dopamine and conduction disturbances were monitored at 0, 3, 6, 12 hours after termination of cardiopulmonary bypass and at extubation period. Although the recovery of respiratory function and left ventricular function were similar in both groups, temporal suppression of right ventricular function was indicated in RC group during early period after surgery, and then recovered to the same values of AC group within 3 hours. In RC group, several type of conduction disturbances were detected in 28 per cent of patients. But none of the persistent conduction disturbances were remained in all patients. We suggest retrograde coronary sinus perfusion may emerge as a valuable alternative to antegrade methods for delivery of cardioplegia.     

The ability of human Schwann cell grafts to promote regeneration in the transected nude rat spinal cord

Advances in the purification and expansion of Schwann cells (SCs) from adult human peripheral nerve, together with biomaterials development, have made the construction of unique grafts with defined properties possible. We have utilized PAN/PVC guidance channels to form solid human SC grafts which can be transplanted either with or without the channel. We studied the ability of grafts placed with and without channels to support regeneration and to influence functional recovery; characteristics of the graft and host/graft interface were also compared. The T9-T10 spinal cord of nude rats was resected and a graft was placed across the gap; methylprednisolone was delivered acutely to decrease secondary injury. Channels minimized the immigration of connective tissue into grafts but contributed to some necrotic tissue loss, especially in the distal spinal cord. Grafts without channels contained more myelinated axons (x = 2129 +/- 785) vs (x = 1442 +/- 514) and were larger in cross-sectional area ( x = 1.53 +/- 0.24 mm2) vs (x = 0.95 +/- 0.86 mm2). The interfaces formed between the host spinal cord and the grafts placed without channels were highly interdigitated and resembled CNS-PNS transition zones; chondroitin sulfate proteoglycans was deposited there. Whereas several neuronal populations including propriospinal, sensory, motoneuronal, and brainstem neurons regenerated into human SC grafts, only propriospinal and sensory neurons were observed to reenter the host spinal cord. Using combinations of anterograde and retrograde tracers, we observed regeneration of propriospinal neurons up to 2.6 mm beyond grafts. We estimate that 1% of the fibers that enter grafts reenter the host spinal cord by 45 days after grafting. Following retrograde tracing from the distal spinal cord, more labeled neurons were unexpectedly found in the region of the dextran amine anterograde tracer injection site where a marked inflammatory reaction had occurred. Animals with bridging grafts obtained modestly higher scores during open field [(x = 8.2 +/- 0.35) vs (x = 6.8 +/- 0.42), P = 0.02] and inclined plane testing (x = 38.6 +/- 0. 542) vs (x = 36.3 +/- 0.53), P = 0.006] than animals with similar grafts in distally capped channels. In summary, this study showed that in the nude rat given methylprednisolone in combination with human SC grafts, some regenerative growth occurred beyond the graft and a modest improvement in function was observed.     

Myocardial preservation by continuous perfusion of Krebs-Henseleit solution--the temperature dependency of the optimal perfusion pressure

The aim of this study was to determine the temperature dependency of the optimal pressure in myocardial preservation by continuous perfusion with Krebs-Henseleit bicarbonate buffer (KHBB) solution. Hearts from Wistar male rats were perfused with KHBB solution and cardiac function (aortic flow) was measured using an isolated working rat heart preparation. In the preliminary experiment, hearts were then preserved using Langendorff perfusion with KHBB solution of 37, 20 or 4 degrees C for 2 hours at a perfusion pressure of 100 cmH2O. This was followed by 15 min of Langendorff perfusion (37 degrees C, 100 cmH2O) and 20 min working perfusion. The 37 degrees C group and 20 degrees C group exhibited better functional recoveries of aortic flow (%AF) in the post-preservation period compared to the 4 degrees C group. In the test experiment, hearts were preserved using Langendorff perfusion for 4 hours at 37 degrees C or for 8 hours at 20 degrees C at various perfusion pressures. At 37 degrees C, %AF after 4 hours of the preservation were 64.7 +/- 2.6, 69.0 +/- 3.2, 81.9 +/- 3.1, 94.7 +/- 3.3 and 63.5 +/- 4.0% (p < 0.05 vs the 100 cmH2O group) at the perfusion pressure of 100, 60, 20, 15 and 10 cmH2O, respectively. %AF after 8 hours of the preservation at 15 cmH2O was 56.3 +/- 2.5%. At 20 degrees C, %AF after 8 hours of the preservatin was 78.9 +/- 3.3, 81.9 +/- 2.3, 67.4 +/- 1.9 and 65.9 +/- 2.2% (p < 0.05 vs the 60 cmH2O group) at the perfusion pressure of 60, 30, 10 and 15 cmH2O, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

An improved isolated, left ventricular ejecting, murine heart model. Functional and metabolic evaluation

An improved, isolated, left ventricular-ejecting, murine heart model is described and evaluated. Special attention was paid to the design and impedance characteristics of the artificial aortic outflow tract and perfusate composition, which contained glucose (10 mM plus insulin) and pyruvate (1.5 mM) as substrates. Temperature of the isolated perfused hearts was maintained at 38.5 degrees C. During antegrade perfusion (preload 10 mm Hg, afterload 50 mm Hg, 2.5 mM Ca2+) proper design of the aortic outflow tract provided baseline values for cardiac output (CO), left ventricular developed pressure (LVDP) and the maximum first derivative of left ventricular pressure (LV dP/dtmax) of 11.1+/-1.7 ml min-1, 83+/-5 mm Hg and 6283+/-552 mm Hg s-1, respectively, resembling findings in the intact mouse. During 100 min normoxic antegrade perfusion CO declined non-significantly by less than 10%. Varying pre- and afterloads resulted in typical Frank-Starling relationships with maximal CO values of 18.6+/-1.8 ml min-1 at pre- and afterload pressures of 25 and 50 mm Hg, respectively. Left ventricular function curves were constructed at free [Ca2+] of 1.5 and 2.5 mM in the perfusion medium. Significantly higher values for CO, LVDP and LV dP/dtmax and LV dP/dtmin were obtained at 2.5 mM Ca2+ at all loading conditions investigated. Phosphocreatine and creatine levels remained stable throughout the perfusion period. Despite a small but significant decline in tissue ATP content, the sum of adenine nucleotides did not change during the normoxic perfusion period. The tissue content of glycogen increased significantly.     

Retrograde perfusion as a method for myocardial revascularization

Retroperfusion of the superficial coronary venous system was studied in 44 canine fibrillating in vivo, normothermic preparations, with exclusion of the systemic circulation using cardiopulmonary bypass techniques in order to assess its value as a method of myocardial revascularization. Perfusion of either the isolated aortic arch via a brachiocephalic cannula or of the coronary sinus through the free end of a vein anastomosed to the atrial rim of the sinus was performed for 1 h at 100 cm3/min in groups II-IV following 30 min of anoxia. Oxygen uptake, vascular resistance, venous outflow and venous enzyme levels (CPK, GDH) were studied. Group I controls (antegrade perfusion, no anoxia) showed continued aerobic metabolism in contrast to group II (antegrade perfusion) and III (retrograde perfusion) which displayed negative lactate balance. Oxygen consumption was greater in group III than II (p less than 0.01) with a higher oxygen extraction in III (p less than 0.005). Group IV, which was given intravenously 30 mg/kg methylprednisolone prior to anoxia and then retroperfused, showed continued aerobic metabolism with low GDH venous levels and adequate oxygen consumption. Three dogs were then subjected to aortoatrial rim coronary sinus vein grafts with ligation of the left common coronary artery at its bifurcation with distal left circumflex and anterior descending artery-internal mammary vein anastomoses for venous drainage. The right coronary artery was left intact. Arterial inflow into the coronary sinus was associated with a left ventricular pressure of 70-80 mm Hg for up to 1.5 h while regular sinus rhythm was maintained. We conclude that retroperfusion of the coronary sinus represents a surgically feasible technique for providing oxygen delivery to the ischemic myocardium.