The red blood cell in vascular occlusion

Red blood cells (RBC) have unique flow-affecting properties--namely, aggregability, deformability and adherence to endothelial cells (EC)--which play major roles in blood flow. Under normal flow-induced shear stress RBC are dispersed, their adherence to EC is insignificant, and they are sufficiently deformable to enable tissue perfusion. However, in pathological conditions that are associated with low-flow states (e.g., trauma, ischemia), elevated plasma components (mainly fibrinogen), or altered RBC properties (e.g., hemoglobinopathies, oxidative stress, inflammation, diabetes), RBC flow properties are altered and present a circulatory risk.     

Cholestasis is associated with hepatic microvascular dysfunction and aberrant energy metabolism before and during ischemia-reperfusion

Abstract Aims: The aim was to investigate the impact of ischemia-reperfusion (I/R) on intrahepatic oxidative stress, oxidative phosphorylation, and nucleotide metabolism in relation to liver damage and inflammation in cholestatic rats to elucidate the molecular mechanisms responsible for post-I/R pathogenesis during cholestasis. Results: Pre-I/R cholestatic livers exhibited mild hepatopathology in the form of oxidative/nitrosative stress, perfusion defects, necrosis and apoptosis, inflammation, and fibrosis. Plasma bilirubin concentration in cholestatic livers was 190?μM. I/R in cholestatic livers exacerbated hepatocellular damage and leukocyte infiltration. However, myeloperoxidase activity in neutrophils at 6?h reperfusion was not elevated in cholestatic livers compared to pre-I/R levels and to control (Ctrl) livers. At 6?h reperfusion, cholestatic livers exhibited severe histological damage, which was absent in Ctrl livers. Despite a lower antioxidative capacity after I/R, no cardiolipin peroxidation and equivalent reduced glutathione/oxidized glutathione ratios and Hsp70 levels were found in cholestatic livers versus Ctrls. Bilirubin acted as a potent and protective antioxidant. Postischemic resumption of oxidative phosphorylation in Ctrl livers proceeded rapidly and encompassed reactive hyperemia, which was significantly impaired in cholestatic livers owing to extensive vasoconstriction and perfusion defects. Normalization of intrahepatic energy status and nucleotide-based metabolic cofactors was delayed in cholestatic livers during reperfusion. Innovation and Conclusions: Cholestatic livers possess sufficient antioxidative capacity to ameliorate radical-mediated damage during I/R. I/R-induced damage in cholestatic livers is predominantly caused by microvascular perfusion defects rather than exuberant oxidative/nitrosative stress. The forestalled rate of oxidative phophorylation and recovery of bioenergetic and possibly metabolic parameters during the early reperfusion phase are responsible for extensive liver damage. Antioxid. Redox Signal. 00, 000-000.     

Influence of electrical stimulation of the posterior hypothalamus on musculocutaneous and renal circulation in anesthetized dogs

Summary Hypertension and tachycardia were consistently induced by electrical stimulation of the median posterior hypothalamus in dogs under chloralose anesthesia, curarized and artificially ventilated. When renal and femoral vascular beds were perfused at a constant blood flow, the renal perfusion, pressure markedly increased, whereas only minor variations of the femoral perfusion pressure occurred. When the renal and femoral vessels were perfused by the heart at the prevailing blood pressure, peri-arterial electromagnetic flow measurements revealed that renal flow decreased and that femoral flow increased during hypothalamic hypertension, both before and after vagotomy. In the same animals, no significant changes of renal or femoral flow occurred during reflexogenic hypertension induced by carotid occlusion. These marked hemodynamic differences between the reflexogenic and the hypothalamic type of hypertension were consistently and repeatedly observed. The indications that baroreflex counter-regulation and ganglionic inhibition due to elevated catecholaminemia contribute to the relative lack of femoral vasoconstriction during hypothalamic hypertension, are discussed.Partly supported by grant nr. 2034 from I.W.O.N.L., Belgium     

Application of in vivo EPR in brain research: monitoring tissue oxygenation, blood flow, and oxidative stress

Although oxygen levels are critical to tissue survival, monitoring tissue oxygen levels in vivo, in real time, remains a technical challenge. This is especially so for repetitive measurements in non-superficial tissue. There currently exist several techniques that can be utilized for tissue oxygen measurement, but technical difficulties have limited their usefulness and general application. Here we describe a relatively new method, electron paramagnetic resonance (EPR) oximetry, for in vivo measurement of brain tissue oxygen, as well as information on blood flow and oxidative stress. In this paper we report experiments designed to assess and illustrate the effectiveness of this new method. Using the unique capability of this approach, we have measured both absolute values and temporal changes of pO2 in ischemic penumbra and core during cerebral ischemia and reperfusion in a rat model. EPR oximetry with particulate probe sensitively reflected differential changes in oxygenation in the core and penumbra during ischemia, reperfusion and also hyperoxic conditions. Simultaneous two-site detection with particulate probes was also obtained with good spatial resolution. Additionally, EPR measurement of oxidative stress, EPR imaging of brain with nitroxide and triarylmethyl soluble probes are also described. These results demonstrate that EPR oximetry with particulate probe can provide accurate and reproducible measurements of localized pO2 in the brain, and it is a versatile and useful method in the measurement of tissue pO2 under a variety of physiological and pathophysiological conditions.     

A central role of heme oxygenase-1 in cardiovascular protection

The intrinsic defense mechanisms of the body are critical in protecting tissues from injury in response to pathological stress. Heme oxygenase-1 (HO-1), a stress response protein, is induced in response to various pathological stimuli to serve a cytoprotective function. By degrading the oxidant heme and generating the antioxidant bilirubin and anti-inflammatory molecule carbon monoxide, HO-1 may protect cell from injury due to oxidative and pathological stress. Oxidative stress in the heart caused by ischemia and reperfusion leads to cardiomyocyte death and subsequent myocardial infarction. Vascular diseases including atherosclerosis, graft failure, and restenosis are all associated with reactive oxygen species-induced injury and inflammation. Given that cardiovascular disease is the leading cause of death worldwide, there is considerable interest in developing new strategies for preventing and treating cardiovascular disease. Since HO-1 is induced in the heart and blood vessels in response to various stresses, a role of HO-1 has been implicated in cardiovascular homeostasis. Numerous studies using pharmacological method or genetic approach have since demonstrated the cardiovascular protective function of HO-1. Importantly, a number of studies have associated human HO-1 gene promoter polymorphisms with risk for vascular diseases. Taken together, HO-1 has a great therapeutic potential for cardiovascular disease.     

A comparison of the acute hemodynamic and delayed effects of 50% exchange transfusion with two different cross-linked hemoglobin based oxygen carrying solutions and Pentastarch

BACKGROUND: Hemoglobin based oxygen carrying solutions (HBOC) have been designed to combine the beneficial effects of colloidal solutions with oxygen carrying capacity. Clinical trials in humans using HBOCs have had variable results. METHODS: We used a rodent 50% exchange model to compare Hemolink and Hemopure HBOC to autologous blood and Pentastarch solution. We monitored hemodynamic parameters, hemoglobin clearance, weight gain and hematocrit over a five-day period. RESULTS: Acute hemodynamic effects between the two HBOCs were similar with mild vasoconstriction. Cardiac output, systemic vascular resistance and renal function were similar to that seen with blood. HBOC's were associated with hemoglobinuria with a half-life in the circulation of 13.8 hrs for Hemolink and 19.2 hrs for Hemopure. Animals resuscitated with HBOCs exhibited delayed weight gain. CONCLUSION: Hemodynamic effects in rodents exchange-transfused with blood, Hemolink, or Hemopure were similar. The delayed weight gain observed with the HBOCs must be investigated.     

A study of magnesium deficiency in human and experimental pulmonary hypertension

Pulmonary hypertension (PH) is defined as an increase in mean pulmonary arterial pressure above 25?mmHg. Pulmonary vasoconstriction, cellular proliferation, inflammation, and oxidative stress are involved in the pathophysiology of PH. Since hypomagnesemia was reported to promote endothelial cell dysfunction leading to inflammation and oxidative stress, we investigated the potential involvement of magnesium (Mg) deficiency in experimental and human PH. Our results indicate that Mg deficiency has no impact on hypoxia-induced PH development or severity, and that no reduction in Mg plasma concentration was observed in patients with severe pulmonary arterial hypertension. Thus, hypomagnesemia does not appear to play a role in the pathophysiology of experimental and human pulmonary hypertension.     

Protective functions of heme oxygenase-1 and carbon monoxide in the respiratory system

The respiratory system, including the lung and upper airways, succumbs to injury and disease through acute or chronic exposures to adverse environmental agents, in particular, those that promote increased oxidative or inflammatory processes. Cigarette smoke and other forms of particulate or gaseous air pollution, allergens, microorganisms infections, and changes in inspired oxygen may contribute to lung injury. Among the intrinsic defenses of the lung, the stress protein heme oxygenase-1 constitutes an inducible defense mechanism that can protect the lung and its constituent cells against such insults. Heme oxygenases degrade heme to biliverdin-IXalpha, carbon monoxide, and iron, each with candidate roles in cytoprotection. At low concentrations, carbon monoxide can confer similar cyto and tissue-protective effects as endogenous heme oxygenase-1 expression, involving antioxidative, antiinflammatory, antiproliferative, and antiapoptotic effects. Lung protection by heme oxygenase-1 or its enzymatic reaction products has been demonstrated in vitro and in vivo in a number of pulmonary disease models, including acute lung injury, cigarette smoke-induced lung injury/chronic obstructive pulmonary disease, interstitial lung diseases, ischemia/reperfusion injury, and asthma/airway inflammation. This review summarizes recent findings on the functions of heme oxygenase-1 in the respiratory system, with an emphasis on possible roles in disease progression and therapies.     

Effects of nutrient and hemoglobin enriched cell free perfusates upon ex vivo isolated rat heart preparation

We evaluated the effects of nutrient enriched medium and hemoglobin based oxygen carrier (HBOC) upon myocardial functional recovery after 15 minutes of warm ischemia in an isovolumic Langendorff rat heart model. Hearts (n = 8/group) were perfused at constant pressure (90 mm Hg) with Krebs-Henseleit buffer or HEPES modified cell culture medium (M199) in the absence and presence of HBOC. Hearts received 15 minutes of normothermic no flow ischemia followed by 60 minutes reperfusion. Hemodynamics, coronary flow, and tissue water content were measured, and microscopic evidence of injury including TUNEL assay was assessed. Preischemic left ventricular performance (left ventricular developed pressure and maximum rate of positive and negative change in systolic pressure) and coronary flow were similar among groups. At 60 minutes of reperfusion, M199 alone provided more stable and complete left ventricular systolic and diastolic functional recovery than any other perfusate. Coronary flow rates reflected left ventricular function observed under each perfusate condition. TUNEL assay showed arterial endothelial cell death in some hearts perfused with HBOC. Tissue water content did not reflect functional recovery. The combination of M199 and HBOC was associated with poor recovery and elevated perfusate methemoglobin. In this system, postischemic dysfunction is prevented by components in M199. Added HBOC does not improve functional recovery and negates the salutary effects of M199, possibly by augmenting methemoglobin formation.     

Hypothesis: selective phosphodiesterase-5 inhibition improves outcome in preeclampsia

The pathogenesis of preeclampsia stems from aberrant changes at the placental interface. The trophoblastic endovascular invasion of tonic spiral arteries that converts them to passive conduits falters. Uteroplacental insufficiency and fetoplacental hypoxemia result. Secondary maternal oxidative stress and an excessive inflammatory response to pregnancy generate the clinical syndrome of preeclampsia. Current treatment focuses on preventing seizures, controlling hypertension, preserving renal function and delivering the baby. We propose that the pathophysiological changes induced by preeclampsia in the placenta parallel those caused by persistent hypoxemia in the lungs at high altitude or with chronic obstructive pulmonary disease. Unrelenting pulmonary hypoxic vasoconstriction induces pulmonary hypertension and cor pulmonale. Inhalation of nitric oxide and phosphodiesterase-5 inhibitors opposes pulmonary hypoxic vasoconstriction, alleviates pulmonary hypertension and improves systemic oxygenation. Notably nitric oxide donor therapy also counters hypoxemic fetoplacental vasoconstriction, a biological response analogous to pulmonary hypoxic vasoconstriction. Fetal oxygenation and nutrition improve. Placental upstream resistance to umbilical arterial blood flow decreases. Fetal right ventricular impedance falls. Heart failure (cor placentale) is avoided. Emergency preterm delivery can be postponed. Other than low dose aspirin and antioxidants vitamins C and E no available therapy specifically targets the underlying disease profile. We hypothesize that, like nitric oxide donation, pharmacological inhibition of placental phosphodiesterase-5 will also protect the fetus but for a longer time. Biological availability of guanosine 3'5'-cyclic monophosphate is boosted due to slowed hydrolysis. Adenosine 3'5'-cyclic monphosphate levels increase in parallel. Cyclic nucleotide accumulation dilates intact tonic spiral arteries and counters hypoxemic fetoplacental vasoconstriction. Intervillous and intravillous perfusion pick up. Maternal to fetal placental circulatory matching improves. Enhanced placental oxygen uptake alleviates hypoxemic fetal stress. Appropriate fetal nutrition resumes. Cor placentale and severe intrauterine growth restriction are averted. Increased maternal cyclic nucleotide concentrations promote systemic vasodilatation so that blood pressures fall. Preemption of oxidative stress initiated by "consumptive" oxidation of nitric oxide stabilizes the vascular endothelium and corrects coagulopathy. Anti-inflammatory and immunosuppressant adenosine 3'5'-cyclic monphosphate offsets the extreme gestational inflammatory response. Cellular injury and multi-organ damage are prevented. One tablet a day of the new long acting phosphodiesterase-5 inhibitor, tadalafil (half life of 17.5 h) theoretically should allow a preterm pregnancy affected by preeclampsia to continue safely. Selective monitoring of vital organ functions guards against life-threatening maternal complications. Regular biophysical profiling warns the obstetrician of impending fetal compromise. Fetal growth and vital organ maturation can continue. As a result workloads imposed upon neonatal intensivists will lighten. Parental anxiety and concern will be allayed. The cost of treating preeclamptic mothers and their extremely low birth weight infants will decrease. Money saved by midwifery services in poorer states can be used to pay for better prenatal care. Severe preeclampsia/eclampsia will be less common. Maternal and perinatal morbidity and mortality will be reduced. Because the human immunodeficiency virus often infects individuals at a workforce eligible age, the global acquired immunodeficiency syndrome pandemic has already brought many nations to the brink of economic ruin. Potentially productive lives saved for the future will help restore them fiscally.     

How to evaluate blood substitutes for endothelial cell toxicity

The most common and widely transplanted tissue worldwide is blood. But concerns about safety and adequacy of blood transfusion have fostered 20 years of research into blood substitutes such as oxygen carriers based on modified hemoglobin (Hb). Chemically modified or genetically engineered Hb developed as oxygen therapeutics are designed to restore blood volume and to correct oxygen deficit due to ischemia in a variety of clinical settings. Uncontrolled oxidative reactions mediated by large amounts of cell-free Hb and their reactions with various oxidant/antioxidant and cell signalling systems emerge as an important pathway of toxicity. Hemoglobin can react with oxygen and NO, leading to the production of reactive oxygen or nitrogen species. Inside the bloodstream, oxidized Hb and ROS/RNS are in direct contact with endothelial cells (EC). Thus, chain reactions may trigger molecular and cellular biology, causing oxidative stress-related pathologies. This editorial presents an overview of interactions between Hb (modified or not) and EC. We also propose a wide range of techniques and methods to assess oxidative stress and inflammation responses of EC after exposure to Hb. This editorial can serve as a guide to evaluate in vitro toxicity of new Hb molecules.     

Reactive oxygen species in renal vascular function

Reactive oxygen species (ROS) are produced by the aerobic metabolism. The imbalance between production of ROS and antioxidant defence in any cell compartment is associated with cell damage and may play an important role in the pathogenesis of renal disease. NADPH oxidase (NOX) family is the major ROS source in the vasculature and modulates renal perfusion. Upregulation of Ang II and adenosine activates NOX via AT1R and A1R in renal microvessels, leading to superoxide production. Oxidative stress in the kidney prompts renal vascular remodelling and increases preglomerular resistance. These are key elements in hypertension, acute and chronic kidney injury, as well as diabetic nephropathy. Renal afferent arterioles (Af), the primary resistance vessel in the kidney, fine tune renal hemodynamics and impact on blood pressure. Vice versa, ROS increase hypertension and diabetes, resulting in upregulation of Af vasoconstriction, enhancement of myogenic responses and change of tubuloglomerular feedback (TGF), which further promotes hypertension and diabetic nephropathy. In the following, we highlight oxidative stress in the function and dysfunction of renal hemodynamics. The renal microcirculatory alterations brought about by ROS importantly contribute to the pathophysiology of kidney injury, hypertension and diabetes.     

氢的选择性抗氧化作用研究进展

H2在机体内具有抗氧化作用。当过度氧化应激发生时,如缺血再灌注损伤、缺血缺氧损伤、急性炎性反应等,H2能够减少细胞毒性活性氧自由基,发挥抗氧化、抗损伤和抗凋亡作用。     

Oxidative Stress-Related Biomarkers in Essential Hypertension and Ischemia-Reperfusion Myocardial Damage

Cardiovascular diseases are a leading cause of mortality and morbidity worldwide, with hypertension being a major risk factor. Numerous studies support the contribution of reactive oxygen and nitrogen species in the pathogenesis of hypertension, as well as other pathologies associated with ischemia/reperfusion. However, the validation of oxidative stress-related biomarkers in these settings is still lacking and novel association of these biomarkers and other biomarkers such as endothelial progenitor cells, endothelial microparticles, and ischemia modified albumin, is just emerging. Oxidative stress has been suggested as a pathogenic factor and therapeutic target in early stages of essential hypertension. Systolic and diastolic blood pressure correlated positively with plasma F2-isoprostane levels and negatively with total antioxidant capacity of plasma in hypertensive and normotensive patients. Cardiac surgery with extracorporeal circulation causes an ischemia/reperfusion event associated with increased lipid peroxidation and protein carbonylation, two biomarkers associated with oxidative damage of cardiac tissue. An enhancement of the antioxidant defense system should contribute to ameliorating functional and structural abnormalities derived from this metabolic impairment. However, data have to be validated with the analysis of the appropriate oxidative stress and/or nitrosative stress biomarkers.     

Association of Heme Oxygenase 1 with the Restoration of Liver Function after Damage in Murine Malaria by Plasmodium yoelii

The liver efficiently restores function after damage induced during malarial infection once the parasites are cleared from the blood. However, the molecular events leading to the restoration of liver function after malaria are still obscure. To study this, we developed a suitable model wherein mice infected with Plasmodium yoelii (45% parasitemia) were treated with the antimalarial α/β-arteether to clear parasites from the blood and, subsequently, restoration of liver function was monitored. Liver function tests clearly indicated that complete recovery of liver function occurred after 25 days of parasite clearance. Analyses of proinflammatory gene expression and neutrophil infiltration further indicated that hepatic inflammation, which was induced immediately after parasite clearance from the blood, was gradually reduced. Moreover, the inflammation in the liver after parasite clearance was found to be correlated positively with oxidative stress and hepatocyte apoptosis. We investigated the role of heme oxygenase 1 (HO-1) in the restoration of liver function after malaria because HO-1 normally renders protection against inflammation, oxidative stress, and apoptosis under various pathological conditions. The expression and activity of HO-1 were found to be increased significantly after parasite clearance. We even found that chemical silencing of HO-1 by use of zinc protoporphyrin enhanced inflammation, oxidative stress, hepatocyte apoptosis, and liver injury. In contrast, stimulation of HO-1 by cobalt protoporphyrin alleviated liver inflammation and reduced oxidative stress, hepatocyte apoptosis, and associated tissue injury. Therefore, we propose that selective induction of HO-1 in the liver would be beneficial for the restoration of liver function after parasite clearance.     

Effects of sympathetic stimulation on cerebral and ocular blood flow. Modification by hypertension, hypercapnia, acetazolamide, PGI2 and papaverine

The effect of unilateral, electrical stimulation of the cervical sympathetic chain in rabbits anesthetized with pentobarbital sodium and vasodilated by hypercapnia, acetazolamide, papaverine or PGI2 was investigated to determine to what extent the sympathetic nerves to the brain and the eye cause vasoconstriction and prevent overperfusion in previously vasodilated animals. Evans blue was given as a tracer for protein leakage. Blood flow determinations were made with the labelled microsphere method during normotension and acute arterial hypertension. Hypertension was induced by ligation of the thoracic aorta and in some animals metaraminol or angiotensin was also used. Acetazolamide caused a two to threefold increase in cerebral blood flow (CBF) and hypercapnia resulted in a fivefold increase. CBF was not markedly affected by papaverine or PGI2. In the choroid plexus, the ciliary body and choroid, papaverine and hypercapnia caused significant blood flow increases on the control side. Sympathetic stimulation induced a 12% blood flow reduction in the brain in normotensive, hypercapnic animals. Marked effects of sympathetic stimulation at normotension were obtained under all conditions in the eye. In the hypertensive state the CBF reduction during sympathetic stimulation was moderate, but highly significant in hypercapnic or papaverine-treated animals as well as in controls. Leakage of Evans blue was more frequently seen on the nonstimulated side of the brain. In the eye there was leakage only on the control side except in PGI2-treated animals where 2 rabbits had bilateral leakage. The effect of sympathetic stimulation on the blood flow in the cerebrum and cerebellum in vasodilated animals seems to be small or absent if the blood pressure is normal. In the eye pronounced vasoconstriction occurs under these conditions. In acute arterial hypertension sympathetic stimulation protects both the cerebral and ocular barriers even under conditions of marked vasodilation.     

Aqueous oxygen attenuation of reperfusion microvascular ischemia in a canine model of myocardial infarction

Uncorrected microvascular ischemia may contribute to left ventricular impairment during reperfusion after prolonged coronary artery occlusion. Attenuation of such ischemia in microvessels with impaired erythrocyte flow may require delivery of oxygen at high levels in plasma. Intraarterial infusion of aqueous oxygen (AO) can be used in a site specific manner to achieve hyperoxemic levels of oxygenation in the perfusate. With this new approach, the hypothesis was tested that reperfusion microvascular ischemia can be attenuated. After a 90 min coronary balloon occlusion in a canine model, AO hyperoxemic intracoronary perfusion was performed for 90 min after a 30 min period of autoreperfusion. Control groups consisted of normoxemic reperfusion, both passive (autoreperfusion) and active (roller pump). A significant improvement in left ventricular ejection fraction (p < 0.05) at 2 hr of reperfusion was noted only in the AO hyperoxemia group (17 +/- 6% by two dimensional echo), without a significant reduction in the improvement 1 hr after termination of treatment. During AO hyperoxemic perfusion, ECG ST segment isoelectric deviation normalized, and frequency of ventricular premature contractions was significantly reduced, in contrast to the autoreperfusion control group (p < 0.05). Microvascular blood flow, measured as the ischemic/normal left ventricular segment ratio by radiolabeled microspheres immediately after AO hyperoxemic perfusion, was double the value of the autoreperfusion control group at 2 hr of reperfusion (p < 0.05). We conclude that reperfusion microvascular ischemia is attenuated by intracoronary AO hyperoxemic perfusion and acutely improves left ventricular function in this model.     

The conservation of mitochondrial function by ischaemia – the ischaemia paradox

The aim of this study was to compare oxidative phosphorylation of rat heart mitochondria, isolated: (i) immediately after excision of the heart; (ii) after 60 min of low flow normoxic perfusion; (iii) after 60 min of high flow normoxic perfusion; (iv) after 30 min of no-flow ischaemia and (v) after 30 min ischaemia followed by 20 min reperfusion. The results, using a retrogradely perfused rat hart as a model, show that mitochondrial oxidative phosphorylation after 30 min of no-flow ischaemia showed no difference from oxidative phosphorylation measured on mitochondria isolated directly after excision of the heart. However, after 30 min no-flow ischaemia followed by 20 min of reperfusion, oxidative phosphorylation deteriorated in comparison with oxidative phosphorylation after 30 min of ischaemia only. Furthermore, oxidative phosphorylation after 60 min of non-ischaemic high flow perfusion (thus high coronary flow), compared better with oxidative phosphorylation after ischaemia-reperfusion than with oxidative phosphorylation after ischaemia alone.     

Sympathetic and metabolic mechanisms of the cerebrovasomotor function of the caudal ventrolateral medulla in rats.

We attempted to elucidate the cerebrovasomotor function of the caudal ventrolateral medulla. Sixty-one rats were anaesthetized, paralysed and artificially ventilated. The microsphere method was employed for the measurement of blood flow. Microinjection of an antagonist of excitatory amino acids, kynurenate (2 nmol), into functionally identified depressor sites within the caudal ventrolateral medulla produced arterial hypertension of about 140 mmHg. We found that the cerebral blood flow was substantially increased, but was maintained at the same level (17 rats) as that observed under phenylephrine-induced hypertension (26 rats). Bilateral severing of the cervical sympathetic trunks resulted in a further increase in blood flow in all brain regions studied (18 rats). The response was most significant in the cerebral parasagittal cortex (164 +/- 31% of baseline without, and 211 +/- 43% with sympathectomy; mean +/- S.D.; P < 0.001). The contributions of the cerebral metabolic mechanism to this flow increase under denervation was minimal, as evidenced by the observation of disproportionately smaller changes in cerebral metabolic rate for oxygen during any type of hypertension. We conclude that the cerebrovasomotor functions of the caudal ventrolateral medulla may operate to keep an equilibrium between simultaneously working tonic inhibitions against sympathetic vasoconstriction as well as against vasodilatation. This dual effect is mediated by excitatory amino acid receptors located within this particular brain area. The vasodilator mechanism may be of neurogenic origin. When the function of the brain area is suppressed, the subsequently disinhibited vasodilator mechanism dominates the cerebrovascular autoregulatory function.(ABSTRACT TRUNCATED AT 250 WORDS)     

Haemodynamic characterization of the isolated (denervated) parabiotically perfused rat jejunum

The isolated (denervated) parabiotically perfused rat jejunum was characterized for base-line haemodynamics, autoregulation of blood flow and oxygen consumption and long-term (3 h) stability with respect to both haemodynamics and the absence of tissue injury. In short-term experiments, the parabiotically perfused preparation autoregulated oxygen consumption but not blood flow over a wide range of perfusion pressures (25-85 mmHg). When the intestinal segment was subjected to near total ischaemia for I h, followed by I h of reperfusion, mucosal injury was induced which could be prevented by i.v. administration of superoxide dismutase after ischaemia just prior to reperfusion, or allopurinol prior to ischaemia. These findings support the concept of post-ischaemic reperfusion injury in the denervated preparation without hepatic ischaemia. This preparation could thus serve as an improved model for the study of the pathophysiology of post-ischaemic reperfusion injury in the rat intestine.