PubMed Health⌕ Search

Biomedical subjects

A Baethmann

Publications and source records attributed to A Baethmann.

At least 145 records · Page 8Linked to original sources
PubMed1987

Permeability and vasomotor response of cerebral vessels during exposure to arachidonic acid.

Release of arachidonic acid (AA) in brain tissue is found in various cerebral insults. Blood-brain barrier function and vasomotor response were studied during cerebral administration of the fatty acid to obtain further evidence on its role as mediator of secondary brain damage under pathological conditions. Na+-fluorescein or fluorescein isothiocyanate (FITC)-dextran were i.v. administered as low- and high-molecular weight blood-brain barrier indicators. Cortical superfusion of arachidonic acid led to moderate constriction of ca. 90% of normal of pial arteries of 60-220 micron phi, whereas the venous diameters remained unaffected. On the other hand, AA caused opening of the blood-brain barrier not only for Na+-fluorescein but also for FITC-dextran (mol.wt. 62,000). Extravasation of Na+-fluorescein started at AA concentrations of 3 X 10(-5) M. Concentrations of 3 X 10(-4) to 3 X 10(-3) M always sufficed to induce barrier opening for fluorescein, whereas 3 X 10(-3) M was required for FITC-dextran. Leakage of the blood-brain barrier indicators started around venules. Pretreatment with indomethacin, or with BW 755 C, a dual inhibitor of both the cyclo- and lipoxygenase pathway did not prevent barrier opening by arachidonate for Na+-fluorescein. However, in the presence of indomethacin higher concentrations of AA were required to open the barrier for Na+-fluorescein, whereas BW 755 C did not influence the dose-effect relationship of AA and barrier opening observed in untreated animals. The latter findings imply that the pathophysiological effects induced by AA are likely to be attributed to the acid itself, rather than to its metabolites, a conclusion which might be in conflict with earlier observations reported in the literature. Electron microscopy revealed marked alterations of the venous endothelium, such as an attachment and eventual penetration of polymorphonuclear granulocytes through the endothelial barrier, while the small arteries and arterioles were unaffected. The findings may indicate that opening of the barrier by AA is mediated by granulocytes and/or their products. Taken together, our findings support the concept that release of AA in primarily damaged brain tissue enhances secondary processes, such as a failure of the blood-brain barrier function. The limited potency or even ineffectiveness, respectively, of indomethacin or BW 755 C provides evidence for a direct involvement of the fatty acid rather than of its metabolic degradation products. Therefore, therapeutic prevention of AA formation under these circumstances might be superior to mere inhibition of its metabolism.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMed1986

Possible role of calcium entry blockers in brain protection.

Cerebral protection in its proper meaning is understood as a method to suppress electrophysiological and metabolic activity of the CNS. More generally, methods which avert injury to the brain, particularly when anticipated, can be considered as cerebral protection. Prevention of secondary brain damage following a primary ischemic or traumatic lesion is a particularly important goal of cerebral protection. The concept of secondary brain damage implies that secondary changes in principle should be prevented by inhibition of the pathomechanisms involved. The introduction of Ca2+ antagonists into the treatment of traumatic or ischemic cerebral injury is an excellent example of a powerful therapeutical method, which is developed on the basis of an understanding of the underlying pathophysiological mechanisms. Ca2+ antagonists may interfere at various levels, e.g. blood flow, cellular destruction or other forms of secondary brain damage. Intracellular Ca2+ overload appears to be a common pathway to failure of pertinent cell functions, and eventually cell death. Thus, inhibition of this process might be central for cell and, hence, cerebral tissue protection. However, the use of Ca2+ antagonists requires careful considerations of the type of drug needed and of their potential side effects.

Animals↗
PubMed1986

The kallikrein-kinin system as mediator in vasogenic brain edema. Part 3: Inhibition of the kallikrein-kinin system in traumatic brain swelling.

Evidence has previously been provided that administration of kinins to the cerebrum causes edema and opening of the blood-brain barrier. It has further been shown that these highly active compounds are formed in the brain under pathophysiological conditions. Their formation was enhanced when cerebral blood flow became compromised by an increase in intracranial pressure. Final evidence, however, was not available as to whether specific inhibition of the kallikrein-kinin (KK) system has a therapeutic function in acute head injury. The authors have demonstrated in rabbits that inhibition of the activating enzyme kallikrein by aprotinin or by aprotinin plus soybean trypsin inhibitor (SBTI), which interfere with plasma and tissue kallikrein, is associated with a decrease in formation of posttraumatic swelling after a standardized cold lesion to the brain. Saline-treated control animals with cerebral cold-induced injury had an increase in hemispheric weight 24 hours later of 13.0% +/- 0.8% (standard error of the mean) in the damaged hemisphere compared to the contralateral nondamaged hemisphere. Administration of aprotinin or aprotinin plus SBTI led to a significant reduction of hemispheric swelling of 10.1% +/- 0.7% or 10.4% +/- 0.7%, respectively. In animals receiving SBTI only, hemispheric swelling evolving from cold injury was not significantly reduced. Therapeutic reduction of brain edema by aprotinin cannot be attributed to a nonspecific effect on the blood pressure, which in the experimental groups remained almost normal as compared to the control animals. Failure of SBTI to influence posttraumatic brain swelling may have resulted from disturbances in intravascular coagulation. Measurements of aprotinin in plasma and tissue demonstrate that the inhibitor doses employed are within an effective therapeutic range. Attenuation of brain edema by specific inhibition of the KK system provides evidence for a mediator role of kinins in vasogenic edema. Clinical trials with inhibitors of the KK system in acute forms of traumatic lesions associated with vasogenic edema appear worthwhile.

Animals↗
PubMed1985

Cell volume regulation of cerebrovascular endothelium in vitro.

Regulation of cell volume as a fundamental cellular function of high biological priority was studied in cultured cerebrovascular endothelium. The use of a multiparameter flow cytometric system allowed simultaneous measurements of cell volume, viability, and membrane potential or intracellular pH. Endothelium, the cellular constituent of the blood-brain barrier (BBB), swells immediately on exposure to low osmolality. This is associated with membrane depolarization and a fall of intracellular pH. Within 30-60 min, cell volume and membrane potential recover completely, although the extracellular osmolality is kept low. Intracellular pH does not normalize fully. Measurements of intracellular K+ and Na+ concentrations reveal their involvement in the regulatory process. The findings strongly suggest that the cerebrovascular endothelium has a highly effective built-in capacity for homeostatic control essential for normal BBB function.

Animals↗
PubMed1985

Intravital fluorescence microscopy for the study of blood-brain-barrier function.

Vascular diameters and blood-brain-barrier (BBB) function were investigated in the parietal cortex of cats using an open skull window technique and intravital fluorescence microscopy. The cortical surface was superfused with artificial cerebrospinal fluid containing: bradykinin (BK), Na+-arachidonate (AA), or xanthine-oxidase (XO). Na+-fluorescein (MW: 376), fluorescein-isothiocyanate-labelled (FITC) albumin (MW: 67 000), or FITC-dextran (MW: 19 400-62 000) were given intravenously as blood-brain-barrier indicators of different molecular size. In control experiments, the effect of continuous exposure of the preparation to the light source used for fluorescence excitation was studied. Dependent on the molecular size of the tracer and light intensity, continuous light exposure led to extravasation and disturbances of the microcirculation in small veins. When Na+-fluorescein was employed as barrier indicator at a magnification of X 40, at least 55 min of continuous illumination were required to induce extravasation. Brief, i.e. 0.5-15 s and discontinuous illumination for taking microphotographs amounting to less than 20 min in total did not induce extravasation in control experiments of 3.5 h. Opening of the blood-brain-barrier was studied during superfusion with a hypertonic solution (2000 mOsmol 1(-1)). The results obtained with bradykinin, Na+-arachidonate, or xanthine-oxidase indicate that opening of the barrier can occur independently from a corresponding vasodilating reaction. BK, or AA led to initial venular leakage as a result of an increase of selective, or global barrier permeability. On the other hand, XO did not induce extravasation, although cerebral vessels were markedly dilated. Taken together, the experimental model presented is suitable to simultaneously analyze dynamic changes of the permeability of cerebral vessels in-vivo with excellent spatial resolution and of the cerebral vasomotor behaviour under physiological and pathological conditions.

Animals↗
PubMed1984

Effects of bradykinin on permeability and diameter of pial vessels in vivo.

The effect of bradykinin on the permeability and vasomotor response of pial vessels has been studied to enhance our understanding of the pathophysiological role of the kallikrein-kinin system in cerebral tissue. Intravital fluorescence microscopy of the pia arachnoidea was conducted using Na+-fluorescein, FITC-dextran, and FITC-albumin as low and high molecular weight blood-brain barrier indicators. Massive arterial dilatation evolved immediately upon administration of bradykinin by superfusion of the exposed cerebral surface. An increase of the arterial diameter by 40% was the maximal response found at bradykinin concentrations of 4 x 10(-5) M. Arterial dilatation became attenuated with continuous superfusion of the preparation with bradykinin. In pial veins, a moderate reduction of the vessel diameter was observed, however, only after prolonged superfusion of the preparation. Bradykinin led to selective opening of the blood-brain barrier for Na+-fluorescein at superfusate concentrations of greater than or equal to 4 x 10(-7) M, but not for FITC-dextran or FITC-albumin. Topical administration of l-isoproterenol (10(-4) M) was found to prevent extravasation of Na+-fluorescein in the presence of bradykinin concentrations of 4 x 10(-6) M. Protection of the blood-brain barrier by isoproterenol was not observed when higher concentrations of bradykinin were employed. Intracarotid infusion of bradykinin were employed. Intracarotid infusion of bradykinin led also to a selective opening of the blood-brain barrier for Na+-fluorescein, but not for FITC-dextran or FITC-albumin. In contrast to superfusion, this route of administration did not induce changes of the vasomotor behavior of the arteries or veins. Additional experiments with B1-agonists and -antagonists suggest that bradykinin causes the openings of the blood-brain barrier th rough an interaction with B2-receptors on endothelial cells, and arterial dilatation via interaction with B2-receptors on vascular smooth muscle cells. Our findings support the concept that the release of kinins in the brain during an acute cerebral lesion mediates secondary damaging processes by the enhancement of blood-brain barrier dysfunction.

Animals↗
PubMed1983

Volume regulation and metabolism of suspended C6 glioma cells: an in vitro model to study cytotoxic brain edema.

The in vitro model presented provides an approach to study the nature of cell volume control as well as of swelling mechanisms under pathophysiological conditions. Pertinent parameters of cell volume control can be analyzed in isolation due to a virtually infinite extracellular environment precluding secondary effects of the suspended cells. Exposure of C6 glial cells to hypotonic medium was investigated as a model to study fundamental aspects of cell volume control. In confirmation of studies on other cell types glial cells suspended in hypotonic medium recover cell volume after transient swelling. Normalization of cell volume is associated with stimulation of respiration. Moreover, normalization of cell volume in hypotonic medium can be pharmacologically influenced. Addition of naftidrofuryl which enhances cellular O2-consumption led to acceleration of cell volume recovery. On the other hand, inhibition of Na+-K+-ATPase by ouabain did not prevent regulatory volume decrease ruling out a major role of the Na+-transport enzyme in this process. Contrary to hypotonic suspension, hypertonic exposure did not result in volume regulation during an observation period of 3 h. However, this may not necessarily exclude a capability of cell volume to normalize in hypertonic conditions as observed in vivo. Volume control of glial cells in abnormal osmotic medium may--on a cellular basis--reflect fundamental adaptive processes of central nervous tissue. Knowledge of the physiological and biochemical basis of cell volume control is not only of scientific interest but also of therapeutical significance in patients suffering from cytotoxic brain edema.

Brain Edema↗
PubMed1983

Therapeutic considerations in blood-brain barrier disturbances.

Current methods of treatment of brain damage, as e.g. edema by steroids and barbiturates, have components which benefit the blood-brain barrier. Protection of the blood-brain barrier may result from: (a) prevention of endothelial lesions, perhaps pinocytosis (b) reduction of secondary necrosis formation, (c) interference with release, or activation of mediator compounds causing endothelial lesions such as: biogenic amines, free fatty acids, prostaglandins, free radicals, or kinins, (d) stabilization of lysosomal membranes, and (e) prevention of microcirculatory disturbances. Other methods, or compounds aiming at mechanisms of barrier damage have a therapeutic potential as shown with regard to indomethacin, free radical scavengers, or phenothiazines. However, further studies appear necessary to demonstrate the benefit of these compounds under clinical circumstances. Reversible opening of the blood-brain barrier may be considered as a therapeutic approach to provide access of drugs to brain tissue which are normally excluded by the barrier.

Animals↗
PubMed1980

Osmotic adaptation of the brains of scalded rats to chronic increase in plasma Na+. Effects of corticosteroids.

The effect of chronically increased plasma Na+ concentration, secondary to scalding, on the cerebral electrolyte and water content was studied in rats. In contrast to findings in acute hypernatremia, the water content of the brain remained constant in these experiments. Cerebral adjustment to chronic hypernatremia is supposed to be brought about by an increase of osmotically active solutes in the brain. Regression analyses of the Na+ concentration in brain water versus the plasma Na+ concentration indicate that accumulation of Na+ in brain tissue is responsible only for about 50--60% of the osmotic adjustment to increased plasma osmolality in chronic hypernatremia. Except for animals receiving prednisolone, the cerebral K+ content remained constant. Therefore, it may be concluded that except for this group, formation of idiogenic osmoles comprises about 40--50% of the extra osmolality in brain. Aldosterone and spirolactone do not seem to influence osmotic adaptation of the brain, or formation of idiogenic osmoles under these circumstances. Prednisolone, however, seems to enhance cerebral accumulation of K+ in chronic hypernatremia. This was concluded from the close correlation between the K+ concentration in brain water and the plasma Na+ concentration found in this group.

Adaptation, Physiological↗
PubMed1975

Electrolyte- and fluid-spaces of rat brain in situ after infusion with dinitrophenol.

Chemical distribution measurements of radioactive sodium-thiosulfate (35S) and of the brain water indicate that infusion of 2.4-dinitrophenol into a carotid artery of rats caused a water uptake and fluid shifts from the extra- into the intracellular compartments in the central nervous system. The extracellular marker compound was administered to the brain via ventriculo-cisternal perfusion and intravenous injection yielding almost equal concentrations in plasma-water and perfusate. In order to prevent an active efflux of the label from the tissue, high concentrations were utilized in the perfusate to saturate potential outward transport mechanisms. The indicator space (based on total brain water) was 16% in controls and 12% in experimental animals when marker equilibrium had been attained, which is equivalent in reduction of the extracellular space of about 1/4. Intracellular water and Na+ rose after DNP, while K+ remained all but unchanged. The fluid shift into the intracellular compartment was found to relate closely with a cellular uptake of Na+. The Na+ concentration both in plasma and in the perfusion fluid leaving the ventricular system was consistently reduced in experimental animals. The K+ concentration was significantly elevated in the plasma of experimental animals but virtually unchanged in the cisternal effluate.

Animals↗
PubMed1975

Aldosterone plasma radioimmunoassay interference by a spirolactone metabolite.

The plasma aldosterone radioimmunoassay developed by Ito et al. was found to be non-specific for aldosterone following administration of the spirolactones, spironolactone and canrenoate-K, in rabbits, dogs and humans. The assay interfering principle was identified as a hydroxylated derivative (M-B) of canrenone, which itself is a metabolite common to both spironolactone and canrenoate-K. The metabolite M-B possessed a high cross-reactivity to the 21-hemisuccinate aldosterone antibody relative to other spirolactones. A modified procedure was developed specific for plasma aldosterone in the presence of M-B. Following single doses of spironolactone and canrenoate-K, aldosterone plasma levels were unchanged in humans and in dogs and decreased in rabbits.

Aldosterone↗