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Biomedical subjects

L Schilling

Publications and source records attributed to L Schilling.

At least 73 records · Page 4Linked to original sources
PubMed1994

Effects of antihistaminics on experimental brain edema.

Histamine has potent effects on cerebral blood vessels which include increased permeability and dilatation. Since its concentrations are found to be increased in brain tissue in different experimental models of brain injury, histamine may act as a mediator of secondary brain damage. Using the cold-lesion model of vasogenic brain edema the effects of application of antihistaminics were studied in rats. Neither mepyramine, an H1 receptor blocker nor zolantidine, an H2 blocker provided any decrease in brain swelling or water content. Experiments with application of dexamethasone yielded a small non-significant decrease of edema while the amino-steroid U74389F did not reduce swelling. The results indicate that histamine is obviously not involved in mediating cold lesion-induced brain edema. Furthermore, generation of lipid peroxides after activation of phospholipase A2 also appears not to have a significant influence on edema in the present study.

Animals↗
PubMed1994

Computerised image analysis in conjunction with fluorescence microscopy for the study of blood-brain barrier permeability in vivo.

The present paper describes a new method using computerised image analysis techniques for quantification of tracer extravasation over the blood-brain barrier as studied by intravital fluorescence microscopy. Cats were equipped with an open cranial window and continuously infused with fluorescein isothiocyanate-labelled dextran (FITC-dextran, mol. wt. 70,000) to maintain a steady plasma concentration. Several cortical fields were recorded in each experiment and the images stored on video tape for off-line analysis. This procedure, which largely eliminates the superficial pial vasculature and allows extraction of the extravasation areas, consists of the following steps: (1) averaging of images, (2) software shading correction based on the original images for compensation of optical non-uniformity, (3) correction of displacement artefacts, (4) intensity adjustment, (5) generation of subtraction images by subtracting the first image of a series from the subsequent ones, (6) median filtering and thresholding, (7) a length recognition algorithm, and (8) elimination of small areas. Compared to the previously described method, step (2) has been newly developed and steps (4) and (8) added to enhance sensitivity for detecting tracer extravasation. The degree of extravasation in a cortical field at a given time point [E(f) value] was calculated as the mean intensity of the remaining pixels. The E(f) is a quantitative value computed by a fully automatised procedure which takes into account the number, as well as the size and intensity, of extravasation areas in a given cortical field. The E(f) values obtained at different times in a series of experiments were averaged to give the E(I) value.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine↗
PubMed1994

Endothelin-induced contraction and relaxation of rat isolated basilar artery: effect of BQ-123.

In ring segments from rat basilar artery (BA) the endothelin (ET) peptides ET-1, ET-2, and ET-3 induced concentration-related contractions. The order of potency was ET-1 = ET-2 > ET-3, while no differences occurred in the maximum contraction. The selective ETA receptor antagonist, BQ-123 (10(-10)-10(-4) M) alone elicited a small contraction only at 10(-4) M. In the presence of BQ-123 (10(-7)-10(-5) M), the concentration-response curve for ET-1 was shifted to the right without any decrease in maximum contraction, indicating competitive inhibition of ET-1 binding to the ETA receptor by BQ-123. The pA2 value calculated for BQ-123 was 6.935; the slope of the regression curve was 0.734. In contrast to ET-1, the contractile action of ET-3 was abolished by 10(-5) M BQ-123. In segments precontracted with 10(-6) M serotonin, ET-3, but not ET-1, induced relaxation at low concentrations (10(-11)-10(-8) M), with maximum relaxation amounting to 17.8 +/- 14.7% of precontraction (mean +/- SD; n = 16). The relaxant action of ET-3 was abolished in vessels incubated with NG-nitro-L-arginine (10(-5) M), an inhibitor of nitric oxide synthase. These results indicate that the ET-induced contraction of the isolated rat BA involves activation of the ETA receptor. The ET-3-induced relaxation of precontracted rat BA is apparently mediated by release of nitric oxide from the endothelium.

Animals↗
PubMed1994

Dilating effect of perivascularly applied potassium channel openers cromakalim and pinacidil in rat and cat pial arteries in situ.

OBJECTIVE: The aim was to test the vasodilator effect of perivascularly applied potassium channel openers cromakalim and pinacidil in pial arteries of cat and rat. METHODS: Using an open cranial window technique the diameter of pial arteries in the parietal cortex of rat and cat was recorded with an image splitting method. Employing micropuncture techniques, test compounds were dissolved in inert cerebrospinal fluid and infused into the perivascular space of individual arteries. RESULTS: Cromakalim (7 x 10(-18)-7 x 10(-13) M) induced concentration dependent dilatation of feline pial arteries with a maximum effect of 26.8(SEM 3.2)% at 7 x 10(-15) M. In rat arteries, cromakalim had a maximum effect of 32.1(4.97)% at 10(-15) M, while pinacidil (10(-10)-10(7) M) exerted a maximum dilatation of 29.5(3.3)% at 10(-8) M. The latter is consistent with previous findings in feline pial arteries. The sulphonylurea glibenclamide (10(-8)-10(-6) M) had no effect on the resting diameter of rat and cat pial arteries, indicating that their resting tone is not influenced by mechanisms involving ATP sensitive potassium channels. However, glibenclamide reduced the dilating effect of cromakalim and pinacidil in rat and cat in a dose dependent manner. CONCLUSIONS: A comparison with previously published data obtained in isolated middle cerebral and basilar arteries showed that potassium channel openers of the benzopyrane and cyanoguanidine type are much more potent in pial arteries than in peripheral arteries in situ or in isolated arteries of the circle of Willis and of peripheral vascular beds.

Animals↗
PubMed1994

Investigation of blood-brain barrier permeability by means of computerized image analysis.

Intravital fluorescence microscopy has been widely used to study changes of blood-brain barrier (BBB) permeability in vivo. However, quantification of tracer extravasation by counting leaky spots provides only a rough estimate of permeability increase. We have therefore developed a new method for measurement of tracer extravasation from cerebral blood vessels by combining image analysis techniques with intravital fluorescence microscopy. This method is based on generation of subtraction images after shading and displacement correction. Subtraction images are further processed to eliminate noise and diminish artefacts due to vessel distortion and/or dilatation. The "degree of extravasation" (E(f) value) which is then calculated takes into account the number and size of leaky spots as well as their intensities. Examples are shown to illustrate that pure vasodilatation does not increase E(f) as long as the BBB-permeability is not disturbed. This newly developed method may prove helpful for comparison of tracer extravasation under different experimental conditions.

Animals↗
PubMed1993

Mediators of vascular and parenchymal mechanisms in secondary brain damage.

Several putative mediators of vasogenic brain edema will be considered with respect to the following criteria: 1) their effect on blood-brain barrier (BBB) permeability, 2) their vasomotor actions which may increase driving forces for transmural bulk flow, 3) their influence on edema formation, 4) their actual tissue concentration in pathological states, and 5) the therapeutic results after specific treatment. Bradykinin (BK) can induce brain edema by increasing BBB permeability to small solutes and enhancing blood pressure in the microcirculation due to arterial dilatation and venous constriction. Its interstitial concentration is enhanced after experimental trauma. Since kallikrein inhibitors reduce brain swelling all criteria favour BK as a mediator of vasogenic edema. Arachidonic acid (AA) opens BBB also for large tracers but exerts only small vasomotor effects. The edema formation is associated with an increase of the AA concentration in the interstitial space. However, convincing therapeutic results on inhibition of AA are still lacking. In addition to the formation of vasogenic edema AA has been found to induce cytotoxic edema. From experiments dealing with the vasomotor effects Ellis et al. (Am J Physiol 255: H397-H400, 1988) concluded an interaction of BK and AA in brain injury. However, our own results do not favour this hypothesis since we found divergent vasomotor and permeability effects of BK and AA. Histamine (HA) opens BBB unspecifically and dilates cerebral vessels, mechanisms by which edema formation can be explained.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute-Phase Proteins↗
PubMed1993

Regulation of cerebral blood flow--a brief review.

Cerebral blood flow is largely independent of perfusion pressure when autoregulation is intact. Cerebral circulation is regulated mainly by changes of vascular resistance. Resistance can be modulated by local-chemical and endothelial factors, by autacoids, and by release of transmitters from perivascular nerves. Local-chemical factors such as H(+)-, K(+)-, Ca(2+)-ions, adenosine, and osmolarity are involved in the regulation of cerebrovascular resistance during cortical activation and under pathological conditions such as hypoxia or ischaemia. Endothelial factors such as thromboxane A2, endothelin (ET), endothelium derived constrictor factor and endothelium derived relaxing (EDRF, identified as nitric oxide, NO) or hyperpolarizing (EDHF) factor, and prostacyclin (PGI2), can be released by physical stimuli such as shear stress or haemorrhage, by autacoids, by neurotransmitters, and by cytokines. Several of these factors (NO, PGI2, ET) can also be released from neurons and astrocytes thus enabling a coupling between parenchymal function and flow. Autacoids like histamine, bradykinin, eicosanoids, and free radicals influence cerebrovascular resistance, capacitance vessels and the permeability of the blood-brain barrier under pathological conditions. They are released by trauma, ischaemia, seizures and inflammation. Cerebral arteries are innervated by several systems. The sympathetic-noradrenergic fibres originate from the superior cervical ganglion. By releasing the constricting transmitters norepinephrine and neuropeptide Y this system extends the range of autoregulation. The parasympathetic cholinergic system with the dilating transmitters acetylcholine and vasoactive intestinal polypeptide may prevent ischaemia. Besides the intracerebral noradrenergic and serotonergic perivascular innervation with an unclear function, a trigeminal innervation has been described.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Analysis of cromakalim-, pinacidil-, and nicorandil-induced relaxation of the 5-hydroxytryptamine precontracted rat isolated basilar artery.

The effects of the K+ channel activators cromakalim, pinacidil, and nicorandil were investigated in endothelium intact, 5-hydroxytryptamine (5-HT) precontracted rat isolated basilar artery. Cromakalim, pinacidil, and nicorandil produced concentration-dependent relaxation of rat isolated basilar artery precontracted with 5-HT with a rank order of potency of cromakalim greater than pinacidil greater than nicorandil. All compounds produced full or nearly full relaxation. The calculated Hill coefficients for cromakalim-, pinacidil-, and nicorandil-induced relaxation of 5-HT-precontracted rat isolated basilar artery were 2.20 +/- 0.36, 1.30 +/- 0.07, and 1.00 +/- 0.01, respectively. Under conditions of increased tone produced by 50 mmol/l KCl (which inhibits cromakalim-induced relaxation) pinacidil and nicorandil produced marked reversal of spasm, with pinacidil being more potent than nicorandil. In arteries precontracted with 5-HT, preincubation with glibenclamide (0.1-1 mumol/l) produced concentration-related inhibition of relaxation with calculated mean pA2 values (and slopes of Schild regression) +/- SEM of 6.84 +/- 0.20 (1.1 +/- 0.20) against cromakalim. 6.60 +/- 0.14 (0.95 +/- 0.23) against nicorandil, and 6.57 +/- 0.26 (1.04 +/- 0.18) against pinacidil. For cromakalim, pinacidil, and nicorandil the slopes of Schild regression were not significantly different from unity. Tolbutamide 10 mumol/l was without effect against the cromakalim-, pinacidil-, or nicorandil-induced relaxation. Tetraethylammonium (TEA; 1-10 mmol/l) produced noncompetitive inhibition of the cromakalim-induced relaxation, but appeared to produce competitive inhibition of the pinacidil- and nicorandil-induced relaxations. We conclude that cromakalim, pinacidil, and nicorandil produce relaxation of the 5-HT precontracted rat basilar artery by similar mechanisms to those identified in other peripheral vascular and visceral smooth muscle.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Comparison of cromakalim-induced relaxation of potassium precontracted rabbit, cat, and rat isolated cerebral arteries.

The effects of cromakalim were investigated in KCl-precontracted cat, rabbit, and rat isolated cerebral arteries with intact endothelium. Potassium induced contraction of all cerebral arteries studied, but exhibited marked vessel and species variation with no spasm to 20 or 30 mmol/l KCl in the rat basilar artery or 20 mmol/l KCl in the rabbit middle cerebral artery. On sustained tension to 20 mmol/l KCl, cromakalim induced concentration-related relaxation in the rabbit basilar artery and the cat basilar and middle cerebral arteries with Hill coefficients greater than unity. Cromakalim was more potent in the rabbit basilar artery precontracted with 20 or 30 mmol/KCl than in the rabbit middle cerebral artery or the cat basilar or middle cerebral artery. Elevation of the KCl concentration to 50 mmol/l inhibited cromakalim-induced relaxation and produced a decrease in the Hill coefficient. Preincubation of cerebral arteries with glibenclamide (100 nmol/l-1 mumol/l) produced concentration-related inhibition of the cromakalim-induced relaxation in the rabbit basilar, cat basilar, and cat middle cerebral arteries precontracted with 20 mmol/l KCl. The degree of rightward shift of concentration-effect curves by glibenclamide was calculated at the EC25, EC50, and EC75 levels. A good correlation was observed between the shifts at the EC50 and EC75 levels. However, the shift in concentration-effect curves for cromakalim produced at the EC25 level was markedly less than the EC50 or EC75 levels in the presence of 1 mumol/l glibenclamide. The pA2 values for glibenclamide calculated at the EC50 level were 6.6 +/- 0.09, 7.1 +/- 0.1, and 6.5 +/- 0.5 in the rabbit basilar, cat basilar, and cat middle cerebral artery, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Analysis of acetylcholine-induced relaxation of rabbit isolated middle cerebral artery: effects of inhibitors of nitric oxide synthesis, Na,K-ATPase, and ATP-sensitive K channels.

The functional importance of membrane hyperpolarization through activation of ATP-sensitive K channels, or activation of the Na,K-ATPase, was investigated for acetylcholine (ACh)-induced relaxation of the rabbit isolated middle cerebral artery (MCA) precontracted with uridine triphosphate. Incubation with glibenclamide (1 microM), a known blocker of ATP-sensitive K channels, or precontraction with a high concentration of KCl (50 mM) had no effect on ACh-induced relaxation. Similarly, inhibition of the Na,K-ATPase with ouabain (10 microM) or incubation with a potassium-free solution had either no or only a small effect on ACh-induced relaxation. In contrast, NG-nitro-L-arginine (NOLAG) (1 to 10 microM), a structural analogue of L-arginine and an inhibitor of nitric oxide synthesis, produced concentration-dependent although apparently noncompetitive inhibition of ACh-induced relaxation. This inhibition was partially reversed by application of L-arginine (100 microM), a putative precursor for nitric oxide synthesis. It is concluded that membrane hyperpolarization induced by activation of ATP-sensitive K channels or Na,K-ATPase does not play a major functional role in ACh-induced relaxation of rabbit MCA. The potent inhibitory actions of NOLAG would suggest that the major mechanism of ACh-induced relaxation is by release of nitric oxide as in other cerebral and peripheral arteries.

Acetylcholine↗
PubMed1990

Effect of L-arginine on haemoglobin-induced inhibition of endothelium-dependent relaxation of isolated cerebral arteries.

The effects of Oxy-haemoglobin were investigated in the rat isolated basilar artery and compared to Methylene blue and NG-Nitro-L-Arginine (NOLAG), as these compounds interfere with the relaxation induced by the endothelium-derived relaxing factor. Acetylcholine induced a concentration-related relaxation of serotonin-precontracted arteries which was further enhanced by the application of L-arginine. Similarly, the spasmolytic activity of L-arginine was enhanced by acetylcholine. Oxy-haemoglobin, Methylene blue and NOLAG induced an increase of resting tension and inhibited acetylcholine-induced relaxation. Furthermore, inhibition of acetylcholine-induced relaxation by Oxy-haemoglobin and NOLAG but not that by Methylene blue was partially reversed by L-arginine.

Acetylcholine↗
PubMed1989

Cerebrovascular effects of prostanoids. In-situ studies in pial arteries of the cat.

The effect of prostaglandin (PG) E2, F2 alpha, the thromboxane A2 mimetic U46619 (9,11-dideoxy-9 alpha,11 alpha-methanoepoxy-prostaglandin F2 alpha) and the prostacyclin mimetic iloprost was investigated in feline and rat pial arteries in-situ using perivascular microapplication and measurement of vascular diameter. U46619 induced a concentration-dependent vasoconstriction with a maximal response of 24% at 10(-6) mol.l-1 and an EC50 of 4.9 x 10(-8) mol.L-1. This effect was inhibited by the thromboxane receptor blocking drugs AH23848 B [[1 alpha(z),2 beta,5 alpha]-(+/-)-7-[5-[(1,1'-(biphenyl)-4- yl]methoxy]-2-(4-morpholinyl)-3-oxocyclo-pentyl]-4-heptenoic acid)] and EP092 [(+/-)-5-endo-(6'-carboxyhex-2'z-enyl)-6-exo[1'-[N- (phenylthiocarbamoyl)-hydrazano]-ethyl]-bicyclo[2,2,1]-hepta ne], indicating the involvement of thromboxane-prostanoid-receptors. PGF2 alpha produced vasodilatation in cats with an increase in vessel diameter of 30% at 10(-3) mol.l-1, but constricted rat pial arteries concentration-dependently with a maximal response of 23% at 10(-4) mol.l-1. PGE2 and iloprost induced concentration-dependent (10(-9)-10(-5) mol.l-1)) dilatations with apparent maximal responses of 39% and 34% at 10(-5) mol.l-1, respectively. The corresponding EC50 values were 2.45 x 10(-7) mol.l-1 (PGE2) and 3.5 x 10(-7) mol.l-1 (iloprost). These data demonstrate the presence of prostanoid receptors mediating constriction and dilatation under in-situ conditions.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Cerebrovascular effects of prostanoids: in-vitro studies in feline middle cerebral and basilar artery.

The effect of prostaglandin (PG) E2, F2 alpha, the thromboxane-A2 mimetic U46619 (9,11-dideoxy-9 alpha,11 alpha-methanoepoxy-prostaglandin F2 alpha) and the prostacyclin mimetic iloprost was investigated in cat middle cerebral and basilar arteries in vitro precontracted with 5-hydroxytryptamine (5-HT) (50nM) in the absence and presence of the cyclooxygenase inhibitor indomethacin or the thromboxane receptor blocker AH23848B [1 alpha (z),2 beta,5 alpha]-(+)-7-[5-[1,1'-(biphenyl)-4-yl] methoxy]-2-(4-morpholinyl)-3-oxocyclopentyl]-4-heptenoic acid). PGF2 alpha and U46619 both produced further concentration-related contractions of basilar and middle cerebral artery, U46619 being approximately 1,000 times more potent than PGF2 alpha. Iloprost produced concentration-related relaxations of precontracted basilar and middle cerebral artery, the mean maximum relaxations produced at a concentration of 1.3 microM being 57.3% and 80.6%, respectively of the contraction produced by 50nM 5-HT. PGE2, 100nM relaxed the basilar and middle cerebral artery, 46.7% and 38.5% respectively. However, at 1 microM, PGE2 caused contraction. Indomethacin, 2.8 microM had no effect on contractile or relaxant responses to any of the prostanoids. Oxyhaemoglobin inhibited the relaxation of both arterial preparations but had no effect on responses to PGE2 or iloprost. The thromboxane-receptor blocker AH23848B antagonised the contractile responses to U46619, PGF2 alpha and PGE2 and had no effect against relaxant responses to PGE2 or iloprost. It is concluded that both contraction- and relaxation-inducing prostanoid receptors are present in the in vitro preparation of feline basilar and middle cerebral artery. Under sustained tension conditions, endothelial factors do not appear to be involved in the responses to dilating prostanoids.

Animals↗
PubMed1989

Cerebrovascular effects of nimodipine in cats.

The effects of nimodipine on feline pial arteries were studied before and after cortical spreading depression (CSD) using perivascular microapplication. Vessel diameter was measured by image splitting technique. Nimodipine was used as liposome suspension. Before CSD nimodipine induced a dilatation of 23.3 +/- 2.7% (mean +/- SEM) at 2.4 x 10(-7) M, while the empty liposomes elicited a nonsignificant constriction of 1.3%. After CSD the nimodipine-induced dilatation was significantly diminished to an average of 15%. This attenuated response to nimodipine is discussed and thought to be due to a more general decrease in cerebrovascular reactivity after CSD.

Animals↗
PubMed1987

Change of cerebrovascular reactivity after cortical spreading depression in cats and rats.

The purpose of the present study was to examine the pial arteriolar diameter and evoked vascular responses after single episodes of cortical spreading depression (CSD) in rats and cats in order to elucidate the mechanisms of the persistent change of cortical perfusion which succeeds CSD. This problem is of potential clinical interest also since CSD may be involved in migraine pathophysiology. Using an open cranial window technique, pial arteriolar diameters were measured with an image splitting method. Vascular reactivity was tested by local perivascular microapplication of mock cerebrospinal fluid (CSF) containing high and low levels of K+, high and low pH, adenosine and bradykinin before and after CSD which was triggered by intracortical injection of KCl. During CSD a monophasic vasodilatation of 26.0 +/- 3.7% (mean +/- S.E.M.; cat) or 64.6 +/- 3.9% (rat) was observed. Following CSD, the cat developed persistent vasodilatation (16.7 +/- 1.9%) while the rat exhibited vasoconstriction (12.1 +/- 1.8%). Both species displayed a severely impaired responsiveness to constrictor and dilating stimuli as compared to pre-CSD values. The responses were reduced by 28-84%, dependent on the substance tested. It is concluded that vascular reactivity is severely impaired after CSD (15-75 min) and that this might explain the impaired coupling between flow and metabolism after CSD.

Adenosine↗
PubMed1986

Antagonism of bencianol (ZY 15051) and idazoxan (RX 781094) to norepinephrine in feline pial arteries in situ.

The anticonstrictor properties of the semisynthetic flavinoid compound bencianol (ZY 15051) and the highly selective alpha 2-antagonist idazoxan (RX 781094) were investigated in pial arteries (resting diameter 60-348 micron) in situ. Using micropuncture technique mock cerebrospinal fluid (CSF) containing the compounds was applied perivascularly, and vascular diameter was measured by means of image splitting. 1. Idazoxan and bencianol (10(-6)-10(-4) M) did not change vascular diameter per se. 2. The constriction (19%) elicited by K+-free mock CSF was not significantly altered by bencianol. 3. The norepinephrine (NE) (2.5 X 10(-3) M) induced constriction (25-28%) was dose dependently reduced by bencianol as well as idazoxan. Both agents had similar potency and maximal effects blocking the NE induced constriction at 10(-4) M each. It is concluded that the NE induced constriction of feline pial arteries in situ is mediated by postjunctional alpha 2-adrenoceptors. Considering the similarities of bencianol and idazoxan in the antagonism to NE an alpha 2-antagonistic action of bencianol appears possible.

Adrenergic alpha-Antagonists↗