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Biomedical subjects

L Schilling

Publications and source records attributed to L Schilling.

At least 37 records · Page 2Linked to original sources
PubMed2000

Improvement of renal dysfunction in rats with chronic heart failure after myocardial infarction by treatment with the endothelin A receptor antagonist, LU 135252.

OBJECTIVE: To investigate the role of an activated endothelin system in the renal dysfunction observed in chronic heart failure after myocardial infarction. METHODS: In rats with heart failure after myocardial infarction and in sham-operated animals (Sham), we investigated the effect on renal function of long-term oral treatment with the selective endothelin A (ETA) receptor antagonist, LU 135252 (30 mg/kg per day; groups MI/LU and Sham/LU) or placebo (groups MI/P, Sham/P). Only animals with extensive myocardial infarction (at least 46% of the left ventricle) were included in the study. Infarct size was matched between groups MI/P and MI/LU. Endogenous creatinine clearance, fractional sodium excretion, and plasma and urinary concentrations of endothelin were determined 12 weeks after myocardial infarction. RESULTS: Endogenous creatinine clearance was significantly lower in group MI/P than in group Sham/P (MI/P: 0.64 +/- 0.05, Sham/P: 0.81 +/- 0.04 ml/min per 100 g body weight; P= 0.01 (means +/- SEM)). Treatment with LU 135252 completely prevented the decline in creatinine clearance in rats with chronic myocardial infarction (MI/LU: 0.98 +/- 0.21; Sham/LU: 0.83 +/- 0.10). Fractional sodium and protein excretion did not differ among the four groups. Group MI/P had a marked increase in plasma endothelin concentrations, which was not affected by treatment with LU 135252. Urinary endothelin excretion was significantly lower in group MI/P than in group Sham/P. In the treatment groups, no difference could be observed between animals that had suffered myocardial infarction and the sham-operated group, although LU 135252 markedly increased the urinary excretion of endothelin. CONCLUSION: Our data demonstrate a restoration of impaired renal function in chronic ischaemic heart failure by treatment with the selective ETA receptor antagonist, LU 135252. These results offer a promising therapeutic option for the treatment of renal insufficiency in patients with chronic heart failure.

Animals↗
PubMed2000

Endothelium-dependent and -independent vasoreactivity of rat basilar artery in chronic heart failure.

Alterations of vasoreactivity are a well-known phenomenon in chronic heart failure (CHF), and activation of the endogenous endothelin (ET) system is suspected to contribute significantly. Regional differences in alterations of vasoreactivity exist; however, nothing is known about cerebrovascular reactivity in CHF. This is of interest in view of increased stroke risk in CHF. Therefore, 12 weeks after coronary artery ligation to induce CHF in rats, studies of vasoreactivity of the isolated basilar artery (BA) were performed and compared with third-order branches (MA-A3) and the main trunk (MA) of the superior mesenteric artery. Some of the animals received long-term ET-receptor antagonism by 11 weeks of treatment with the selective ET(A)-receptor antagonist LU 135252 or the mixed ET(A)/ET(B)-receptor antagonist bosentan. In rats with CHF, endothelium-dependent relaxation by acetylcholine and A23187 as well as endothelium-independent relaxation by sodium nitroprusside (SNP) was largely unaffected in BA or MA. However, in MA-A3, potency of SNP was diminished without change of maximal effect. ET-1-induced contraction did not differ in arteries from CHF and control rats, either in placeboor ET-receptor antagonist-treated animals. In summary, there was essentially no change of vascular reactivity in similar sized arteries obtained from brain and mesentery. This is in contrast to results on arteries from a variety of vascular regions published previously, thus supporting the concept of organ- and probably time-related changes of vascular function in the development of CHF. The absence of significant alteration of cerebral vasoreactivity may be taken to indicate that changes in cerebral blood flow and increased incidence of ischemic stroke in patients with CHF are caused not by local alterations of vascular function.

Acetylcholine↗
PubMed2000

Measuring VEGF-Flk-1 activity and consequences of VEGF-Flk-1 targeting in vivo using intravital microscopy: clinical applications.

Vascular endothelial growth factor (VEGF)-Flk-1/KDR tyrosine kinase signaling pathway plays a pivotal role in tumor angiogenesis. Targeting this angiogenic signaling pathway presents a promising alternative for the treatment of neoplasms. However, recent experimental and clinical studies have suggested that VEGF-Flk-1/KDR activity is unevenly distributed throughout the tumor microvasculature. To further evaluate this phenomenon, the regional differences in VEGF-Flk-1/KDR signaling activities in vivo were studied using intravital fluorescence videomicroscopy in an experimental murine brain tumor model. Regional VEGF-Flk-1/KDR was assessed using the small molecule inhibitor SU5416, which selectively inhibits the tyrosine kinase receptor Flk-1. C(6) glioblastoma cells were implanted into the dorsal skinfold chamber preparation of nude mice. The process of tumor vascularization was repeatedly assessed over 22 days. SU5416 treatment resulted in a significant reduction in tumor vascular density (p<0.05). Regional microvascular evaluation indicated that the magnitude of this antiangiogenic effect was pronounced in the more angiogenic and better vascularized peritumoral areas than in the intratumoral areas of the tumor microvasculature. These results demonstrate regional differences in Flk-1 activity in vivo that may have significant impact on the susceptibility of tumors to compounds that target VEGF-Flk-1/KDR. This finding should be considered in upcoming clinical trials targeting individual signal transduction systems in cancer patients.

Analysis of Variance↗
PubMed2000

Continuous monitoring of regional cerebral blood flow: experimental and clinical validation of a novel thermal diffusion microprobe.

OBJECT: Current clinical neuromonitoring techniques lack adequate surveillance of cerebral perfusion. In this article, a novel thermal diffusion (TD) microprobe is evaluated for the continuous and quantitative assessment of intraparenchymal regional cerebral blood flow (rCBF). METHODS: To characterize the temporal resolution of this new technique, rCBF measured using the TD microprobe (TD-rCBF) was compared with rCBF levels measured by laser Doppler (LD) flowmetry during standardized variations of CBF in a sheep model. For validation of absolute values, the microprobe was implanted subcortically (20 mm below the level of dura) into 16 brain-injured patients, and TD-rCBF was compared with simultaneous rCBF measurements obtained using stable xenon-enhanced computerized tomography scanning (sXe-rCBF). The two techniques were compared using linear regression analysis as well as the Bland and Altman method. Stable TD-rCBF measurements could be obtained throughout all 3- to 5-hour sheep experiments. During hypercapnia, TD-rCBF increased from 49.3+/-15.8 ml/100 g/min (mean +/- standard deviation) to 119.6+/-47.3 ml/100 g/ min, whereas hypocapnia produced a decline in TD-rCBF from 51.2+/-12.8 ml/100 g/min to 39.3+/-5.6 m/100 g/min. Variations in mean arterial blood pressure revealed an intact autoregulation with pressure limits of approximately 65 mm Hg and approximately 170 mm Hg. After cardiac arrest TD-rCBF declined rapidly to 0 ml/100 g/min. The dynamics of changes in TD-rCBF corresponded well to the dynamics of the LD readings. A comparison of TD-rCBF and sXe-rCBF revealed a good correlation (r = 0.89; p < 0.0001) and a mean difference of 1.1+/-5.2 ml/100 g/min between the two techniques. CONCLUSIONS: The novel TD microprobe provides a sensitive, continuous, and real-time assessment of intraparenchymal rCBF in absolute flow values that are in good agreement with sXe-rCBF measurements. This study provides the basis for the integration of TD-rCBF into multimodal monitoring of patients who are at risk for secondary brain injury.

Adolescent↗
PubMed2000

Effects of 30% stable xenon on regional cerebral blood flow in patients with intracranial pathology.

Regional cerebral blood flow was assessed continuously in 22 patients with severe intracranial pathology undergoing xenon-enhanced computed tomography by means of an intraparenchymal thermodiffusion based microprobe. Thirty-four blood flow studies were analysed revealing an overall xenon-induced flow activation from about 12%. Regional CBF rose from 25 +/- 17 ml/100 g/min (mean +/- sd; range: 5.2-41.8 ml/100 g/min) before xenon administration to 28 +/- 21 ml/100 g/min (p = 0.012; range: 6.5-46.4 ml/100 g/min) when "steady-state" during xenon "wash-in" was reached. Flow activation curve demonstrated a logarithmic shape with an increase in rCBF between 3% and 7% within the first 90 seconds of xenon "wash-in", 12% after 160 seconds, and showed no further augmentation until the end of the blood flow study after 310 seconds. It is concluded that xenon inhalation leads to flow augmentation in patients with cerebral insult, which does not exceed flow activation obtained in normal subjects. The impact of the results on xenon-enhanced computed tomography cerebral blood flow calculations remains to be established.

Adult↗
PubMed1999

Endothelin converting enzyme activity in primary rat astrocytes is modulated by endothelin B receptors.

Astrocytes express endothelin-1 (ET-1), ET-3, and their receptors, ET(A) and ET(B). We report here that activated astrocytes in vivo also express endothelin converting enzyme-1 (ECE-1). Higher basal ET-1 concentrations in astrocyte media from ET(B)-deficient (sl/sl) versus wildtype (+/+) rats suggested that altered ECE activity may be related to the absence of ET(B) receptors. Quantification of ECE activity in membranes from sl/sl astrocytes yielded a 50% higher conversion compared to +/+ astrocytes, with indistinguishable ECE-1 mRNA and protein levels. Kinetic analysis of ECE activity revealed similar V(max) values in sl/sl and +/+ astrocytes. Enzyme activity was competitively inhibited by phosphoramidon with K(i) values of 0. 6 and 0.3 microM, respectively. The K(m) value of ECE was 0.5 microM in +/+ and 0.2 microM in sl/sl astrocytes. Two-dimensional focussing of astrocytic ECE-1 uncovered heterogeneity of charge and molecular weight. ECE-1 from sl/sl revealed a glycosylation pattern different from +/+ astrocytes. In conclusion, the ET(B) receptor may, via ECE-1 glycosylation, exert a negative feedback on ECE activity in the astrocytic endothelin system.

Animals↗
PubMed1999

Temporal profile of expression and cellular localization of inducible nitric oxide synthase, interleukin-1beta and interleukin converting enzyme after cryogenic lesion of the rat parietal cortex.

We used in situ hybridization, RT PCR and immunohistochemistry to study the time course of expression and the cellular localization of inducible nitric oxide synthase (iNOS) and interleukin-1beta (IL-1beta) during the first 7 days after induction of a standardized cryogenic lesion on the right parietal cortex in male rats. Cryogenic lesion induced iNOS mRNA in the lesioned hemisphere after 6 to 72 h with a maximum (15+/-2 cells/mm2, n=4, p<0.01 vs. sham) at 24 h. Microglia, invading monocytes and granulocytes in and around the lesion expressed iNOS immunoreactivity starting at 12 h and peaking (29+/-10 cells/mm2, n=4, p<0.05 vs. sham) at 24 h after lesion. Induction of IL-1beta mRNA expression was immediate with a peak (9+/-1 cells/mm2, n=4, p<0.01 vs. sham) at 24 h after cryogenic lesion. The number of round cells with IL-1beta immunoreactivity around the lesion was maximal (8+/-2 cells/0.1 mm2, n=3, p<0.01 vs. sham) at 24 h. A weak astrocytic expression of IL-1beta-immunoreactivity was seen in sham animal brains. Astrocytic IL-1beta-expression was significantly increased in the lesion hemisphere and both hippocampi. Interleukin converting enzyme (ICE) was expressed in astrocytes and microglia around the lesion 6 h after injury. The number of ICE immunoreactive cells (8+/-2 cells/0. 1 mm2, n=3, p<0.05 vs. sham) peaked at 72 h after lesion. Neuronal expression of ICE and IL-1beta was seen in the lesion periphery 72 h and 7 days after injury. At this time, morphological features of apoptosis were evident in cells in the lesion periphery. The data indicate an early activation of microglia and monocyte invasion into the lesion hemisphere leading to multicellular expression of iNOS, ICE, and IL-1beta. These events may contribute to the expansion of neuronal damage after brain injury.

Animals↗
PubMed1999

Mediators of cerebral edema.

The blood-brain barrier (BBB) which is located in the continuous endothelial lining of cerebral blood vessels rigidly controls exchange of water soluble compounds under physiological conditions. Under pathological conditions such as trauma or ischemia, BBB permeability may increase thus allowing plasma constituents to escape into brain tissue. This "opening" of the BBB may, at least in part, be mediated by massive release of autacoids resulting in vasogenic brain edema. Five criteria have to be fulfilled by an individual autacoid to be considered a mediator candidate of cerebral edema: i) a permeability-enhancing action under physiological conditions, ii) a vasodilatory action, iii) the ability to induce vasogenic brain edema, iv) an increase of concentration in the tissue or interstitial fluid under pathological conditions, and v) a decrease of brain edema by specific interference with the release or action of a given autacoid. Among the mediator candidates considered, bradykinin is the only one to meet all criteria. Histamine, arachidonic acid and free radicals including nitric oxide may also be considered mediators of brain edema, but for each of these compounds evidence is less clear than for bradykinin. Although the concept of mediators inducing brain edema is well established by experimental studies, only a bradykinin receptor antagonist has so far gained entrance into clinical evaluation.

Animals↗
PubMed1999

Specific attentional dysfunction in adults following early start of cannabis use.

RATIONALE AND OBJECTIVE: The present study tested the hypothesis that chronic interference by cannabis with endogenous cannabinoid systems during peripubertal development causes specific and persistent brain alterations in humans. As an index of cannabinoid action, visual scanning, along with other attentional functions, was chosen. Visual scanning undergoes a major maturation process around age 12-15 years and, in addition, the visual system is known to react specifically and sensitively to cannabinoids. METHODS: From 250 individuals consuming cannabis regularly, 99 healthy pure cannabis users were selected. They were free of any other past or present drug abuse, or history of neuropsychiatric disease. After an interview, physical examination, analysis of routine laboratory parameters, plasma/urine analyses for drugs, and MMPI testing, users and respective controls were subjected to a computer-assisted attention test battery comprising visual scanning, alertness, divided attention, flexibility, and working memory. RESULTS: Of the potential predictors of test performance within the user group, including present age, age of onset of cannabis use, degree of acute intoxication (THC+THCOH plasma levels), and cumulative toxicity (estimated total life dose), an early age of onset turned out to be the only predictor, predicting impaired reaction times exclusively in visual scanning. Early-onset users (onset before age 16; n = 48) showed a significant impairment in reaction times in this function, whereas late-onset users (onset after age 16; n = 51) did not differ from controls (n = 49). CONCLUSIONS: These data suggest that beginning cannabis use during early adolescence may lead to enduring effects on specific attentional functions in adulthood. Apparently, vulnerable periods during brain development exist that are subject to persistent alterations by interfering exogenous cannabinoids.

Adolescent↗
PubMed1999

Endothelin B receptor-deficient rats as a subtraction model to study the cerebral endothelin system.

Endothelins, due to their potent vasoactivity and mitogenicity, appear to play an important role in the brain, where all components of the endothelin system, peptides, receptors and converting enzyme, are expressed. To further elucidate the role of the cerebral endothelin system, astrocytes and cerebral vessels from sl/sl rats, devoid of functional endothelin B receptors, have been employed. Astrocytes from sl/sl rats display the following abnormalities as compared to wild-type (+/+) cells: (i) elevated basal extracellular endothelin-1 levels; (ii) exclusive presence of functional endothelin A receptors; (iii) increased extracellular endothelin-1 levels upon endothelin A receptor blockade; (iv) augmented basal endothelin-converting enzyme activity; (v) altered calcium response to endothelin-1. The basilar artery of sl/sl rats shows an enhanced constricting response to endothelin-1 and fails to dilate in response to endothelin-3, shifting the endothelin vasomotor balance to constriction. In conclusion, endothelin B receptors may be essential for restricting extracellular endothelin-1 levels in the brain, as well as for a balanced cerebral vasomotor action of endothelins.

Animals↗
PubMed1999

Inhibition of tumor growth, angiogenesis, and microcirculation by the novel Flk-1 inhibitor SU5416 as assessed by intravital multi-fluorescence videomicroscopy.

Vascular endothelial growth factor (VEGF) plays a fundamental role in mediating tumor angiogenesis and tumor growth. Here we investigate the direct effect of a novel small molecule inhibitor of the Flk-1-mediated signal transduction pathway of VEGF, SU5416, on tumor angiogenesis and microhemodynamics of an experimental glioblastoma by using intravital multifluorescence videomicroscopy. SU5416 treatment significantly suppressed tumor growth. In parallel, SU5416 demonstrated a potent antiangiogenic activity, resulting in a significant reduction of both the total and functional vascular density of the tumor microvasculature, which indicates an impaired vascularization as well as significant perfusion failure in treated tumors. This malperfusion was not compensated for by changes in vessel diameter or recruitment of nonperfused vessels. Analyses of the tumor microcirculation revealed significant microhemodynamic changes after angiogenesis blockage such as a higher red blood cell velocity and blood flow in remnant tumor vessels when compared with controls. Our results demonstrate that the novel antiangiogenic concept of targeting the tyrosine kinase of Flk-1/KDR by means of a small molecule inhibitor represents an efficient strategy to control growth and progression of angiogenesis-dependent tumors. This study provides insight into microvascular consequences of Flk-1/KDR targeting in vivo and may have important implications for the future treatment of angiogenesis-dependent neoplasms.

Animals↗
PubMed1999

Hypertonic saline solution for control of elevated intracranial pressure in patients with exhausted response to mannitol and barbiturates.

Critically elevated intracranial pressure (ICP) represents the most important cause of morbidity and mortality in patients suffering from severe traumatic brain injury (TBI) and is a serious complication after subarachnoid hemorrhage (SAH). Thus new strategies for the control of ICP are required. Based on the evidence available hypertonic saline solution (HSS) may be a promising approach. It was therefore the aim of the present study to evaluate in a prospective manner the effects of HSS on ICP and cerebral perfusion pressure (CPP) in patients with therapy-resistant elevation of ICP. A total of 48 bolus infusions of HSS (7.5%, 2 ml kg-1 b.w.; infusion rate 20 ml min-1) were given intravenously (range 1-15 per patient) to 10 patients (age 41 +/- 6 years) with TBI and SAH. Only patients with ICP > 25 mmHg not responding to standard ICP-management protocol and plasma sodium (Na+) concentration < 150 mmol l-1 were included in the study. Within the first hour after HSS application, ICP decreased from 33 +/- 9 mmHg to 19 +/- 6 mmHg (p < 0.05) and further to 18 +/- 5 mmHg at the time of maximum effect (98 +/- 11 min post bolus). Decrease of ICP was accompanied by a rise of CPP from 68 +/- 11 mmHg to 79 +/- 11 mmHg (p < 0.05) after 1 h and further to 81 +/- 11 mmHg at the time of maximum effect. Plasma Na+ concentration was 141 +/- 6 mmol l-1 before and 143 +/- 5 mmol l-1 1 h after HSS bolus. Corresponding values for plasma osmolality were 302 +/- 11 and 308 +/- 12 mOsm l-1. When the ICP lowering effect was transient, subsequent HSS bolus was necessary 163 +/- 54 min after previous dosing. The present results indicate that repeated bolus application of HSS (7.5% NaCl, 2 ml kg-1 b.w.) is an effective measure to decrease ICP which is otherwise refractory to standard therapeutic approaches. Whether or not the therapy scheme is also suited as primary measure for the control of ICP remains to be established.

Adult↗
PubMed1999

[Effect of symptom-related vs. distraction-focused attention on dysphoric mood].

Within the framework of the "response styles theory" Nolen-Hoeksema (1991) argues that depressive episodes are prolonged or intensified by symptom-focused rumination. In contrast, depressed mood can be reduced by responses which focus the attention away from the symptoms of depression and its possible causes and consequences. In the present study these assumptions were examined under conditions derived from a critical analysis of earlier empirical studies. 70 students took part in the experiment. Depressed (n = 30) and non-depressed (n = 40) subjects were randomly assigned to either a symptom-focused or a distracting task. Self-report data were used to compare pre- and post-task mood. Results are mainly consistent with predictions. However, in contrast to the findings of Nolen-Hoeksema and her colleagues, no significant increase in depressed mood was observed in the symptom-focused condition and the empirical effect in the distracting condition was weaker than in previous studies using the same distracting task. These inconsistent findings are attributed to differences in the experimental settings. Theoretical and methodical implications are discussed.

Adaptation, Psychological↗
PubMed1999

Regression of left ventricular hypertrophy after stentless versus conventional aortic valve replacement.

The goal of this study was to analyze regression of left ventricular hypertrophy after randomization to conventional biological versus stentless aortic valve replacement. Stentless (Freestyle, Toronto, n = 106) or conventional biological aortic valves (Carpentier-Edwards, n = 74) were evaluated prospectively. Preoperatively there were no differences with regard to aortic valve pathology, left ventricular function, and pressure gradients between the two patient groups. The patient annulus index (13.55 vs. 13.46 mm; NS) measured intraoperatively was used as baseline for further comparison. Postoperatively, left ventricular mass index was 213+/-77 g/m2 (stentless) compared with 202+/-72 (conventional group) g/m2 (NS), whereas after 6 months it was 141+/-41 g/m2 in the stentless and 170+/-43 g/m2 in the conventional group (P<.05). Regression of left ventricular hypertrophy occurs in all patients after aortic valve replacement. Nevertheless, the use of stentless bioprostheses leads to a significant enhancement, which may result in a reduction of the cardiac risk profile for the patient.

Aged↗
PubMed1998

ETA and ETB receptor antagonists synergistically increase extracellular endothelin-1 levels in primary rat astrocyte cultures.

Astrocytes produce and bind endothelins (ETs), suggesting that these cells have ET autoregulatory and eliminatory functions. To further investigate these functions in primary rat astrocytes, ET-1 levels in the cell culture media (RIA/HPLC) and intracellular content of ET-1 mRNA (RT PCR) were measured under basal and stimulated (thrombin, 2.2 U/ml) conditions in the presence and absence of ETA and ETB selective antagonists (BQ123 or LU135252, and BQ788, respectively). Neither basal nor stimulated ET-1 levels in astrocyte media were influenced by ETA or ETB antagonists alone, but were significantly increased by a combination of both. ir ET-3 levels were not affected by antagonist treatment. Exogenous ET-1, added to the cultures, was rapidly cleared from the supernatant; this clearance was markedly inhibited by a combination of BQ123 and BQ788. ET-1 mRNA levels were not altered by any treatment. To conclude, in primary rat astrocyte cultures, extracellular ET-1 is cleared by binding to ET-receptors, apparently involving both, ETA and ETB sites. Thus, a blockade of the astrocytic ET eliminatory function as a consequence of the in vivo application of non-selective ET receptor antagonists may lead to increased extracellular ET levels in the brain.

Animals↗
PubMed1998

Characterization of the relaxant action of urocortin, a new peptide related to corticotropin-releasing factor in the rat isolated basilar artery.

In addition to its well established neuroendocrine and neurotransmitter effects, corticotropin releasing factor (CRF) exerts a potent vasorelaxant action. Recently, a CRF-related peptide, urocortin, has been identified in the mammalian brain. In the present study, the cerebral vasomotor action of this peptide and the mechanism underlying its relaxant effect are characterized. Ring segments obtained from the rat basilar artery were used for measurement of isometric force. The relaxant action of urocortin, CRF and sauvagine was studied in segments with a functionally intact endothelium. In segments precontracted with prostaglandin F2alpha, urocortin, CRF and sauvagine induced concentration-related relaxation. The order of potency was as follows (pD2+/-s.e.m. given in brackets): urocortin (9.32+/-0.07) > sauvagine (9.08+/-0.08) > CRF (7.50+/-0.07). Complete relaxation was achieved with each agonist. Relaxation was not affected by removal of the endothelium but was markedly attenuated in segments precontracted with 50 mM K+ Krebs solution. The relaxant effect of urocortin was inhibited by astressin in an apparently competitive manner. A pA2 value of 7.52 was estimated for astressin. Inhibition of urocortin-induced relaxation was also observed in the presence of the adenylate cyclase inhibitor SQ22536 (pD2 in the presence of 300 microM SQ22536, 9.36+/-0.05) and the K+ channel blockers tetraethylammonium (10 mM; pD2, 8.65+/-0.07), iberiotoxin (100 nM; pD2, 8.88+/-0.08) and apamin (10 nM; pD2, 8.94+/-0.07). However, the inhibitory actions of SQ22536 and apamin or iberiotoxin were not additive. The results suggest that urocortin induces relaxation of cerebral arteries by activating CRF-R2 receptors present in the vascular wall. Relaxation appears to be mediated by adenylate cyclase stimulation and activation of Ca2+-dependent K+ channels.

Amphibian Proteins↗