TY - JOUR A1 - Hopp, Sarah A1 - Albert-Weissenberger, Christiane A1 - Mencl, Stine A1 - Bieber, Michael A1 - Schuhmann, Michael K. A1 - Stetter, Christian A1 - Nieswandt, Bernhard A1 - Schmidt, Peter M. A1 - Monoranu, Camelia-Maria A1 - Alafuzoff, Irina A1 - Marklund, Niklas A1 - Nolte, Marc W. A1 - Sirén, Anna-Leena A1 - Kleinschnitz, Christoph T1 - Targeting coagulation factor XII as a novel therapeutic option in brain trauma JF - Annals of Neurology N2 - Objective: Traumatic brain injury is a major global public health problem for which specific therapeutic interventions are lacking. There is, therefore, a pressing need to identify innovative pathomechanism-based effective therapies for this condition. Thrombus formation in the cerebral microcirculation has been proposed to contribute to secondary brain damage by causing pericontusional ischemia, but previous studies have failed to harness this finding for therapeutic use. The aim of this study was to obtain preclinical evidence supporting the hypothesis that targeting factor XII prevents thrombus formation and has a beneficial effect on outcome after traumatic brain injury. Methods: We investigated the impact of genetic deficiency of factor XII and acute inhibition of activated factor XII with a single bolus injection of recombinant human albumin-fused infestin-4 (rHA-Infestin-4) on trauma-induced microvascular thrombus formation and the subsequent outcome in 2 mouse models of traumatic brain injury. Results: Our study showed that both genetic deficiency of factor XII and an inhibition of activated factor XII in mice minimize trauma-induced microvascular thrombus formation and improve outcome, as reflected by better motor function, reduced brain lesion volume, and diminished neurodegeneration. Administration of human factor XII in factor XII-deficient mice fully restored injury-induced microvascular thrombus formation and brain damage. Interpretation: The robust protective effect of rHA-Infestin-4 points to a novel treatment option that can decrease ischemic injury after traumatic brain injury without increasing bleeding tendencies. KW - Molecular-weight heparin KW - Thrombus formation KW - Cerebral-ischemia KW - in-vivo KW - Intravascular coagulation KW - Hemodynamic depression KW - Head-injury KW - Rats KW - Model KW - Mice Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-188800 VL - 79 IS - 6 ER - TY - JOUR A1 - Israel, Ina A1 - Ohsiek, Andrea A1 - Al-Momani, Ehab A1 - Albert-Weissenberger, Christiane A1 - Stetter, Christian A1 - Mencl, Stine A1 - Buck, Andreas K. A1 - Kleinschnitz, Christoph A1 - Samnick, Samuel A1 - Sirén, Anna-Leena T1 - Combined [\(^{18}\)F]DPA-714 micro-positron emission tomography and autoradiography imaging of microglia activation after closed head injury in mice JF - Journal of Neuroinflammation N2 - Background Traumatic brain injury (TBI) is a major cause of death and disability. Neuroinflammation contributes to acute damage after TBI and modulates long-term evolution of degenerative and regenerative responses to injury. The aim of the present study was to evaluate the relationship of microglia activation to trauma severity, brain energy metabolism, and cellular reactions to injury in a mouse closed head injury model using combined in vivo PET imaging, ex vivo autoradiography, and immunohistochemistry. Methods A weight-drop closed head injury model was used to produce a mixed diffuse and focal TBI or a purely diffuse mild TBI (mTBI) in C57BL6 mice. Lesion severity was determined by evaluating histological damage and functional outcome using a standardized neuroscore (NSS), gliosis, and axonal injury by immunohistochemistry. Repeated intra-individual in vivo μPET imaging with the specific 18-kDa translocator protein (TSPO) radioligand [\(^{18}\)F]DPA-714 was performed on day 1, 7, and 16 and [\(^{18}\)F]FDG-μPET imaging for energy metabolism on days 2–5 after trauma using freshly synthesized radiotracers. Immediately after [\(^{18}\)F]DPA-714-μPET imaging on days 7 and 16, cellular identity of the [\(^{18}\)F]DPA-714 uptake was confirmed by exposing freshly cut cryosections to film autoradiography and successive immunostaining with antibodies against the microglia/macrophage marker IBA-1. Results Functional outcome correlated with focal brain lesions, gliosis, and axonal injury. [\(^{18}\)F]DPA-714-μPET showed increased radiotracer uptake in focal brain lesions on days 7 and 16 after TBI and correlated with reduced cerebral [\(^{18}\)F]FDG uptake on days 2–5, with functional outcome and number of IBA-1 positive cells on day 7. In autoradiography, [\(^{18}\)F]DPA-714 uptake co-localized with areas of IBA1-positive staining and correlated strongly with both NSS and the number of IBA1-positive cells, gliosis, and axonal injury. After mTBI, numbers of IBA-1 positive cells with microglial morphology increased in both brain hemispheres; however, uptake of [\(^{18}\)F]DPA-714 was not increased in autoradiography or in μPET imaging. Conclusions [\(^{18}\)F]DPA-714 uptake in μPET/autoradiography correlates with trauma severity, brain metabolic deficits, and microglia activation after closed head TBI. KW - neuroinflammation KW - TBI KW - immunohistochemistry KW - weight drop KW - PET KW - diffuse KW - focal KW - TSPO KW - autoradiography KW - IBA-1 Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-146606 VL - 13 IS - 140 ER - TY - JOUR A1 - Albert-Weissenberger, Christiane A1 - Sirén, Anna-Leena T1 - Experimental traumatic brain injury N2 - Traumatic brain injury, a leading cause of death and disability, is a result of an outside force causing mechanical disruption of brain tissue and delayed pathogenic events which collectively exacerbate the injury. These pathogenic injury processes are poorly understood and accordingly no effective neuroprotective treatment is available so far. Experimental models are essential for further clarification of the highly complex pathology of traumatic brain injury towards the development of novel treatments. Among the rodent models of traumatic brain injury the most commonly used are the weight-drop, the fluid percussion, and the cortical contusion injury models. As the entire spectrum of events that might occur in traumatic brain injury cannot be covered by one single rodent model, the design and choice of a specific model represents a major challenge for neuroscientists. This review summarizes and evaluates the strengths and weaknesses of the currently available rodent models for traumatic brain injury. KW - Trauma Y1 - 2010 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-68131 ER - TY - JOUR A1 - Eimerl, J. A1 - Sirén, Anna-Leena A1 - Feuerstein, G. T1 - Systemic and regional hemodynamic effects of leukotrienes D\(_4\) and E\(_4\) in the conscious rat N2 - No abstract available KW - Neurobiologie Y1 - 1986 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-63317 ER - TY - JOUR A1 - Sirén, Anna-Leena T1 - Differences in central actions of arachidonic acid and prostaglandin F\(_{2\alpha}\) between spontaneously hypertensive and normotensive rats N2 - Prostag1andin F\(_{2\alpha}\) (PGF\(_{2\alpha}\)) is one of the most common metabo1ites of arachidonic acid (M) in rat brain. When administered intracerebroventricularly (i.c.v.) to rats, both AA and PGFal exert dose-related hypertensive, tachycardic and hyperthermic effects. Metabolie alterations in the endogenaus formation of some prostaglandins in the brain-stem of spontaneously hypertensive rats (SHR) have been reported. Therefore the central effects of AA and PGF \(_{2\alpha}\) on blood pressure, heart rate and body temperature were studied both in SHR and nonootensive Wistar rats (NR) under urethane-anaesthesia. The hypertensive effect of AA i.c.v. (0.01-100 \(\mu\)g/rat) was larger in magni tude in SHR than in NR, but there was no significant difference in the M-induced changes of heart rate and body temperature between the groups. Pretreatment of NR wi th soditm1 :meclofenamate (1 mg/rat i.c.v.) antagonised the central effects of M indicating that these effects are not due to M itself but to its conversion to prostaglandins. Unlike the effects of AA, the central hypertensive, tachycardic and hyperthennic responses to PGF\(_{2\alpha}\) (0.5-50 l-lg/rat i.c.v .) were significantly attenuated in SHR. The present results obtained with M are conpatible with the previous assumption that the synthesis of prostaglandins in the brain of SHR might differ from that in NR. The results also demonstrate that the central effects of PGF\(_{2\alpha}\) are reduced in SHR. KW - Neurobiologie Y1 - 1982 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-63324 ER - TY - JOUR A1 - Sirén, Anna-Leena A1 - Feuerstein, G. T1 - Effect of PAF and BN 52021 on cardiac function and regional blood flow in the conscious rat N2 - No abstract available KW - Neurobiologie Y1 - 1989 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-63145 ER - TY - JOUR A1 - Sirén, Anna-Leena A1 - Feuerstein, G. T1 - Thyrotropin releasing hormone-induced hindquarter vasodilation is mediated by \(\beta _2\)-adrenoceptors N2 - No abstract available KW - Neurobiologie Y1 - 1989 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-63155 ER - TY - JOUR A1 - Sirén, Anna-Leena A1 - Feuerstein, G. T1 - Hemodynamic effects of endothelin after systemic and central nervous System administration in the conscious rat N2 - No abstract available KW - Neurobiologie Y1 - 1989 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-63165 ER - TY - JOUR A1 - Feuerstein, G. A1 - Letts, G. A1 - Sirén, Anna-Leena T1 - N-Ac-Leukotriene E\(_4\): Unique vascular activity in the conscious rat N2 - No abstract available KW - Neurobiologie Y1 - 1988 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-63171 ER - TY - JOUR A1 - Sirén, Anna-Leena A1 - Lake, C. R. A1 - Feuerstein, G. T1 - Hemodynamic and neural mechanisms of action of thyrotropin releasing hormone in the rat N2 - Tbe mechanisms mediating the etl'ects ofthyrotropin-releasing hormone (TRH) on the cardiovascular system were studied in the conscious rat. Intracerebroventricolar (i.c. v.) injection of TRH (8 pmol-80 nmollkg) induced dose-dependent lncreases in mean arterial pressure, heart rate, and cardiac index. Rindquarter blood Oow increased due to vasodilation, while an lncrease in renal and mesenteric vascular resistance caused a decrease in blood Oow in the respective organs. The plasma Ievels of norepinephrine a~d epinephrine were increased by TRH, while there was no change in plasma renin activity or vasopressin. Tbe cardiovascular actions of i.c. v. TRH were not in.fluenced by blockade of the renin-angiotensin system or vasopressin receptors. Tbe ganglion blocker chlorisondamine and the a 1- aod al-adrenoreceptor antagooist phentolamlne (2 mg/kg i.v.) abolished the increase in blood pressure and mesenteric vasoconstriction after i.c. v. TRH. Propranolol (2 mg/kg i. v.) blocked the TRH-ioduced increase in cardiac index, heart rate, and hindquarter blood flow. The hindquarter vasodllatlon lnduced by TRH was also blocked by the selective ß1-adrenocept9r antagonist ICI 188,551 (1 or 2 mg/kg i.v.), while tbe ,8,-adrenoceptor blocker practolol (10 mg/kg i.v.) had no eft'ect on the hindquarter vasodiJation produced by TRH but totally blocked the increase in cardiac Index. In adrenal demedullated rats, the systemic hemodynamic eft'ects ofi.c. v. TRH were dimlnished along with the decrease in renal blood flow and lncrease in renal vascular resistance; however, the iocrease in hfndquarter blood flow was attenuated only in adrenal demedullated rats pretreated with the sympathetlc blocker bretylium. The renal vasoconstriction induced by i.c. v. TRH was not abolished by renal denervation. In sinoaortic debufl'ered rats, the pressor, tachycardic, and mesenteric vasoconstrictor responses to centrally administered TRH were significantly potentiated. Taken together, these data soggest that the putative rieurotransmitter TRH may play a role in central regulation of cardiac functions and organ blood flow distribution through both tbe sympathetic nerves and the adrenal medulla. A pivotal roJe for ß1-adrenoceptors in mediation ofhindquarter vasodilation ls also demonstrated. KW - Neurobiologie Y1 - 1988 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-63183 ER - TY - JOUR A1 - Sirén, Anna-Leena A1 - Letts, G. A1 - Feuerstein, G. T1 - N-Acetyl-leukotriene E\(_4\) is a potent constrictor of rat mesenteric vessels N2 - N-Acetyl-leukotriene E\(_4\) administered to conscious freely moving rats produced a dose-dependent vasoconstriction in the mesenteric vessels which led to profound reduction of blood flow to the gut. Renal and hindquarter blood flow and vascular resistance were not affected even by high doses of N-acetyl-leukotriene E\(_4\) . N-Acetyl-leukotriene E\(_4\) was 10-fold more potent than the thromboxane analog U-46619 and 1000-fold more potent than prostaglandin F\(_{2a}\) but 2-5-fold less potent than leukotriene D\(_4\)/E\(_4\) to induce mesenteric vasoconstriction. These data indicatc that N-acetylleukotriene E\(_4\) is a biologically active metabolite of peptide leukotrienes, and might play a role in cardiovascular derangements mediated by leukotrienes. KW - Neurobiologie KW - Peptide-leukotrienes KW - N-Acetyl-leukotriene E4 KW - Prostaglandins KW - Mesenteric circulation KW - Anaphylactic shock Y1 - 1988 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-63196 ER - TY - JOUR A1 - Feuerstein, G. A1 - Sirén, Anna-Leena T1 - Mesenteric vascular responses to i.v. administration of lipoxin A\(_4\) and lipoxin B\(_4\) in the conscious rat N2 - Lipoxin A (LXA\(_4\)) and lipoxin B\(_4\)(LXB\(_4\)) are newly discovered lipoxygenase-interacting products of leukocytes which might have a role in cardiovascular events associated with anaphylaxis. We have tested this possibility by systemic administration of both LXA\(_4\) and LXB\(_4\) to the conscious rat while monitaring systemic and regional hemodynamic changes. LXA\(_4\) and' LXB\(_4\) (l-100 pg/kg) produced dose-dependent constriction of the mesenteric vessels, up to + 123±23% and +50±9% for LXA\(_4\)/B\(_4\) , respectively. Dose-related changes were not observed in arterial blood pressure, heart rate, renal (LXB\(_4\)) and hindquarter blood ftow. We suggest that LXA\(_4\) and LXB\(_4\) might affect selective vascular beds, such as the mesenteric vessels, and contribute to variations in blood flow in specific pathophysiological states. KW - Neurobiologie KW - Lipoxin KW - Anaphylaxis KW - Mesenteric circulation KW - Renal circulation KW - Icosanoid Y1 - 1988 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-63200 ER - TY - JOUR A1 - Sirén, Anna-Leena T1 - Cardiovascular pharmacology of thyrotropin releasing hormone KW - Neurobiologie Y1 - 1988 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-63214 ER - TY - JOUR A1 - Feuerstein, G. A1 - Sirén, Anna-Leena T1 - Hypothalamic µ-receptors in the cardiovascular control: a review N2 - The endogenous opioid system includes three major families of peptides [22): dynorphins (derived from pre-proenkephalin B); endorphins (derived from pre-proopiomelanocortin) and enkephalins (derived from pre-proenkephalin A). Multiple species of opioid peptides are derived from these major precursors and many of them possess potent cardiovascular properties. Multiple forms of opioid receptors have been defined in the central nervous system. Although the relationship of these receptors to the multiple actions of the opioid systems is not weil understood, some predications can be made: in vitro the dynorphin-related peptidesbind preferentially to kappa-opioid receptors; the enkephalins bind preferentially to delta and JL-opioid receptors and while beta-endorphin binds to mu- and delta-, but not to kappa-opioid receptors. While littleis known on the roJe ofthe opioid system in normal cardiovascular regulation, it has become clear that cardiovascular stress situations substantially modify the activity ofthe endogenous opioid system. This review focuses on the mu-opioid system in the hypothalamus with special emphasis on its potential roJe in cardiovascular control of both normal and pathophysiologic states. KW - Neurobiologie KW - µ opioid receptors KW - Hypothalamus KW - Cardiovascular system KW - Sympathetic nervous system Y1 - 1988 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-63228 ER - TY - JOUR A1 - Sirén, Anna-Leena A1 - Feuerstein, G. T1 - Cardiovascular effects of rat calcitonin gene-related peptide in the conscious rat KW - Neurobiologie Y1 - 1988 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-63236 ER - TY - JOUR A1 - Feuerstein, G. A1 - Leader, P. A1 - Sirén, Anna-Leena A1 - Braquet, P. T1 - Protective effect of PAF-acether antagonist, BN 52021, in trichothecen toxicosis N2 - Trichothecenes are mycotoxins which produce Iethai toxicosis in humans and animals, yet no adequate therapeutic regimen has been developed. This study provides evidence that the selective platelet activating factor (PAF) antagonist, BN 52021 (5-15 mg/kg i.v.) can prolong the survival of conscious rats exposed to a highly Iethai T -2 toxicosis. These data also suggest that P AF is an important mediator of this unique toxicosis. KW - Neurobiologie KW - T-2 toxin KW - mycotoxin KW - PAF-acether KW - BN 52021 KW - rat Y1 - 1987 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-63244 ER - TY - JOUR A1 - Labroo, V. M. A1 - Cohen, L. A. A1 - Lozovsky, D. A1 - Sirén, Anna-Leena A1 - Feuerstein, G. T1 - Dissociation of the cardiovascular and prolactin-releasing activities of TRH by histidine replacement N2 - No abstract available KW - Neurobiologie Y1 - 1987 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-63253 ER - TY - JOUR A1 - Paakkari, I. A1 - Nurminen, M-L. A1 - Sirén, Anna-Leena T1 - Cardioventilatory effects of TRH in anesthetized rats: role of the brainstem N2 - Cardioventilator responses were studied in anaesthetized rats after injections of TRH into either the lateral (i.c.v. lat) or the fourth (i.c.v. IV) cerebral ventricles. TRH induced a morerapid hypertensive effect i.c.v. IV than i.c.v. lat. Blocking of the cerebral aqueduct abolished the hypertensive and tachypnoeic effects of TRH i.c.v. lat but not those of TRH i.c.v. IV. It is concluded that TRH increased blood pressure and ventilation rate via brain stem structures close to the fourtli ventricle. KW - Neurobiologie KW - TRH KW - Cardiovascular KW - Ventilation KW - Brain stem Y1 - 1986 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-63277 ER - TY - JOUR A1 - Sirén, Anna-Leena A1 - Powell, E. A1 - Feuerstein, G. T1 - Thyrotropin releasing hormone in hypovolemia: a hemodynamic evaluation in the rat N2 - ln the present study the effects of thyrotropin releasing hormone (TRH) and its stable analogue, CG3703, on cardiac output (thermodilution, Cardiomax) and regional blood flow (BF; directional pulsed Doppler technique) were investigated in hypovolemic hypotension in the rat. In urethan-anesthetized rats TRH (0.5 or 2 mg/ kg ia) or CG3703 (0.05 or 0.5 mg/kg ia) reversed the bleeding (27% of the blood volume)-induced decreases in mean arterial ... KW - Neurobiologie KW - cardiac output KW - total peripheral resistance KW - regional blood flow Y1 - 1986 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-63288 ER - TY - JOUR A1 - Sirén, Anna-Leena A1 - Feuerstein, G. T1 - Effect of T-2 toxin on regional blood flow and vascular resistance in the conscious rat N2 - The acute effect ofT-2 toxemia on local blood flow and vascular resistance in hindquarter. mesenteric. and renal vascular beds was continuously measured by the directional pulsed Doppler technique in conscious, male Sprague-Dawley rats. Intravenous injection ofT-2 toxin (I mg/kg) in the conscious rat reduced blood flow and increased vascular resistance in all blood vessels studied but had no significant effect on mean arterial pressure or heart rate. The blood flow in hindquarters gradually decreased to a minimum of -77 ± 9% (mean ±SE) 6 hr after the toxin injection. The hindquarter vascular resistance concomitantly increased to a maximum value of + 323 ± 69% above thc resistance before toxin administration. Mesenteric and renal blood flow initially increased (slightly) and then gradually decreased. The maximum drop of blood flow, -90 ± 13% and -76 ± 13% for the mesenteric and renal vascular beds, respectively, was achieved 4 hr after T-2 toxin injection and the blood flow values remained low for up to 6 hr. Simultaneously with the impairment of KW - Neurobiologie Y1 - 1986 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-63293 ER - TY - JOUR A1 - Sirén, Anna-Leena A1 - Feuerstein, G. A1 - Labroo, V. M. A1 - Coleen, L. A. A1 - Lozovsky, D. T1 - Effect of thyrotropin releasing hormone and some of its histidine analogs on the cardiovascular system and prolactin release in the conscious rat N2 - The cardiovascular and endocrine activity of three analogs of thyrotropin releasing hor.mone (TRH), 4-nitro-imidazole TRH (4-nitroTRH), 2-trifluoro-methyl-imidazole TRH (2-TFM-TRH) and 4-trifluoromethyl- imidazole TRH (4-TFM-TRH), was compared to TRH in conscious rats. Injection of TRH or the three analogs (1 mg/kg or 5 mg/kg) into the arterial line induced increases in mean arterial pressure, pulse pressure and heart rate and raised plasma prolactin (PRL). None of the analogs were more potent than TRH in inducing cardiovascular changes. The 4-TFM-TRH was significantly less potent than the 2-TFM-TRH in increasing blood pressure, while the nitro-TRH was more potent than the 2-TFM-TRH in producing tachycardia. TRH induced a two-fold increase in PRL at the 5 mg/kg dose, while both the fluorinated analogs elici ted a 4 to 5 fold increase in PRL at the higher dose. The present results suggest that the receptors for TRH-elicited PRL release differ from TRH-receptors involved in its cardiovascular actions. KW - Neurobiologie Y1 - 1986 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-63307 ER - TY - JOUR A1 - Sirén, Anna-Leena A1 - Paakkari, P. A1 - Goldstein, D. S. A1 - Feuerstein, G. T1 - Mechanism of central hemodynamic and sympathetic regulation by µ-opioid receptors: Effects of dermorphin in the conscious rat N2 - The effects of i.c.v. administered dermorphin, a highly selective \(\mu\)-opioid agonist, on cardiac function and renal, mesenteric and hindquarter blood ftow were studied in conscious rats. Core temperature, blood gases, arterial plasma levels of norepinephrine, epinephrine, dopamine, 3,4-dihydroxyphenylalanine and dihydroxyphenylacetic acid (DOPAC) also were examined. Cardiac output was rneasured using a thermodilution technique and regional blood ftows using directional pulsed Doppler velocimetry. Dermorphin, at doses of 0.1-100 nmol/kg, increased blood pressure and hindquarter blood flow, renal and mesenteric resistance, and core temperature. Higher doses (1-5 \(\mu\)mol/kg) caused respiratory depression, acidosis, and shock despite profaund sympatho-adrenomedullary stimulation. Circulating Ieveis of catecholamines were significantly increased at the dermorphin doses of 0.1-1 00 nmol/kg. At the 100 nmol/kg dose, plasma levels of epinephrine, norepinephrine, the dopamine metabellte dihydroxyphenylacetic acid and the catecholamine precursor 3,4,-dihydroxyphenylalanine were increased by 2-15-fold. The data indicate that mu opioid receptor Stimulation exerts potent effects on cardiorespiratory functions, activates the sympathoadrenomedullary system and produces a pattem of blood flow changes consistent with the stress-induced •detense· response (skeletal muscle vasodilation and splanchnic vasoconstriction). Excessive mu opioid receptor Stimulation Ieads to shock due to respiratory and hemodynamic collapse. KW - Neurobiologie Y1 - 1989 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-63123 ER - TY - JOUR A1 - Sirén, Anna-Leena A1 - Eimerl, J. A1 - Feuerstein, G. T1 - L-649,923 : An antagonist of cardiac and vascular leukotriene D\(_4\) receptors N2 - The capacity of L-649,923-sodium ( ßS, -yR * )-4-(3-( 4-acetyl-3-hydroxy-2-propylphenoxy)propylthio)-- y-hydroxy-ß-methylbenzene butanoate-to block vascular receptors of leukotriene D\(_4\) ( L TD\(_4\)) was examined in the conscious rat. Hindquarter (HQ), renal, and mesenteric blood flow and vascular resistance were evaluated in the conscious rat chronically equipped with miniaturized Doppler probes for organ blood flow measurement by directional pulsed Doppler technique. In addition, cardiac outpul was measured by thermodilution technique in conscious rats equipped with minithermistors in the ascending aorta. Systemic hemodynamic variables. mean arterial pressure, and heart rate were monitored through femoral catheters. L TD\(_4\) (I or 10 \(\mu\)g/kg) produced a marked dose dependent increase in the mesenteric vascular resistance associated with a marked decrease in blood flow whereas no consistent effects were demonstrated in the renal circulation. L TD\(_4\) • at I \(\mu\)g/kg. increased the HQ blood flow whereas the higher dose of LTD\(_4\) produced a biphasic response: an early increase followed by a decrease in blood flow. Infusion of L TD\(_4\) • 3 \(\mu\)g/kg per min over 10 min decreased cardiac output and increased total peripheral resistance. L-649,923 (10 or 30 mg/kg, i.v.) effectively blocked the L TD4-induced mesenteric constriction and the second I phase of HQ vasoconstriction but did not modify the , LTD\(_4\) induced HQ vasodilation. L-649,923 also effectively attenuated the cardiac effects of LTD\(_4\) infusion. I These studies suggest that L-649,923 could preserve cardiac and vascular functions in pathologic states mediated by cysteinylleukotrienes, such as traumatic or endotoxin shock. Key Words: Leukotriene D4 -Cardiovascular system- Leukotriene antagonist- Mesenteric blood tlow-Renal blood flow-Hindquarter blood flowAnaphylaxis. KW - Neurobiologie Y1 - 1989 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-63134 ER - TY - JOUR A1 - Sirén, Anna-Leena A1 - McCarron, R. M. A1 - Liu, Y. A1 - Barone, F. A1 - Spatz, M. A1 - Feuerstein, G. A1 - Hallenbeck, J. M. T1 - Perivascular monocyte/macrophage interaction with endothelium as a mechanism through which stroke-risk factors operate to increase stroke likelihood. Research Initiatives in Vascular Disease; SPECIAL COMMUNICATION N2 - No abstract available KW - Neurobiologie Y1 - 1993 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-63006 ER - TY - JOUR A1 - Paakkari, P. A1 - Paakkari, I. A1 - Feuerstein, G. A1 - Sirén, Anna-Leena T1 - Evidence for differential opioid µ\(_1\)- and µ\(_2\)-receptor regulation of heart rate in the conscious rat N2 - The possibility that \(\mu\)Opioid-induced tachycardia and bradycardia could be mediated by different subtypes of the \(\mu\)·receptor was studied in conscious Sprague-Dawley rats. The selective \(\mu\)·receptor agonist dermorphin and its analog, TAPS (Tyr-o-Arg-Phe-sarcosine), a putative \(\mu _1\)-receptor agonist, were given centrally. Tyr-o-Arg-Phe-sarcosine increased the heart rate, the response being inversely correlated to the dose (an increase of 71 ± 22, 49 ± 14 and 30 ± 17 beats/min at doses of 0.3, 3 and 30 pmol, respectively). Dermorphin induced less clear changes in heart rate (maximum increase of 39 ± 14 beats/min at the dose of 1 pmol). Aftertreatment with the Jl 1-selective antagonist naloxonazine (NAZ), TAPS 30 pmol and dennorphin I pmol decreased heart rate by -22 ± 10 and -24 ± 7 bpm, respectively. The bradycardic effect oflarger doses of dennorphin was potentiated by NAZ (from -25 ± 8 to -97 ± 22 bpm) but abolished by the non-selective antagonist naloxone. These data suggest that the high affinity \(\mu _1\)-opioid receptors mediate tachycardic responses and \(\mu _2\)-receptors mediate bradycardic responses. KW - Neurobiologie KW - dennorphin KW - naloxonazine KW - naloxone KW - heart rate KW - blood pressure KW - µ·Opioid receptor subtypes Y1 - 1992 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-63017 ER - TY - JOUR A1 - Adeyemo, M. A1 - Sirén, Anna-Leena T1 - Cardio-respiratory changes and mortality in the conscious rat induced by (+)- and (±)- anatoxin-a N2 - 0. M. ADEYEMO and A.-L. SIREN. Cardio-respiratory changes and mortality in the conscious rat induced by ( + )- and ( ± )-anatoxin-a. Toxicon 30, 899-905, 1992.-Anatoxin-a (AnTx-a) isapotent nicotinic cholinergic receptor agonist. The relative potencies of the ( + )-AnTx-a and the racemic mixture ( ± )-AnTxa were investigated in the conscious rat by comparing their effects on mean arterial blood pressure (BP), heart rate (HR), blood oxygen and carbon dioxide pressures (p02 and pC02, respective1y), acid-base balance (pH) and mortality. The present experiments show that while both forms of AnTx-a produce dose-dependent increases in BP and decreases in HR, ( + )-AnTx-a is about IO-fo1d morepotent than the optically inactive isomer. ( + )-AnTx-a was also 6-fo1d more potent than ( ± )-AnTx-a in produclog severe hypoxemia, and more than 4-fold as potent as the (±}-AnTx-a in producing significant hypercapnia accompanied with severe acidosis. The approximate median Iethai dose (Ln so) of ( + )-AnTx-a was about 5-fold less than that of ( ± )-AnTx-a. We conclude that ( + )-AnTx-a is more potent than the ( ± )-AnTx-a racemic mixture in causing detrimental cardio-respiratory changes and therefore increased mortality in the rat. KW - Neurobiologie Y1 - 1992 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-63027 ER - TY - JOUR A1 - Sirén, Anna-Leena A1 - Feuerstein, G. T1 - The Opioid System in circulatory control N2 - Opioid peptidesandmultiple opioid receptors are found in brain cardiovascular nuclei, autonomic ganglia, the heart, and blood vessels, and opioids induce potent cardiovascular changes. The role of endogenaus opioids in normal cardiovascular homeostasis is unclear; however, current data suggest opioid involvement in stress. KW - Neurobiologie Y1 - 1992 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-63045 ER - TY - JOUR A1 - Doron, D. A. A1 - McCarron, D. M. A1 - Heldman, E. A1 - Sirén, Anna-Leena A1 - Spatz, M. A1 - Feuerstein, G. A1 - Pollard, H. B. A1 - Hallenbeck, J. M. T1 - Comparison of stimulated tissue factor expression by brain microvascular endothelial cells from normotensive (WKY) and hypertensive (SHR) rats N2 - The amounts of tissue factor (TF) expressed by brain microvascular endothelial cells (BMECs) from normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) were compared after stimulating the cells with different doses of lipopolysaccharide (LPS), thrombin, phorbol myristic acid (PMA), Ca\(^{2+}\)·ionophore (A23187), or tumor necrosis factor (TNF) and interleukin·l (IL.l). Treatment ofcultured BMECs fron. WKY and SHR with all of these factors dose·dependently increased their total amount of TF; no substantive differences in the Ieveis of enhanced TF expression were observed between WKY and SHR BMECs. We conclude that stimulated endothelium from rats with hypertension, a major stroke risk factor, is not hyperresponsive with respect to TF expression when compared to normotensive controls. KW - Neurobiologie KW - Endothelium KW - Thromboplastin KW - Lipopolysaccharide Y1 - 1992 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-63032 ER - TY - JOUR A1 - Feuerstein, G. A1 - Zerbe, R. L. A1 - Sirén, Anna-Leena T1 - Supraoptic nuclei in vasopressin and hemodynamic responses to hemorrhage in rats N2 - CARDIOVASCULAR and vasopressin (A VP) responses to hcmorrhagc wcrc studicd in rats with lesions of the hypothalamic supraoptic nuclei (SONL). Bleeding caused hypotension and increase in heart rate (HR) and A VP. SONL rats failed to fully recover from bleeding as compared to normal rats. Plasma A VP in SONL rats was in the normal in basal conditions, but failed to increase to levels attained in normal rats throughout the post-hemorrhage period. These data suggcst that the supraoptic nuclei are the primary regulatory sitcs for A VP release in rcsponse to hemorrhage and that lack of adequate A VP release significantly retards blood pressure recovery after bleeding. KW - Neurobiologie KW - Hypothalamus KW - Supraoptic nucleus KW - Hemorrhage KW - Vasopressin Y1 - 1991 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-63057 ER - TY - JOUR A1 - Sirén, Anna-Leena A1 - Feuerstein, G. T1 - Hypothalamic opioid µ-receptors regulate discrete hemodynamic functions in the conscious rat N2 - The effect of the selective \(\mu\)-opioid agonist o-Ala\(^2\)-Me-Phe\(^4\)-Gly-ol'-enkephalin (DAGO), injected into the medial preoptic nucleus of hypothalamus, on cardiac output and regional blood flow was studied in the conscious rat and the effect of DAGO on renal sympathetic nerve activity and renal blood flow was studied in anesthetized rats. In conscious rats, injections of DAGO (1 or 10 nmol) into the preoptic nucleus increased the blood pressure in a dose-related manner. The maximum rises of mean arterial pressure and pulse pressure after the larger dose were +23 ± 5 mmHg (mean ±SEM, P < 0.01) and + 17 ± 3 mmHg(P < 0.01), respectively. A small dose (0.1 nmol) increased heart rate ( +47 ± 13 bpm, P < 0.05); thc 1 nmol dosc produced bradycardia (- 39 ± 11 bpm, P < 0.05), while the 10 nmol dose initially decreased heart rate ( -68 ± 15 bpm (P < 0.01) and then gradually increased heart rate to a maximum of + 74 ± 13 bpm, (P < 0.0 1). A long-lasting increase in cardiac output was also elicited by DAGO, with maximum changes after 1 and 10 nmol of + 14 ± 6% and +22 ± 7% (P < 0.01), respectively. B1ood flow in the hindquarters increascd after DAGO but the mesenteric and renal blood ftow decreased in a dose-related manner. Significant responscs in hindquarter and mesenteric blood fl.ow after DAGO were independent of systemic hemodynamic responses at the dose ofO.l nmol. The vascular resistance in the hindquarters significantly decreased after a small dose of DAGO while the larger doses dose-dependently increased mesenteric and renal vascular resistance. A crucial role of the sympathetic nervous system in the hemodynamic effects of DAGO was demonstrated: (1) by the profound activation of renal sympathetic nerve activity after injections of DAGO (I nmol/100 nl) into the preoptic nucleus, (2) by blockade of the pressor, tachycardic and regional hemodynamic effects of DAGO (I nmol) by the ganglion blocker ch1orisondamine (5 mg/kg i.v.). The results suggest that the pressor effect of DAGO in preoptic nucleus is due primarily to an increase in cardiac output. The differential changes in blood ftow in organs further suggest that the opioid \(\mu\)-receptors in the preoptic nucleus might be involved in the integration of peripheral blood ftow in the hypothalamus during affective behavior. KW - Neurobiologie KW - chlorisondamine KW - blood pressure KW - heart rate KW - cardiac output KW - regional blood ftow KW - sympathetic nerve activity. Y1 - 1991 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-63069 ER - TY - JOUR A1 - Vonhof, S. A1 - Sirén, Anna-Leena A1 - Feuerstein, G. T1 - Central ventilatory effects of thyrotropin-releasing hormone in the conscious rat N2 - Thyrotropin-releasing hormonewas shown to exert potent ventilatory effects after centrat administration. These data, however, were derived from studies using anesthetized animal preparations. Since TRH elicits strong arousal reactions, the observed ventilatory effects of TRH under anesthesia may have been due to nonspecific reduction in the anesthetic state of the animals. In order to clarify the extent to which the reversal of anesthesia may change ventilatory parameters after TRH application, we investigated the effect of TRH on Ventilation rate, relative tidal volume, relative respiratory minute volume, CO\(_2\) production CO\(_2\) consumption, and locomotor activity in the conscious, unrestrained rat. Intracerebroventricular application of TRH induced a dose-dependent, sustained increase in ventilation rate, relative tidal volume, and relative respiratory minute volume of maximally 128%, 890%, and 235%, respectively. In addition, CO\(_2\) production and O\(_2\) consumption were elevated by 4.6 and 11.7 fold, whiJe no significant changes in locomotor activity were observed. The results suggest that TRH stimulates ventilation by a mechanism independent of its analeptic properties. KW - Neurobiologie Y1 - 1991 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-63075 ER - TY - JOUR A1 - Adeyemo, O. M. A1 - Shapira, S. A1 - Tombaccini, D. A1 - Pollard, H. A1 - Feuerstein, G. A1 - Sirén, Anna-Leena T1 - A goldfish model for evaluation of the neurotoxicit of \(\omega\)-conotoxin GVIA and screening of monoclonal antibodies N2 - A Goldfish Model for Evaluation of the Neurotaxicity of \(\omega\)-Conotoxin GVI A and Screening of Monoclonal Antibodies. ADEYEMO, 0. M .. SHAPIRA, S., TOMBACCINI, D., POLLARD, H. 8 .• FEUERSTEIN, G .. AND SIREN, A-L. ( 1991 ). Toxicol. App/. Pharmaco/. 108, 489-496. The neurotoxicity of \(\omega\)-conotoxin (\(\omega\)-CgTx), a potent neuronal voltage-sensitive calcium channel blocker, was measured using a new bioassay. \(\omega\)-CgTx was administered intraperitoneally (ip) to goldfish weighing approximately 1.6 g, and dose-related changes were observed over a 2-hr period. \(\omega\)CgTx induced time- and dose-dependent abnormal swimming behavior (ASB) and mortality. The antitoxin activity of the antiborlies was investigated in vivo by either ( l) preincubation of the antibody with w-CgTx at 4°C overnight, or (2) pretreatment with antibody, 30 min before \(\omega\)CgTx injection in a 10:1 antibody/\(\omega\)-CgTx molar ratio. The LD50 dose of \(\omega\)-CgTx in goldfish was 5 nmol/kg ip, and preincubation of monoclonal antibody (50 nmol/kg ip) with \(\omega\)-CgTx (5 nmol/kg ip) significantly (p < 0.05) reduced mortality. ASB, and toxicity time. The antitoxin activity of the monoclonal antiborlies evidenced in the goldfish bioassay was further tested in the conscious rat. In the rat, the increases in mean arterial pressure and heart rate induced by \(\omega\)-CgTx (0.03 nmol/rat icv) were significantly (p < 0.02 and p < 0.0 l, respectively) attenuated by preincubation of the toxin with the antibody (0.3 nmol/rat). We conclude that the goldfish bioassay provides a simple. accurate, and inexpensive in vivo model for the study of the toxicity of \(\omega\)CgTx KW - Neurobiologie Y1 - 1991 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-63087 ER - TY - JOUR A1 - Sirén, Anna-Leena A1 - Vonhof, S. A1 - Feuerstein, G. T1 - Hemodynamic defense response to thyrotropin-releasing hormone injected into medial preoptic nucleus in rats N2 - No abstract available KW - Neurobiologie Y1 - 1991 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-63099 ER - TY - JOUR A1 - Sirén, Anna-Leena A1 - Feuerstein, G. T1 - Cardiovascular effects of anatoxin-a in the conscious rat N2 - Cardiovascular Effects of Anatoxin-A in the Conscious Rat. SJREN, A.-L., AND FEUERSTEIN, G. (1990). Toxicol. Appl. Pharmacol. 102,91-100. The effects ofanatoxin-A on mean arterial pressure (MAP), heart rate, cardiac index (CI), and blood flow (BF) in hindquarter (HQ), renal (R). and mesenteric (M) vascular beds were studied after intravenous (iv) and intracerebroventricular (icv) administration in the conscious rat. The pharmacological profile of anatoxin-A was further compared to nicotine administered iv and icv. MAP and heart rate were measured from femoral artery, CI by thermodilution method, and blood flow by Doppler velocimetry. Anatoxin-A and nicotine (30, 100 and 300 1-!g/kg iv) produced an increase in MAP with concomitant bradycardia. The highest doses increased Cl. MBF and RBF decreased due to a vasoconstriction in M and R vasculature. These effects were attenuated by the ganglion blocker chlorisondamine (5 mg/kg, iv). Anatoxin-A ( 100 1-!g/k~ iv) increased plasma epinephrine Ievels by 2- fold with virtually no effect on norepinephrine whereas nicotine ( 100 ~oLg/kg, iv) increased plasma epinephrine and norepinephrine by 20- to 30-fold. Central administration of anatoxin-A and nicotine (30-100 ,ug/kg icv) increased MAP with no effect on heart rate and produced M and R vasoconstriction. In summary, the present study demonstrates that anatoxin-A acts as a nicotinic cholinergic agonist in the c.onscious rat after both systemic and centrat administration. Anatoxin-A and nicotine produced pressor and reno-splanchnic vasoconstrictor responses and at high doses increased cardiac output. These effects were mediated by activation ofthe nicotinic receptors in the adrenal medulla and sympathetic ganglia. However, marked differences were found in the potency ofanatoxin-A versus nicotine to stimulate the sympathoadrenomedullary axis. KW - Neurobiologie Y1 - 1990 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-63103 ER - TY - JOUR A1 - Paakkari, P. A1 - Paakkari, I. A1 - Sirén, Anna-Leena A1 - Feuerstein, G. T1 - Respiratory and locomotor stimulation by low doses of dermorphin - a Mu\(_1\)-receptor mediated effect N2 - The selective opioid mu receptor agonist dermorphin increased the locomotor activity of rats dose dependently at 1 0 to 1 00 pmol/kg i.c.v. Respiratory rate, relative tidal volume and respiratory minute volume also increased unrelated to changes in locomotor activity. Higher doses, on the other hand, produced catalepsy and respiratory depression. Pretreatment of the rats with the mu,-selective antagonist naloxonazine (10 mg/kg i.v.) blocked the stimulant locomotor and respiratory effects of low doses of dermorphin (1 0--1 00 pmol/kg), but potentiated the respiratory depressant effect of a high dose (1 0 nmol/kg) of dermorphin. The selective benzodiazepine antagonist flumazenil (5 mg/kg), which has been shown previously to antagonize catalepsy and respiratory depression produced by relatively high doses of dermorphin, did not antagonize the respiratory or locomotor stimulant effect of dermorphin. The data suggest that mu\(_1\)-opioid receptors are responsible for the low dose stimulant effects of dermorphin on locomotor activity and respiration whereas mu\(_2\) receptors mediate the respiratory depressant effect of dermorphin. KW - Neurobiologie Y1 - 1990 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-63110 ER - TY - JOUR A1 - McCarron, R. M. A1 - Wang, L. A1 - Sirén, Anna-Leena A1 - Spatz, M. A1 - Hallenbeck, J. M. T1 - Monocyte adhesion to cerebromicrovascular endothelial cells derived from hypertensive and normotensive rats N2 - No abstract available KW - Neurobiologie Y1 - 1994 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-62960 ER - TY - JOUR A1 - Paakkari, P. A1 - Paakkari, I. A1 - Landes, P. A1 - Sirén, Anna-Leena A1 - Feuerstein, G. T1 - Respiratory \(\mu\)-Opioid and benzodiazepine interactions in the understrained rat N2 - lnteractions of p-opioid receptors with the benzodiazepine system were studied by examining the modulatory effects of flumazenil (a benzodiazepine antagonist) and alprazolam (a benzodiazepine agonist) on the respiratory effects ofthe opioid peptide dermorphin. Dermorphin, 1-30 nmol administered i.c.v., to conscious, unrestrained rats decreased ventilation rate (VR) and minute volume (MV) dose-dependently. The ventilatory depression was antagonized by naloxone and by the benzodiazepine antagonist flumazenil. The benzodiazepine alprazolam potentiateri the respiratory inhibition of a small (I nmol) dose of dermorphin but antagonized that of a higher dos:~ (3 nmol). The results suggest that the benzodiazepine/GABA receptor complex modulates respiratory depression induced by centrat p-receptor Stimulation in the rat. KW - Neurobiologie KW - dermorphin KW - opioid receptors KW - opioid-benzodiazepine interactions KW - respiration KW - flumazenil KW - benzodiazepine antagonist. Y1 - 1993 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-62974 ER - TY - JOUR A1 - Paakkari, P. A1 - Paakkari, I. A1 - Vonhof, S. A1 - Feuerstein, G. A1 - Sirén, Anna-Leena T1 - Dermorphin analog Tyr-D-Arg\(^2\)-Phe-sarcosine-induces opioid analgesia and respiratory stimulation - the role of Mu\(_1\)- receptors? N2 - Tyr-o-Arg\(^2\)-Phe-sarcosine\(^4\) (TAPS), a mu-selective tetrapeptide analog of dermorphin, induced sustained antinociception and stimulated ventilatory minute volume (MV) at the doses of 3 to 100 pmol i.c.v. The doses of 30 and 100 pmol i.c.v. induced catalepsy. The effect of TAPS on MV was in negative correlation with the dose and the maximal response was achieved by the lowest (3 pmol) dose (+63 ± 23%, P < .05). Morphine, an agonist at both mu\(_1\) and mu\(_2\) sites, at a dose of 150 nmol i.c.v. (equianalgetic to 100 pmol of TAPS decreased the MV by 30%, due to a decrease in ventilatory tidal volume. The antinociceptive effect of TAPS was antagonized by naloxone and the mu, receptor antagonist, naloxonazine. Naloxonazine also attenuated the catalepsy produced by 1 00 pmol of TAPS i.c. v. and the respiratory Stimulation produced by 3 pmol of TAPS i.c.v. Pretreatment with 30 pmol of TAPS antagonized the respiratory depression induced by the mu opioid agonist dermorphin (changes in MV after dermorphin alone at 1 or 3 nmol were -22 ± 1 0% and -60 ± 9% and, after pretreatment with TAPS, +44 ± 11 % and -18 ± 5%, respectively). After combined pretreatment with naloxonazine and TAPS, 1 nmol of dermorphin had no significant effect on ventilation. In contrast, pretreatment with a low respiratory stimulant dose (10 pmol i.c.v.) of dermorphin did not modify the effect of 1 nmol of dermorphin. ln conclusion, the antinociceptive, cataleptic and respiratory stimulant effects of TAPS appear to be a related to its agonist action at the mu, opioid receptors. TAPS did not induce respiratory depression (a mu\(_2\) opioid effect) but antagonized the respiratory depressant effect of another mu agonist. Thus, in vivo TAPS appears to act as a mu\(_2\) receptor antagonist. KW - Neurobiologie Y1 - 1993 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-62984 ER - TY - JOUR A1 - Xu, K. A1 - Näveri, L. A1 - Frerichs, K. A1 - Hallenbeck, J. M. A1 - Feuerstein, G. A1 - Davis, J. N. A1 - Sirén, Anna-Leena T1 - Extracellular catecholamine levels in rat hippocampus after a selective alpha2-adrenoceptor antagonist or a selective dopamnie uptake inhibitor: Evidence for dopamine release from local dopaminergic nerve terminals N2 - The effect of 6-chloro-2,3,4,5-tetrahydro-3-methyi-1-H-3-benzazepine (SKF 86466), a selectlve nonimldazoline alpha-2 adrenoceptor antagonlst, on hippocampal re1ease of norepinephrine and dopamlne in conscious rats was lnvestigated by /n vlvo mlcrodialysis and high-pressure liquid chromatography. Additionally, extracellular concentrations of hippocampal dopamine (DA) and norepinephrtne (NE), durtng Infusion of selective monoamine uptake Inhibitors, were determined in freely moving rats. The basal concentration of NE in the dialysate was 4.9 ± 0.3 pg/20 pl. lntravenous admlnistratlon of 5 or 10 mgJkg of SKF 86466 was associated wlth a transierlt inc:rease (30 min) of 2-fold (12 ± 1 pg/20 ,d; p < .05) and 8-fold (39 ± 3 pg/20 pl; p < .05), respectlvely, in dlalysate NE, whereas a 1-mgfkg dose had no effect. DA was not detected in basal dlalysates, but after the adminlstratlon of 5 or 10 mgJkg of SKF 86466, 3.9 ± 0.4 and 6.4 ± 0.6 pg/20 pl, respectlvely, was present in the dialysates. The rnaxlmum increase in dialysate DA was reached 60 to 90 min after SKF 86466. The DA was not derived from plasma because plasma NE was elevated after the 5 mgJkg dose of SKF 86466 whereas no plasma DA was detected. ln order to determlne whether DA was present in noradrenergic nerve termlnals, the dopamine ß-hydroxylase Inhibitor SKF 1 02698 was administered (50 mgJkg i.p.). The Inhibitor decreased dialysate NE but DA was stin not detected in the dialysate. When SKF 86466 (5 mgJkg t.v.) was adminlstered 4 hr after SKF 102698, DA appeared in the dialysate but there was no lncrease in dialysate NE. Administration through the dialysis probe of the DA uptake Inhibitor, GBR-12909 (0.1 and 1 pM), dose-dependently lnaeased DA Ieveis to 5.7 ± 1.2 and 9.6 ± 2.8 pg/20 pl, respectively. GBR-12909 had no effect on hippocampal NE. Desipramine (5 and 10 pM) lncreased dose-dependently dialysate NE and lncreased DA concentrations to detectable Ieveis (2.7 ± 0.5 and 3.5 ± 0.7 pg/20 ,d, respectively). These results suggest that the a/pha-2 adrenoceptors modulate both NE and DA release in the rat hlppocampus and that DA detected in the hlppocampal dialysate might be released from dopaminergic neurons. KW - Neurobiologie Y1 - 1993 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-62997 ER - TY - JOUR A1 - Sirèn, Anna-Leena A1 - Liu, Y. A1 - Feuerstein, G. A1 - Hallenbeck, JM T1 - Increased release of tumor necrosis factor alpha into the cerebrospinal fluid and peripheral circulation of aged rats N2 - Background and Purpose: We earlier reported that risk factors for stroke prepare brain stem tissue for a modified Shwartzman reaction, incIuding the development of ischemia and hemorrhage and the production of tumor necrosis factor-a, after a provocative dose of lipopolysaccharide. In the present study, we sought to determine whether blood and central nervous system cells of rats with the stroke risk factor of advanced age produce more proinflammatory and prothrombotic media tors than do those of young rats of the same strain. Methods: Levels of tumor necrosis factor-a and platelet activating factor in the cerebrospinal fluid and tumor necrosis factor-a in the serum of 2-year-old and 16-week-old Sprague-Dawley rats were monitored before and after challenge with lipopolysaccharide. Results: No consistent tumor necrosis factor-a activity was found in the cerebrospinal fluid or blood of control animals. Intravenous administration of lipopolysaccharide (1.8 mg/kg) increased serum tumor necrosis factor-a levels but had no effect on tumor necrosis factor-a in the cerebrospinal fluid. Serum tumor necrosis factor-a increased much more in aged rats than in young rats. When lipopolysaccharide was injected intracerebroventricularly, tumor necrosis factor-a activity in cerebrospinal fluid increased significantly more in old rats than in young rats. Baseline levels of platelet activating factor in cerebrospinal fluid were significantly higher in old rats than in young rats, and the levels increased to a greater degree in aged rats on stimulation. Conclusions: Rats with the stroke risk factor of advanced age respond to lipopolysaccharide with a more exuberant production of tumor necrosis factor-a and platelet activating factor than young rats of the same strain. These findings are consistent with our working hypothesis that perivascular cells are capable of exaggerated signaling of endothelium through cytokines such as tumor necrosis factor-a in animals with stroke risk factors. The effect of such signaling might be to prepare the endothelium of the local vascular segment for thrombosis or hemorrhage in accord with the local Shwartzman reaction paradigm. KW - Gehirn KW - Durchblutung KW - lipopolysaccharides KW - platelet activating factor KW - tumor necrosis factor KW - rats Y1 - 1993 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-47997 ER - TY - JOUR A1 - Liu, T. A1 - McDonnell, PC A1 - Young, PR A1 - White, RF A1 - Sirèn, Anna-Leena A1 - Hallenbeck, JM A1 - Barone, FC A1 - Feuerstein, Giora T1 - Interleukin-1ß mRNA expression in ischemic rat cortex N2 - Background and Pur pose: Interleukin-1ß is a proinftammatory cytokine produced by blood-borne and resident brain inftammatory cells. The present study was conducted to determine if interleukin-1ß mRNA was produced in the brain of rats subjected to permanent focal ischemia. Methods: Rat interleukin-1ß cDNA, synthesized from stimulated rat peritoneal macrophage RNA by reverse transcription and polymerase chain reaction and c10ned in plasmid Bluescript KS+, was used to evaluate the expression of interleukin-1ß mRNA in cerebral cortex from spontaneously hypertensive rats and normotensive rats subjected to permanent middle cerebral artery occlusion. Interleukin-1ß mRNA was quantified by Northern blot analysis and compared with rat macrophage RNA standard. To correct for gel loading, blots were also analyzed with cyclophilin cDNA, which encodes an abundant, conserved protein that was unchanged by the experimental conditions. Results: Interleukin-1ß mRNA produced in the ischemic zone was significantly increased from 6 hours to 120 hours, with a maximum of211±24% ofinterleukin-1ß reference standard, ie, 0.2 ng stimulated rat macrophage RNA, mRNA compared with the level in nonischemic cortices (4±2%) at 12 hours after ischemia (P<.OI; n=6). Interleukin-1ß mRNA at 12 hours after ischemia was markedly elevated in hypertensive rats over levels found in two normotensive rat strains. Neurological deficits were also apparent only in the hypertensive rats. Conclusions: Brain interleukin-1ß mRNA is elevated acutely after permanent focal ischemia and especially in hypertensive rats. These data suggest that this potent proinflammatory and procoagulant cytokine might have a role in brain damage following ischemia. KW - Gehirn KW - Durchblutung KW - cerebraI ischemia KW - cytokines KW - neuronal damage KW - rats Y1 - 1993 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-47442 ER - TY - JOUR A1 - Feuerstein, G. A1 - Sirén, Anna-Leena A1 - Goldstein, DS A1 - Johnson, AK A1 - Zerbe, RL T1 - The effect of morphine on the hemodynamic and neuroendocrine responses to hemorrhagic shock in conscious rats N2 - We have previously reported that analgesic doses of morphine accelerate mortality of rats exposed to hemorrhage (Feuerstein and Siren: Circ Shock 19:293-300, 1986). To study the potential mechanisms involved in this phenomenon, rats were chronically implanted with catheters in the femoral vessels and morphine (1.5 or 5 mg/kg) was administered 30 min or 24 hr after bleeding (8.5 mll300 g over 5 min) while arterial blood pressure and heart rate were continuously monitored. Furthermore, the effect of morphine (5 mg/kg) on cardiac output (CO) response to hemorrhage was studied in rats chronically equipped with a mini thermistor for CO monitoring by a thermodilution technique. In addition, plasma catecholamines (HPLC), plasma renin activity (PRA, RIA), vasopressin (RIA), pH, and blood gases were also determined. Morphine administration 30 min after hemorrhage produced a pressor response and tachycardia which were in marked contrast to its depressor effect in intact rats. Morphine elevated PRA and epinephrine but not vasopressin, while blood pH and gases showed no consistent change as compared to salinetreated hemorrhaged rats. Morphine given after the bleeding resulted in enhanced cardiac depression in response to a second bleed of 2 m1l300 g. Our data suggest that activation of pressor mechanisms by morphine during hypovolemic hypotension might enhance vasoconstriction in essential organs, depress cardiac function, and further reduce effective tissue perfusion. KW - Medizin KW - hemorrhagic shock KW - opiates KW - catecholamlnes KW - renin KW - vasopressin Y1 - 1989 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-49033 ER - TY - JOUR A1 - Hallenbeck, JM A1 - Dutka, AJ A1 - Kochanek, PM A1 - Sirén, Anna-Leena A1 - Pezeskpour, GH A1 - Feuerstein, G. T1 - Stroke risk factors prepare rat brainstem tissues for a modified localized Shwartzman reaction N2 - Stroke risk factors such as hypertension, diabetes, advanced age, and genetic predisposition to stroke were demonstrated to prepare rat brainstem tissues for a modified local Shwartzman reaction. A single intracisternal injection of endotoxin provoked the reaction, and affected rats manifested neurologie deficits accompanied by pathologie lesions. Brainstem infarcts developed in only a small proportion of rats without recognized risk factors after intracisternal injection of endotoxin. Thus, stroke risk factors, whieh are ordinarily regarded as operating through acceleration of atherosclerosis, may predispose to brain ischemia by local effects on brain mierocirculation such as those thought to underlie preparation of a tissue for the local Shwartzman reaction. KW - Gehirn KW - Durchblutung Y1 - 1988 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-47971 ER - TY - JOUR A1 - Feuerstein, Giora A1 - Sirén, Anna-Leena T1 - The Opioid System in cardiac and vascular regulation of normal and hypertensive states N2 - The endogenous opioid system includes three major families of peptides: dynorphins (derived from pre-proenkephalin B), endorphins (derived from pre-proopiomelanocortin), and enkephalins (derived from pre-proenkephalin A). Multiple species of opioid peptides are derived from these major precursors and many of them possess potent cardiovascular properties. Opioid peptides and opioid receptors, of which multiple forms have been defined, are present in the central nervous system and peripheral neural elements. In the central nervous system, opioid peptides and receptors are found in forebrain and hindbrain nuclei involved in baroregulation, sympathoadrenal activation, and several other vital autonomic functions. In the periphery, opioid peptides are found in autonomic ganglia, adrenal gland, heart, and other organs; multiple opioid receptors are also found in vascular tissue, heart, and kidneys. Although little is known to date on the regulatory mechanisms of the opioid system in normal cardiovascular states, it became clear that cardiovascular stress situations substantially modify the activity of the endogenous opioid system. The purpose of this review is to clarify the sites of interaction of the opioid system with all major components of the cardiovascular system and indicate the potential role of this system in the ontogenesis of cardiac malfunction, vascular diseases, and hypertension. KW - Medizin Y1 - 1987 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-47418 ER - TY - JOUR A1 - Feuerstein, G. A1 - Sirén, Anna-Leena T1 - Cardiovascular effects of enkephalins N2 - Enkephalins and their receptors are found in neurons and nerve terminals known to be involved in central cardiovascular control as well as the peripheral sympathetic and parasympathetic systems. Enkephalins and opioid receptors were also iden tified in the heart, kidneys, and blood vessels. The enkephalins interact with several specific receptors, of which p, 0, and K have been best characterized. Enkephalins administered to humans or animals produce cardiovascular effects which depend on the spedes, route of administration, anesthesia, and the selectivity for receptor subtype. While little information exists on the role of enkephalins in normal cardiovascular control, current data suggest that enkephalins might have a role in cardiovascular stress responses such os in shock and trauma. KW - Medizin Y1 - 1987 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-49048 ER - TY - JOUR A1 - Sirén, Anna-Leena A1 - Feuerstein, Giera T1 - Central autonomic pharmacology of thyrotropin releasing hormone N2 - Thyrotropin releasing hormone (TRH, I-pyroglutamyl-l-histidyl-l-prolinamide) was the fIrst hypothalamic releasing SUbstance to be isolated, chemically characterized and synthetized /1/. The studies to date have revealed that the thyrotropin release from the pituitary gland is only one of the numerous actions of TRH. In addition to its endocrine actions (TSH and prolactin release) this tripeptide has central nervous system actions totally unrelated to its effects on the hypothalamo-pituitary axis. This review aims to summarize the studies on the central nervous system' actions of TRH with special emphasis on the autonomic pharmacology of this peptide. KW - Medizin Y1 - 1987 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-49051 ER - TY - JOUR A1 - Feuerstein, G. A1 - Sirén, Anna-Leena T1 - Effect of naloxone and morphine on survival of conscious rats after hemorrhage N2 - The endogenous opioid system has been reported to depress the cardiovascular system during shock states, since naloxone, a potent opiate antagonist, enhances recovery of hemodynamic variables in various shock states. However, the effect of naloxone on long-term survival of experimental animals exposed to hypovolemic hypotension is not clear. The present studies tested the capacity of various doses of naloxone to protect conscious rats from mortality following various bleeding paradigms. In addition, the effect of morphine on survival of rats exposed to hemorrhage was also examined. In the six different experimental protocols tested, naloxone treatments failed to improve short- or long-term survival; in fact, naloxone treatment reduced short-term survival in two of the experimental protocols. Morphine injection, however, enhanced the mortality of rats exposed to hemorrhage in a dose-dependent manner. It is concluded that while opiates administered exogenously decrease survival after acute bleeding, naloxone has no protective action in such states and, like morphine, it may decrease survival in some situations. KW - Medizin KW - shock KW - opioid peptides KW - hypovolemic hypotension Y1 - 1986 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-48669 ER - TY - JOUR A1 - Sirén, Anna-Leena A1 - Svarström-Fraser, M. A1 - Paakkari, I. T1 - Central cardiovascular effects of the endoperoxide analogue U-46619 i.c.v. in rats N2 - Thromboxanes are abundantly present in the rat brain but their possible physiological functions in the brain are not known. The prostaglandin endoperoxide analogue U-46619 is a selective agonist of TxA2 receptors in many peripheral tissues. In the present study the ·central cardiovascular and ventilatory effects of U-46619 were investigated in rats. In conscious spontaneously hypertensive rats (SHR) U-46619 (1-100 nmol/kg i.c.v.) induced a strong dose-related increase in blood pressure but had no significant effect on heart rate. In conscious normotensive rats (NR) neither blood pressure nor heart rate was significantly affected. Furthermore, U-46619 (0.1-100 nmol/kg i.c.v.) had no significant effect on blood pressure, heart rate or ventilation in urethane-anaesthetised NR . The results demonstrate an increased sensitivity of SHR to TxA2. KW - Medizin Y1 - 1985 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-49064 ER - TY - JOUR A1 - Sirén, Anna-Leena A1 - Paakkari, I. T1 - Cardiovascular effects of TRH i.c.v. in conscious rats N2 - In addition to the endocrine effects, the thyrotropin releasing hormone (TRH) is known to induce dose-dependent increases in blood pressure and heart rate after intracerebroventricular (i.c.v.) administration in urethane-anaesthetised rats (1, 2). The a~ of the present study was to investigate whether TRH has similar effects in conscious rats of various strains i.e. spontaneously hypertensive rats (SHR), normotensive Wistar-Kyoto (WKY) and Wistar (NR) rats. KW - Medizin Y1 - 1984 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-49071 ER - TY - JOUR A1 - Sirén, Anna-Leena T1 - Central cardiovascular and thermal effects of Prostaglandin E2 in rats N2 - Prostaglandin E2 (PGE2) increased the blood pressure, heart rate and body temperature, when administered at the doses ofO.OOI-IO,ug into the lateral cerebral ventricle (i.c.v.) of the urethane-anesthetised rat. The highest dose of 10 ,ug/rat induced a strong initial hypotensive effect. lntravenously (i.v.), PGE2 at the doses of 0.01-10 ,ug/rat caused a biphasic blood pressure response with dose-related initial decreases followed by slight increases in blood pressure. The heart rate and body temperature were slightly increased by i.v. administrations of PGE2 . The highest i.v. dose of 10 ,ug/rat initially decreased also the heart rate. Central pretreatment with indomethacin ( I mg/rat i.c.v.) partly antagonised all of the recorded central effects of PGE2 , while sodium meclofenamate (I mg/rat i.c. v.) abolished the hypertensive response to i.c. v. administered PGE2 but failed to significantly affect the PGE2-induced rises of heart rate and body temperature. The results support the previous suggestions that PGE2 may participate in the central cardiovascular and thermoregulatory contro!. The results also suggest that indomethacin and sodium meclofenamate antagonize the effects of exogenous prostaglandins. Since sodium meclofenamate, unlike indomethacin, affected preferentially the hypertensive response to centrally administered PGE2 , there may be differences in the sites and/or modes of action between these drugs. KW - Physiologie Y1 - 1982 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-47960 ER -