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 -