Refine
Has Fulltext
- yes (85)
Is part of the Bibliography
- yes (85)
Year of publication
Document Type
- Journal article (82)
- Report (2)
- Review (1)
Language
- English (85)
Keywords
- Neurobiologie (41)
- Medizin (10)
- Durchblutung (5)
- Gehirn (5)
- rats (5)
- active zone (4)
- traumatic brain injury (4)
- Hypothalamus (3)
- Prostaglandine (3)
- TRH (3)
Institute
- Neurochirurgische Klinik und Poliklinik (80)
- Neurologische Klinik und Poliklinik (9)
- Physiologisches Institut (9)
- Klinik und Poliklinik für Unfall-, Hand-, Plastische und Wiederherstellungschirurgie (Chirurgische Klinik II) (4)
- Center for Computational and Theoretical Biology (3)
- Theodor-Boveri-Institut für Biowissenschaften (3)
- Institut für Medizinische Strahlenkunde und Zellforschung (2)
- Kinderklinik und Poliklinik (2)
- Klinik und Poliklinik für Psychiatrie, Psychosomatik und Psychotherapie (2)
- Rudolf-Virchow-Zentrum (2)
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.
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.
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
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.
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.
Lipopolysaccharidc (LPS)-induced (i.v. or i.c.v., 1.8 mg/kg) release of von Willebrand factor (vWF) ·was examined in spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats. SHR rats releascd significantly (P < 0.05) more vWF than WKY rats in response to LPS. LPS also inhibited factor VIII procoagulant activity (FVIII: c) which may indicate an increase in thrombin activity. Cultured cerebrovascular endothelial cells (EC) derived from both SHR and WKY rats, as weil as human umbilical vein EC (HUVEC) cultures constitutively released vWF. Treatment with agonists including LPS, thrombin and tumor necrosis factor-a (TNFa) did not affect the in vitro secretion of vWF by cerebrovascular EC cultures but significantly upregulated vWF release by HUVEC cultur~s. Preincubation of cerebrovascular EC cultures with interleukin-1 OL-l) ± TNFa or co-culturing in the presence of LPS-activated syngeneic monocytes had no effect on vWF secretion. The findings demoostrate that conditions of hypertension may affect endothelial cells and make them more responsive to agonist Stimulation and thereby increase secretion of vWF, an important factqr in hemostasis as weil as thrombosis. The capacity of LPS to significantly affect the in vivo secretion of vWF in SHR and WKY rats but not cultured cerebrovascular EC indicates that observed elevations in plasma vWF were not derived from cerebrovascular EC. lt is suggested that hypertension may function as a risk factor for thrombotic stroke by influencing factors involved in coagulation processes, such as vWF and factor VIII : c.
The expression of intercellular adhesion molecule 1 (ICAM-1) was studied in rat focal ischemic cortex. A significant increase in ICAM-1 mRNA expression in the ischemic cortex over Ievels in contralateral (nonischemic) site was observed by means of Northern blot analysis following either permanent or temporary occlusion with reperfusion of the middle cerebral artery (PMCAO or MCAO with reperfusion) in spontaneously hypertensive rats. In the ischemic cortex, Ievels of ICAM-1 mRNA increased significantly at 3 h (2.6-fold, n = 3, P < 0.05), peaked at 6 to 12 h (6.0-fold, P < 0.01) and remained elevated up to 5 days (2.5-fold, P < 0.05) after PMCAO. The profile of ICAM-1 mRNA expression in the ischemic cortex following MCAO with reperfusion was similar to that following PMCAO, except that ICAM-1 mRNA was significantly increased as early as 1 h (6.3-fold, n = 3, P < 0.05) and then gradually reached a peak at 12 h (12-fold, P < 0.01) after reperfusion. ICAM-1 mRNA expression in ischemic cortex following PMCAO was significantly greater in hypertensive rats than in two normotensive rat strains. Immunostaining using anti-ICAM-1 antiborlies indicated that upregulated ICAM-1 expressionwas localized to endotheIial cells of intraparenchymal blood vessels in the ischemic but not contralateral cortex. The data suggest that an upregulation of ICAM-1 mRNA and protein on brain capillary endothelium may play an important rote in leukocyte migration into ischemic brain tissue.
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.
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.
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.
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.
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.
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.
Stroke risk factors prepare rat brainstem tissues for a modified localized Shwartzman reaction
(1988)
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.
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.
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.
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.
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.