Propranolol antagonizes hypotension induced by alpha-blockers but not by sodium nitroprusside or methacholine

A pressor response has been observed with propranolol, a nonselective beta-adrenoceptor antagonist, in animals given a nonselective alpha-adrenoceptor antagonist. This study investigates whether a pressor response to propranolol occurs in conscious unrestrained rats following a hypotensive response induced by phentolamine (nonselective alpha-antagonist), prazosin (selective alpha 1-antagonist) and (or) rauwolscine (selective alpha 2-antagonist), sodium nitroprusside (smooth muscle relaxant), or methacholine (muscarinic agonist). The rats were subjected to a continuous infusion of a hypotensive agent or normal saline followed by i.v. injection of propranolol. The infusion of phentolamine significantly decreased mean arterial pressure (MAP). Subsequent injection of propranolol restored MAP to the control level. Prazosin and rauwolscine each caused a small but not significant decrease in MAP which was reversed by propranolol. Concurrent infusions of prazosin and rauwolscine caused a significant decrease in MAP. Subsequent injection of propranolol caused a large pressor response which increased MAP to 20% above control MAP prior to the administration of drugs. Nitroprusside or methacholine each caused a significant decrease in MAP, but the hypotension was not antagonized by propranolol. The concurrent infusions of a low dose of nitroprusside and prazosin caused a significant decrease in MAP which was reversed by propranolol. The infusion of saline did not alter MAP, and propranolol did not cause a pressor response. It is concluded that propranolol antagonizes the hypotensive effect of an alpha-blocker but not that of sodium nitroprusside or methacholine. Our results suggest the presence of a specific interaction between alpha- and beta-antagonists.     

Supraspinal FMRFamide antagonizes morphine-induced horizontal, but not vertical, locomotor activity

Morphine and the molluscan neuropeptide Phe-Met-Arg-Phe-NH2 (FMRFamide) were administered to mice alone or in combination intracerebroventricularly (ICV) and the effect on locomotor activity was measured. Morphine given alone (0.5 micrograms) significantly increased horizontal locomotor activity compared to vehicle-treated controls. FMRFamide at low doses (0.01-10 micrograms) had no effect of its own, but blocked the morphine-induced increase in horizontal locomotor activity. Unlike the opiate antagonist naloxone (1.0 micrograms), FMRFamide (up to 10 micrograms) had no effect on morphine-induced decrease in vertical activity. These data further support a role for FMRFamide as a modulator of opiate action, but comparison to naloxone suggests that FMRFamide might not act as a pure competitive antagonist of this opiate effect.     

Quinacrine antagonizes the effects of Na,K-ATPase inhibitors on renal prostaglandin E2 release but not their effects on renin secretion

Previous results have demonstrated that two inhibitors of Na-and-K-activated adenosine triphosphatase (ouabain, vanadate) lead to stimulated prostaglandin E2 release and to inhibited renin secretion in the rat renal cortical slice preparation. It was speculated that stimulation of phospholipase A2 activity accounted for the effect on prostaglandin E2 release. We used the same preparation in the present experiments, and showed that another inhibitor of Na-and-K-activated adenosine triphosphatase (K-free incubation medium) stimulates prostaglandin E2 release and inhibits renin secretion. Quinacrine antagonized the stimulatory effects of ouabain, vanadate, and K-free medium on prostaglandin E2 release (consistent with phospholipase A2 involvement), but did not antagonize their inhibitory effects on renin secretion. Collectively, these observations lend further weight to the argument against a mediatory role of prostaglandin synthesis in the renin secretory process.     

G-CSF, but not corticosterone, mediates circulating neutrophilia induced by febrile-range hyperthermia.

We previously showed that sustained exposure to febrile-range hyperthermia (FRH) for 24 h caused an increase in circulating granulocyte colony-stimulating factor (G-CSF) levels and a peripheral neutrophilia in mice (Hasday J, Garrison A, Singh I, Standiford T, Ellis G, Rao S, He JR, Rice P, Frank M, Goldblum S, and Viscardi R. Am J Pathol 162: 2005-2017, 2003). In this study, we utilized a conscious temperature-clamped mouse model to analyze the kinetics of G-CSF expression and peripheral neutrophil expansion and the contributions of FRH-induced G-CSF expression, glucocorticoid generation, and catecholamine-induced neutrophil demargination. In conscious mice housed at an ambient temperature of 34.5 degrees C, core temperature rapidly equilibrated at 39.5-40 degrees C. Peripheral neutrophil counts increased 2-fold after 24-h exposure to hyperthermia, peaked at 3.6-fold baseline levels after 36-h exposure to FRH, and returned to baseline levels after 42 h of sustained hyperthermia. Plasma G-CSF levels were increased by 6.8-fold after 24 h and peaked at 40-fold baseline levels after 36 h in the hyperthermic mice. Plasma corticosterone levels peaked at 3.3-fold baseline levels after 30-h sustained hyperthermia and returned to baseline by 42 h. Immunoneutralization of G-CSF blocked FRH-induced peripheral neutrophilia, but blockade of the glucocorticoid receptor with mifepristone failed to modify FRH-induced neutrophilia. Epinephrine induced similar increases in peripheral blood absolute neutrophil counts in euthermic mice (2.2-fold increase) and mice exposed to FRH for 36 h (1.8-fold increase). Collectively, these data suggest that FRH-induced expression of G-CSF drives the sustained peripheral neutrophilia that occurs during sustained (36 h) hyperthermia, whereas glucocorticoid generation and catecholamine-induced demargination play little role in this response.     

Thalidomide suppresses NF-kappa B activation induced by TNF and H2O2, but not that activated by ceramide, lipopolysaccharides, or phorbol ester

Thalidomide ([+]-alpha-phthalimidoglutarimide), a psychoactive drug that readily crosses the blood-brain barrier, has been shown to exhibit anti-inflammatory, antiangiogenic, and immunosuppressive properties through a mechanism that is not fully established. Due to the central role of NF-kappaB in these responses, we postulated that thalidomide mediates its effects through suppression of NF-kappaB activation. We investigated the effects of thalidomide on NF-kappaB activation induced by various inflammatory agents in Jurkat cells. The treatment of these cells with thalidomide suppressed TNF-induced NF-kappaB activation, with optimum effect occurring at 50 microg/ml thalidomide. These effects were not restricted to T cells, as other hematopoietic and epithelial cell types were also inhibited. Thalidomide suppressed H(2)O(2)-induced NF-kappaB activation but had no effect on NF-kappaB activation induced by PMA, LPS, okadaic acid, or ceramide, suggesting selectivity in suppression of NF-kappaB. The suppression of TNF-induced NF-kappaB activation by thalidomide correlated with partial inhibition of TNF-induced degradation of an inhibitory subunit of NF-kappaB (IkappaBalpha), abrogation of IkappaBalpha kinase activation, and inhibition of NF-kappaB-dependent reporter gene expression. Thalidomide abolished the NF-kappaB-dependent reporter gene expression activated by overexpression of TNFR1, TNFR-associated factor-2, and NF-kappaB-inducing kinase, but not that activated by the p65 subunit of NF-kappaB. Overall, our results clearly demonstrate that thalidomide suppresses NF-kappaB activation specifically induced by TNF and H(2)O(2) and that this may contribute to its role in suppression of proliferation, inflammation, angiogenesis, and the immune system.     

Cytoplasmic truncation of the p55 tumour necrosis factor (TNF) receptor abolishes signalling, but not induced shedding of the receptor.

The mechanistic relationship between the signalling for the TNF effects by the human p55 TNF receptor (hu-p55-TNF-R) and the formation of a soluble form of the receptor, which is inhibitory to these effects, was explored by examining the function of C-terminally truncated mutants of the receptor, expressed in rodent cells. The 'wild-type' receptor signalled for a cytocidal effect when cross-linked with specific antibodies and exhibited spontaneous shedding. Shedding of the receptor was not affected by TNF but was markedly enhanced by 4 beta-phorbol-12-myristate-13-acetate (PMA). Receptor mutants with 53%, 83% and 96% C-terminal deletions could not signal for the cytocidal effect. Furthermore, they were found to associate with the endogenous rodent receptors, interfering with their signalling. Yet even the deletion of 96% of the intracellular domain did not abolish shedding of the receptor in response to PMA. These findings suggest that signalling and shedding of the p55 TNF-R are mechanistically distinct.     

Human gastric mucosal bleeding induced by low dose aspirin,but not warfarin.

OBJECTIVE--To investigate the suitability of treatment with low dose aspirin or warfarin, or both, as possible prophylaxis against cardiovascular disease by determining the effect on gastric mucosal bleeding. DESIGN--Randomised crossover trial. SETTING--Academic department of therapeutics. SUBJECTS--Twenty healthy male volunteers aged 19-22. INTERVENTIONS--On separate occasions and in randomised order all subjects received aspirin 75 mg, warfarin, or aspirin 75 mg combined with warfarin. Each treatment was given for 12 days or (when warfarin was used) for longer if necessary until the international normalised ratio of the prothrombin time was stable at 1.4-1.6. END POINT--Loss of blood over 10 minutes into gastric washings. MEASUREMENTS AND MAIN RESULTS--Bleeding over 10 minutes into gastric washings under baseline conditions and after five days, and at end of each regimen of treatment. Aspirin 75 mg increased bleeding from 0.60 (95% confidence interval 0.36 to 0.99) microliters/10 minutes to 1.26 (0.71 to 2.25) microliters/10 minutes at five days, with no evidence of either progressive change or adaptation thereafter. Warfarin had no effect on bleeding either alone or when combined with aspirin. CONCLUSIONS--Aspirin 75 mg causes gastric mucosal bleeding. Low dose warfarin neither induces gastric mucosal bleeding nor enhances that caused by aspirin.     

MIF-1 antagonizes warm-, but not cold-water stress-induced analgesia: Dissociation from immobility

Forced swimming in warm or cold water can lead to immobility and analgesia in mice. In this report we demonstrate that the peptide MIF-1 (Pro-Leu-Gly-NH₂) was able to attenuate the analgesia induced by swimming in warm water, but not that induced by swimming in cold water. In addition, we show that the analgesia and the immobility may be differentially mediated since MIF-1 was able to reduce the immobility at doses different from those necessary to reduce the analgesia. These results confirm previous research indicating that MIF-1 may act as an anti-opiate and further demonstrate that MIF-1 affects analgesia induced by stress.     

Central dopamine modulates anapyrexia but not hyperventilation induced by hypoxia.

Hypoxia causes hyperventilation and decreases body temperature (T(b)) and metabolism [O(2) consumption (VO(2))]. Because dopamine (DA) is released centrally in response to peripheral chemoreceptor stimulation, we tested the hypothesis that central DA mediates the ventilatory, thermal, and metabolic responses to hypoxia. Thus we predicted that injection of haloperidol (a DA D(2)-receptor antagonist) into the third ventricle would augment hyperventilation and attenuate the drop in T(b) and VO(2) in conscious rats. We measured ventilation, T(b), and VO(2) before and after intracerebroventricular injection of haloperidol or vehicle (5% DMSO in saline), followed by a 30-min period of hypoxia exposure. Haloperidol did not change T(b) or VO(2) during normoxia; however, breathing frequency was decreased. During hypoxia, haloperidol significantly attenuated the falls in T(b) and VO(2), although hyperventilation persisted. The present study shows that central DA participates in the thermal and metabolic responses to hypoxia without affecting hyperventilation, showing that DA is not a common mediator of this interaction.     

Parenchymal,but not leukocyte,TNF receptor 2 mediates T cell-dependent hepatitis in mice

TNF-alpha is a central mediator of T cell activation-induced hepatitis in mice, e.g., induced by Pseudomonas exotoxin A (PEA). In this in vivo mouse model of T cell-dependent hepatitis, liver injury depends on both TNFRs. Whereas TNFR1 can directly mediate hepatocyte death, the in vivo functions of TNFR2 in pathophysiology remained unclear. TNFR2 has been implicated in deleterious leukocyte activation in a transgenic mouse model and in enhancement of TNFR1-mediated cell death in cell lines. In this study, we clarify the role of hepatocyte- vs leukocyte-expressed TNFR2 in T cell-dependent liver injury in vivo, using the PEA-induced hepatitis model. Several types of TNFR2-expressing leukocytes, especially neutrophils and NK cells, accumulated within the liver throughout the pathogenic process. Surprisingly, only parenchymal TNFR2 expression, but not the TNFR2 expression on leukocytes, contributed to PEA-induced hepatitis, as shown by analysis of wild-type --> tnfr2 degrees and the reciprocal mouse bone marrow chimeras. Furthermore, PEA induced NF-kappaB activation and cytokine production in the livers of both wild-type and tnfr2 degrees mice, whereas only primary mouse hepatocytes from wild-type, but not from tnfr2 degrees, mice were susceptible to cell death induced by a combination of agonistic anti-TNFR1 and anti-TNFR2 Abs. Our results suggest that parenchymal, but not leukocyte, TNFR2 mediates T cell-dependent hepatitis in vivo. The activation of leukocytes does not appear to be disturbed by the absence of TNFR2.     

Fusion of mouse alveolar macrophages induced by 1 alpha,25-dihydroxyvitamin D3 involves extracellular, but not intracellular, calcium

We have reported that the active form of vitamin D3, 1 alpha, 25-dihydroxy-vitamin D3 [1 alpha, 25(OH)2D3], directly induces the fusion of mouse alveolar macrophages (Abe et al: Proc. Natl. Acad. Sci. USA 80:5583-5587, 1983). The fusion process can be divided into two phases: the 1 alpha,25(OH)2D3-dependent priming phase (0-18 hr) and the calcium-dependent progression phase (18-72 hr) (Jin et al: J. Cell. Physiol. 137:110-116, 1988). In the present study, we examined the role of calcium in the progression phase of macrophage fusion induced by 1 alpha,25(OH)2D3. Macrophages pretreated with 1 alpha,25(OH)2D3 for 48 hr in a low-calcium (0.13 mM) medium began to fuse quickly 30 min after the culture medium was switched to a normal calcium (1.85 mM) medium. Of various cations tested, calcium was the most effective in inducing fusion, followed by strontium and manganese. Magnesium, potassium, and sodium had no effect. Calcium ionophores such as A23187 and ionomycin did not induce fusion in the low-calcium medium, nor did they potentiate fusion in the media containing higher concentrations of calcium. The intracellular concentration of free Ca2+, measured by a fluorescent method using fura-2 AM, was 116 +/- 1 nM in the macrophages pretreated with 1 alpha,25(OH)2D3 for 48 hr in the low-calcium medium. When calcium chloride was added to the assay system at a final concentration of 1.85 mM, the cytosolic free Ca2+ concentration did not increase appreciably (from 116 to 144 nM). But the macrophages began to fuse quickly when CaCl2 was added. In contrast, adding ionomycin increased cytosolic free Ca2+ from 116 to 440 nM, but no fusion occurred. These results clearly indicate that the extracellular, but not the intracellular, calcium is involved in the progression phase of the fusion of mouse alveolar macrophages primed by 1 alpha,25(OH)2D3.     

Proglumide: Selective antagonism of the rumination but not gastric motor effects induced by pentagastrin in sheep

The effect of intravenous (IV) vs intracerebroventricular (ICV) administrations of pentagastrin on gastro-intestinal motility and rumination were investigated by electromyography in sheep ; these effects were compared to those obtained after a previous IV or ICV injection of proglumide. When ICV administered at a dose of 20 ng.kg^?1, pentagastrin did not significantly affect the frequency of reticular and abomasal spiking activity but elicited a 13 to 37 min period of rumination after a delay of 23 ± 7 min. In contrast, when IV infused at a rate of 20 ng.kg^?1.h^?1 during 20 min, pentagastrin inhibited significantly the frequency of reticular and abomasal contractions for 30 to 40 min but did not induce rumination. Proglumide ICV administered (0.8 mg/kg^?1) abolished the rumination induced by central injection of pentagastrin whereas a 10 times higher dose administered systematically (8 mg.kg^?1 IV) did not block these effects. Both of ICV and IV administrations of proglumide at respectively 0.8 and 8 mg.kg^?1 were unable to antagonize the inhibitory effects of pentagastrin on reticulum and abomasum motility.     

Secretion of VLDL, but not HDL, by rat hepatocytes is inhibited by the ethanolamine analogue N-monomethylethanolamine.

The role of phospholipids in the assembly and secretion of very low density lipoproteins (VLDL) has been investigated by incubation of monolayer cultures of rat hepatocytes with monomethylethanolamine, an analogue of ethanolamine and choline. The cellular concentration of phosphatidylmonomethylethanolamine was increased 17-fold in response to treatment of hepatocytes with monomethylethanolamine. The secretion of phosphatidylcholine, triacylglycerol, and the apolipoproteins BH, BL, and E into VLDL was inhibited by approximately 50% in hepatocytes incubated with monomethylethanolamine, compared to untreated cells. Cell viability was unaffected by treatment with the ethanolamine analogue, as was cellular protein synthesis. The mechanism by which monomethylethanolamine reduced VLDL secretion was examined. Since monomethylethanolamine is a structural analogue of ethanolamine and choline, an obvious hypothesis for explanation of the effect on VLDL secretion was that phosphatidylcholine biosynthesis, which is required for VLDL secretion (Z. Yao and D. E. Vance. 1988. J. Biol. Chem. 263: 2998-3004) was inhibited. However, the biosynthesis of phosphatidylcholine from [3H]choline or from [3H]glycerol was not significantly reduced in the analogue-treated, compared with the untreated, hepatocytes. Nor was the incorporation of [3H]glycerol into cellular triacylglycerol altered in the monomethylethanolamine-treated cells. Furthermore, addition of monomethylethanolamine to hepatocytes did not reduce the rate of biosynthesis of phosphatidylethanolamine either from CDP-ethanolamine or from phosphatidylserine, nor was phosphatidylserine biosynthesis from [3-3H]serine affected. The 50% inhibition of VLDL secretion elicited by monomethylethanolamine was apparently specific for VLDL because there was no difference in secretion of HDL (lipid or apoprotein moieties) or albumin by cells incubated with or without the ethanolamine analogue. The experiments showed that inhibition of VLDL secretion by monomethylethanolamine was not the result of decreased biosynthesis of phospholipids, triacylglycerols, or cholesteryl esters. More subtle effects of the ethanolamine/choline analogue, for example interference by the increased amount of phosphatidylmonomethylethanolamine, in the process of assembly of lipids with apoB remain a possibility.     

Cellular fibronectin is induced by epidermal growth factor, but not by dexamethasone or cyclic AMP in rat liver epithelial cells

Epidermal growth factor (EGF) induces fibronectin (FN) and FN mRNA in rat liver epithelial cells, under conditions where the factor also induces the cells to migrate. Newly synthesized protein is secreted into the medium and deposited as substratum-bound extracellular matrix. The levels of mRNA and the amount of protein synthesized are not influenced by cyclic AMP or dexamethasone, factors that have been found to modulate FN expression in other cells. However, the cells are sensitive to the factors, suggesting a cell-specific regulation. The EGF-induced RNA contains the sequences EIIIA and EIIIB characteristic of cellular fibronectin.     

Cellular retinoic acid-binding protein II gene expression is directly induced by estrogen,but not retinoic acid,in rat uterus

It has been suggested that cellular retinoic acid-binding protein (II) (CRABP(II)) may have a role in the movement of retinoic acid (RA) to its nuclear receptors, thereby enhancing the action of RA in the cells in which it is expressed. RA has also been shown to increase expression of CRABP(II). Previous work from our laboratory has shown that 17 beta-estradiol (E2) administration to prepubertal female rats leads to acquisition of the ability of the lining epithelium to synthesize RA as well as to express CRABP(II). To determine whether this appearance of CRABP(II) was dependent on the production of RA, both E2 and RA were administered to ovariectomized rats. E2 administration induced expression of the CRABP(II) gene in the uterus within 4 h, and this induction was not inhibited by prior administration of puromycin, indicating that the induction was direct. In contrast, RA caused no change in CRABP(II) message level, even at times as late as 48 h after administration. Isolation and analysis of 4.5 kb of the 5'-flanking region of the gene revealed no apparent E2-response element. Using this portion of the gene to drive expression of the luciferase gene in transfected cells allowed identification of a region containing an imperfect estrogen-response element and estrogen-response element half-site, necessary for E2-driven induction. A possible Sp1 binding site in the 5'-flanking region of the CRABP(II) gene was also required for this induction. The ability of E2 to induce expression of CRABP(II) suggests that it can enhance the activity of RA, directly affecting expression of retinoid-responsive genes.     

Spinally-mediated antinociception is induced in mice by an adenosine kinase-, but not by an adenosine deaminase-, inhibitor.

Relative involvement of adenosine deaminase and adenosine kinase in antinociception induced by endogenous adenosine was investigated. Antinociception induced by 5'-amino 5'-deoxyadenosine (5'-ADAdo; an adenosine kinase inhibitor) and deoxycoformycin (dCF; an adenosine deaminase inhibitor) administered i.t. was determined using the mouse tail-flick assay. Dose- and time-dependent antinociception was observed following i.t. administration of 5'-ADAdo, but not dCF. Antinociception induced by 5'-ADAdo was reversed by coadministration i.t. of theophylline, an adenosine receptor antagonist, in a dose-dependent manner. These data provide preliminary evidence that adenosine kinase plays a more significant physiological role than adenosine deaminase in the regulation of adenosine involved in spinally-mediated antinociception.     

Inhibitory interactions between alpha 2-adrenergic and opoid but not NPY mechanisms controlling the CRF-ACTH axis in the rat.

Following a series of investigations supporting the concept that the brain stem catecholaminergic (CA) system played a major stimulatory role on both basal and stress-triggered states of the hypothalamic-pituitary-adrenocortical (HPA) axis, across alpha 1 and beta receptors and also via alpha 2 receptors, the present study was designed to gain a deeper insight into the fine mechanism of functional interactions between the alpha 2 receptors mediated CA system and two peptidergic mechanisms, both shown to take part in the stimulatory control of the HPA axis: beta-endorphin and NPY. All experiments were conducted on rats whose noradrenergic bundles, which directly innervate the CRF neurons and are strongly implicated in the ether stress-induced corticotropic response, had been bilaterally obliterated by an intracerebral (i.c.) injection of 6-OHDA (NAB-X). Results showed that: (1) the blockade of the ether-stress induced ACTH response resulting from NAB-X was entirely reversed by an intraventricular (i.c.v.) infusion of the alpha 2 antagonist idazoxan (10 nmol), which appeared ineffective under basal conditions; (2) the restoration of a normal post-stress ACTH surge by i.c.v. idazoxan was itself blunted by an i.c.v. pretreatment with naloxone (10 nmol), whereas an i.c. pretreatment with an anti-NPY serum appeared ineffective. These data suggest that, in addition to a stimulatory control exerted by postsynaptic alpha 2 receptors directly on CRF neurons, other alpha 2 receptors participate, exclusively under the stress conditions above, in a tonic inhibitory control, indirectly mediated to the HPA axis across a stimulatory opioid, but not NPY regulatory component.     

Lipolysis induced by alloxan in rat adipocytes is not inhibited by insulin.

Isolated rat adipocytes were incubated with adrenaline, adrenaline plus insulin, alloxan or alloxan plus insulin. Glycerol release was taken as a measure of lipolysis. It was observed that alloxan in the concentration of 3, 10 and 20 mmol/l intensifies lipolysis in adipocytes in the absence of adrenaline. Insulin (10(-6) mol/l) treatment of cells did not inhibit lipolysis caused by this compound, but significantly restricted lipolysis induced by adrenaline (10(-6) mol/l). It was also shown that alloxan in the concentration of 3 and 10 mmol/l intensified lipolysis stimulated by adrenaline (10(-6) mol/l). Addition of 20 mmol/l of alloxan strongly inhibited glycerol release in the presence of adrenaline. The results presented here clearly indicate that the action of alloxan concerns cells of the white adipose tissue.     

IGFs, basic FGF, and glucose modulate proliferation and apoptosis induced by IFNgamma but not by IL-1beta in rat INS-1E beta-cells.

We investigated the effects of glucose and beta-cell growth factors (IGF-I, IGF-II, bFGF) on growth and apoptosis in the presence and absence of apoptosis inducing cytokines (IFNgamma, Il-1beta, TNFalpha). Rat INS-1E beta-cell viability was measured by WST-1 viability assay and cell counting, apoptosis by FACS analysis of annexin-V-FITC and fluorescein-dUTP (TUNEL-staining)-positive cells. Glucose alone maintained INS-1E beta-cell viability at high physiological concentrations (6.2-12.5 mmol/l), addition of IGF-II alone or in combination with bFGF further increased these glucose effects. The cytokines IFNg and IL-1beta, but not TNFalpha strongly induced INS-1E beta-cell apoptosis. Interestingly, glucose alone induced apoptosis at extremely low or very high concentrations. In combination with IFNg, low glucose (1.6 mmol/l) increased apoptosis by 25.6% (1SD 5.0%) and high glucose (50 mmol/l) by 22.8% (1SD 2.8%) compared to 12.5 mmol/l glucose. In contrast, glucose failed to modulate IL-1beta-induced apoptosis. Most importantly, IGF-II and bFGF inhibited apoptosis induced by IFNg, but not by IL-1beta. Therefore, IGF signaling, supported by bFGF and optimal glucose levels, maintains beta-cell viability in vitro. Cytokines IFNg and IL-1beta differentially interfere with intracellular signaling cascades stimulated by IGFs and bFGF or glucose, respectively.     

Potentiation of amphetamine-induced hyperactivity by acute but not by chronic para-chlorophenylalanine treatment in the rat.

Acute pre-treatment with para-chlorophenylalanine potentiated amphetamine-induced hyperactivity. Chronic pre-treatment with para-chlorophenylalanine failed to produce potentiation of the amphetamine effect. Activity levels were slightly depressed following acute para-chlorophenylalanine treatment alone and significantly depressed following chronic para-chlorophenylalanine alone. The findings indicate that the acute effects of a drug can be different from its chronic effects. The data may be consistent with the notion that a gradual adjustment to para-chlorophenylalanine took place with time.