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Dietary fatty acid modulates actions of nucleotides on humoral immune responses.

Polynucleotides enhance T cell-dependent antibody production in culture. Impaired antibody production in mice fed a nucleotide-free diet can be easily restored by in vivo supplementation of both a mononucleotide-nucleoside mixture (OG-VI) and polynucleotides. Polynucleotides appear to act partly by modulating antigen presentation processes mediated by cell surface molecules. We examined whether dietary fatty acid manipulation alters nucleotides' actions on humoral immunity. Antibody production was studied in C57B1/6 mice fed I) a nucleotide-free diet high in saturated fatty acid (SFA diet), 2) a nucleotide-free diet high in polyunsaturated fatty acid (PUFA diet), and 3) a regular nucleotide-free diet (control). In vivo and in vitro T cell-dependent antibody production decreased in all groups, but mice fed the SFA diet produced more antibody in vivo than did mice in the other diet groups. Spleen cells from mice fed the SFA diet also produced more interferon-alpha when stimulated with mitogens than did those from mice fed the control diet. In contrast, polynucleotides enhanced in vitro antibody production much less efficiently in mice fed the SFA diet than in the other mice and in vivo supplementation of OG-VI was also less effective in restoring impaired antibody production in these mice. A diet with a high content of SFA may alter nucleotides' action on humoral immune responses, in addition to its direct effects on immune functions.

Animals↗

Rate-dependent prolongation of action potential duration in isolated rat ventricular myocytes.

Rate-dependent alterations of action potential duration (APD) in rat ventricular myocytes were investigated. Action potentials of the isolated myocytes were recorded with patch electrodes containing EGTA (11 mM), and showed a marked rate-dependent prolongation in the APD (0.2-5 Hz). This prolongation was significantly inhibited in the presence of 4-aminopyridine (4-AP), a blocker of the transient outward K+ current (Ito). Thus, the rate-dependent decrease in Ito may underlie the change in APD. In contrast, the action potentials recorded from rat ventricular papillary muscles with conventional microelectrodes did not show rate-dependent alterations in the APD, i.e., the APD remained practically unaltered at the frequency range of 0.2-5 Hz. These results suggest that the rate-dependent prolongation of APD (due to rate-dependent blockade of Ito) becomes evident when the intracellular Ca2+ was chelated by the internal application of EGTA via patch pipette. We speculate that the rate-dependent prolongation of APD (via decreases in Ito) is masked in the ventricular papillary muscles, probably due to rate-dependent decreases in the inward current (e.g., electrogenic Na(+)-Ca2+ exchange current) that is regulated by the intracellular calcium.

4-Aminopyridine↗

Fine structural alterations associated with venom action on squid giant nerve fibers.

(1) Block of conduction and marked increase in permeability of the squid giant axon, when surrounded by adhering small nerve fibers, is caused by the venoms of cottonmouth, ringhals, and cobra snakes and by phospholipase A (PhA). This phenomenon is associated with a marked breakdown of the substructure of the Schwann sheath into masses of cytoplasmic globules. Low concentrations of these agents which render the axons sensitive to curare cause less marked changes in the structure of the sheath. (2) Rattlesnake venom, the direct lytic factor obtained from ringhals venom, and hyaluronidase caused few observable changes in structure, correlating with the inability of these agents to increase permeability. (3) Cottonmouth venom did not alter the structure of giant axons freed of all adhering small nerve fibers. This is in agreement with previous evidence that the venom effects are due to an action of lysophosphatides liberated as a result of PhA action. Cetyltrimethylammonium chloride, a cationic detergent, produces effects that resemble those of venom and PhA. (4) The results provide evidence that PhA is the component of the venoms that is responsible for their effects. It also appears that the Schwann cell and possibly the axonal membrane are the major permeability barriers in the squid giant axon.

Action Potentials↗

Manganese action on protein synthesis in diabetic rat pancreas: evidence for a possible physiological role.

The actions of manganese on [3H]phenylalanine incorporation into pancreatic acinar protein from streptozotocin-diabetic rats were compared with the actions of several divalent cations, insulin, and pancreatic secretagogues. In the presence of Ca2+, 7 X 10(-4) M manganese greatly enhanced [3H]phenylalanine incorporation. Under similar incubation conditions, magnesium exerted only a slight stimulatory effect on incorporation, whereas cobalt and nickel failed to enhance incorporation. Removal of Ca2+ from incubation medium, or replacement of Ca2+ by either barium or strontium, abolished the stimulatory effect of manganese on incorporation. Lanthanum, at a concentration that inhibits stimulated Ca2+ influx in acini (10(-4) M), also blocked the stimulatory effect of manganese but did not alter the actions of insulin on incorporation. Dibutyryl cyclic GMP, a competitive antagonist of cholecystokinin-octapeptide, and atropine, a competitive antagonist of carbachol, blocked the stimulatory effects of the respective secretagogues on incorporation. Neither antagonist altered the actions of manganese. These findings suggest that in the face of insulin deficiency manganese enhances pancreatic protein synthesis in diabetic rats via a Ca2+-dependent mechanism that is distinct from the actions of other divalent cations, insulin and pancreatic secretagogues.

Animals↗

Alterations in transport path differentially affect temporal and spatial movement parameters.

Many studies have examined the coordination of reach-to-grasp movements. However, there is debate regarding the mechanism of coordination between the transport and grasp components. The current study investigated the stability of temporal and spatial measures for reaches in which transport path was altered early or late in the reaching action. Transport alteration was accomplished by placing an obstacle either 10 cm (near) or 20 cm (far) from the hand starting position. Obstacle location affected the formation of transport path such that maximum wrist elevation coincided with the location of the obstacle. Kinematic analyses revealed that reaches over the near obstacle significantly prolonged transport time and time to maximum velocity compared with reaches over the far obstacle. A similar pattern of results was observed for the grasp component; reaches over the near obstacle resulted in a prolongation of grip duration, time to maximum aperture, and time to maximum opening and closing velocity. Grip closing velocity was decreased in the obstacle conditions. These results confirm findings from earlier studies that have shown that changes in the transport component affect grasp formation. A spatial and temporal analysis of grasp opening and closing was also performed. Grasp closing time varied significantly between conditions, while closing distance or the distance traveled by the wrist after maximum aperture remained essentially constant across conditions. These results suggest that the central nervous system may be using a spatial controller to coordinate prehensile components.

Adult↗

Intravenous estrogens increase insulin clearance and action in postmenopausal women.

To test the hypothesis that estrogens alter insulin action, we evaluated the effects of intravenous conjugated estrogens (CE) on insulin-stimulated steady-state glucose infusion rate (SSGIR) and suppression of plasma glycerol in postmenopausal women (mean +/- SD; 56 +/- 4 yr; n = 12) not using hormone replacement. SSGIR and glycerol were measured during a two-stage (8 and 40 mU. m-2. min-1) hyperinsulinemic euglycemic clamp on 2 days, with or without a 2.5-mg intravenous CE bolus. Serum estradiol concentrations were increased approximately 200% on the estrogen (EST) compared with the control (CON) days. Serum insulin was reduced (P < 0.01) during stage 2 of the clamp for EST (63.3 +/- 12.8 micro U/ml) vs. CON (78.2 +/- 15.8 micro U/ml). Mean SSGIR and plasma glycerol did not differ between CON and EST days. With adjustment for differences in insulin concentration between conditions, stage 2 glucose disposals were significantly higher (8.63 vs. 7.20 mg. kg-1. min-1) and plasma glycerol concentrations were significantly lower (29.4 vs. 35.0 micro mol/l) for EST vs. CON. Our findings suggest that acute CE administration increases insulin clearance and action in postmenopausal women.

Body Composition↗

Effect of dopamine2 blockade on renal function under varied sodium intake.

This study explored the role of the dopamine-2 receptor (DA2) in the control of renal blood flow (RBF) and the influence of variations in sodium intake. These relationships have not been previously defined in man. Seven normotensive male subjects underwent a low dose dopamine (DA) infusion (1 microgram/kg.min) for 3 h, known to activate both DA1 and DA2 receptors. The effect of DA2 receptor on renal hemodynamics was studied using a relatively specific DA2 blocker [domperidone (DOM); 60 mg, orally] alone and with a DA infusion. Systemic and renal hemodynamics parameters were measured noninvasively. Urinary prostacyclin was measured in 3-h urine specimens, obtained during the DA infusion. The DA infusion increased RBF and prostacyclin during both normal and high salt diets, but this effect was attenuated on a low salt diet. DOM alone significantly reduced basal RBF during normal (1304 +/- 48 vs. 1175 +/- 45 mL/min.1.73 m2; P < 0.01) and low salt diets (1402 +/- 80 vs. 1220 +/- 101 mL/min.1.73 m2; P < 0.02), but was without effect during high sodium intake. DOM had no effect on prostacyclin excretion at any level of salt intake. These results suggest that both DA1 and DA2 are activated in renal vessels by DA, and that DA2 receptors play a role in the renal vasodilating action of DA. Changes in sodium balance alter the actions of the two receptors (DA1 and DA2) in a coordinated fashion in the regulation of RBF.

Adult↗

Possible effects of endocrine disruptors on male reproductive function.

Endocrine disruptors act to alter blood hormone levels or the subsequent action of hormones, including effects on hormone production, release, transport, metabolism and/or elimination together with effects on cognate receptor binding and/or subsequent intracellular receptor actions. Confirmed alterations in reproductive development in wildlife species together with reports touting an increase in the incidence of human male reproductive tract abnormalities and decreased adult sperm counts in some parts of the world have increased public concern with endocrine disruptors. A biological plausible hypothesis has suggested that man-made chemicals act as endocrine disruptors resulting in altered development of the reproductive tract causing the observed effects. Based on current knowledge, the impact of endocrine disruptors on the male reproductive function remains to be appreciated. Epidemiological human studies are necessary to fill in the gap in our knowledge. Disturbances of hormonal regulation during fetal or postnatal development in humans may induce adverse effects on the male reproductive system, but these adverse effects of endocrine disruptors on humans are subtle, and difficult to research and detect. We have investigated fetal exposure to endocrine disruptors in Japan by analyzing umbilical cords, and changes of testis-weight in Japanese men by using analytical data of necropsy. This mini-review summarizes current endocrine disruptor issues on possible effects of endocrine disruptors on male reproductive function and the results of our recent research.

Cryptorchidism↗

Evidence for a putatively new angiotensin II-generating enzyme in the vascular wall.

An inhibitor of angiotensin I (ANG I) converting enzyme, SA446, reduced the response to ANG I of blood vessels isolated from dogs and monkeys, but did not abolish the response even at high concentrations. The residual action of ANG I in the presence of high concentrations of SA446 could be abolished by (Sar1, Ala8)-ANG II. Vascular strips and crude extracts of vessels and lungs possessed the enzymic activity generating ANG II from ANG I, or hippuric acid from hippuryl-histidyl-leucine (HHL). The HHL-hydrolysing activity of the crude extracts was completely inhibited by SA446 (10(-7) mol/l) and/or Na2-EDTA (10(-3) mol/l). However, the octapeptide generation was not abolished despite the combined treatment with SA446 (5 X 10(-4) mol/l) and Na2-EDTA (5 x 10(-3) mol/l). The residual activity forming ANG II was inhibited by chymostatin and soybean trypsin inhibitor, which however did not affect the HHL-hydrolysis. Combined treatment with SA446 (10(-5) mol/l) and chymostatin (2.5 X 10(-5) mol/l) abolished the vascular action of ANG I but did not alter the action of ANG II. These results strongly suggest that besides the ANG I converting enzyme, another enzyme which generates ANG II is present in vascular tissues and lungs, and may play an important role in the local generation of ANG II, which possibly regulates the regional vascular tone.

3-Mercaptopropionic Acid↗

Effects of genetically altered brain glucocorticoid receptor action on behavior and adrenal axis regulation in mice.

Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is associated with vulnerability to a number of psychiatric diseases including major depression, bipolar disorder, anxiety disorders, and schizophrenia. The HPA axis is activated in response to stress and in a characteristic circadian rhythm, resulting in the release of glucocorticoid hormones from the adrenal cortex. These hormones act on peripheral target tissues to restore homeostasis to the organism and engage glucocorticoid receptors (GR) in the CNS to control the intensity and duration of the stress response. Alterations in this glucocorticoid sensing system may underlie the HPA axis changes associated with psychiatric disorders. Recently, a number of lines of mice with genetically altered GR signaling in the CNS have been generated to address this hypothesis. Here, we summarize findings from new genetic models that indicate a critical role for GR signaling in the CNS in normal regulation of the HPA axis and behavioral/emotional stability.

Animals↗

Central and peripheral actions of salicylate in altering nonpyrogenic thermoregulation of rats.

The effects on body temperature of intracerebroventricular and intraperitoneal sodium salicylate were evaluated in anesthetized and nonanesthetized, nonrestrained rats. Also, the effects of various neurotransmitter receptor blocking drugs were evaluated on salicylate-induced hypothermia of nonanesthetized animals. Sodium salicylate, 150-350 mg/kg induced a dose-related hypothermia of unanesthetized animals. However, in anesthetized animals, marked hyperthermia was observed. In unanesthetized, unrestrained rats, intracerebroventricular administration of 1.0 mg/h salicylate caused greater hypothermia than peripheral administration of salicylate, 350 mg/kg. Salicylate hypothermia was unaffected by para-chlorophenylalanine, cyproheptadine, or naloxone, and was only partially inhibited by pimozide. These results strongly suggest a potent direct action of salicylate within the central nervous system to induce hypothermia, and suggest possible involvement of dopaminergic neurons in this process.

Animals↗

Comparison of the effects of trimethadione and its primary metabolite dimethadione on neuromuscular function and the effects of altered pH on the actions of dimethadione.

The effects of the anticonvulsant trimethadione (TMO) and its primary metabolite dimethadione (DMO) were investigated at the frog neuromuscular junction using intracellular recording techniques. TMO (1, 2 and 5 mM) caused dose-dependent decreases in miniature end-plate potential (MEPP) and end-plate potential (EPP) amplitudes, decreased quantal content only at the highest dose and did not affect MEPP frequency. DMO (2 and 5 mM) at the normal pH of 7.2 significantly decreased quantal content and decreased EPP amplitude at the higher concentration used. Neither MEPP amplitude nor frequency was significantly affected by DMO at pH 7.2. When 2 mM DMO was added at the same time that pH was lowered to 6.6, considerably larger decreases in EPP( amplitude and quantal content were observed. Under these conditions, DMO still did not alter MEPP amplitude but did cause about a doubling in MEPP frequency. The effects of pH 6.6 alone were also examined, but lowered pH did not account for all of the exaggerated effect of DMO in pH 6.6. Presumably, more DMO accumulates intracellularly in low pH conditions because it is a weak acid and sensitive to alterations in pH. In conclusion, both TMO and DMO cause depression of neuromuscular transmission; however, their mechanisms for depression are different, especially when therapeutically relevant concentrations are considered. TMO acts primarily by suppressing postjunctional sensitivity to acetylcholine, whereas DMO primarily decreases transmitter release from the nerve terminal.

Animals↗

Haloperidol-induced alteration in the physiological actions of group I mGlus in the subthalamic nucleus and the substantia nigra pars reticulata.

Excitatory glutamatergic inputs to the subthalamic nucleus (STN), and subthalamic afferents to the substantia nigra pars reticulata (SNr) are believed to play a key role in the pathophysiology of Parkinson's disease (PD). Previously, we have shown that activation of the group I mGlus in the STN and SNr induces a direct depolarization of the neurons in these nuclei. Surprisingly, although both group I mGlus were present in the STN and SNr, mGlu5 alone mediated the DHPG-induced depolarization of the STN, and mGlu1 alone mediated the DHPG-induced depolarization of the SNr. We now report that both mGlu1 and mGlu5 are coexpressed in the same cells in both of these brain regions, and that both receptors play a role in mediating the DHPG-induced increase in intracellular calcium. Furthermore, we demonstrate that the induction of an acute PD-like state using a 16 h haloperidol treatment produces an alteration in the coupling of the group I receptors, such that post-haloperidol, DHPG-induced depolarizations are mediated by both mGlu1 and mGlu5 in the STN and SNr. Therefore, the pharmacology of the group I mGlu-mediated depolarization depends on the state of the system, and alterations in receptor coupling may be evident in pathological states such as PD.

Animals↗

Viewing chemokines as a third major system of communication in the brain.

There is irrefutable proof that opioids and other classes of centrally acting drugs have profound effects on the immune system. Evidence is mounting that products of the immune system, such as chemokines, can reciprocally alter the actions of these drugs and the endogenous ligands for their receptors. Chemokines are a family of small (8 to 12 kDa) proteins involved in cellular migration and intercellular communication. With a few exceptions, they act on more than one receptor. Although the chemokines and their G protein-coupled receptors are located in both glia and neurons throughout the brain, they are not uniformly distributed. They are found in such brain areas as the hypothalamus, nucleus accumbens, limbic system, hippocampus, thalamus, cortex, and cerebellum. Among the chemokines differentially localized in brain neurons and glia are CCL2/MCP-1, CXCL12/SDF-1alpha, CX3CL1/fractalkine, CXCL10/IP 10, CCL3/MIP-1alpha, and CCL5/RANTES. Functional roles for the chemokine system, composed of the chemokine ligands and their receptors, have been suggested in brain development and heterologous desensitization. The system can alter the actions of neuronally active pharmacological agents such as opioids and cannabinoids and interact with neurotransmitter systems. In this review, we propose that the endogenous chemokine system in the brain acts in concert with the neurotransmitter and neuropeptide systems to govern brain function. It can thus be thought of as the third major system in the brain.

Animals↗

Characterization of the class I antiarrhythmic activity of cibenzoline succinate in guinea pig papillary muscle.

The effects of cibenzoline on transmembrane action potentials were examined in guinea pig papillary muscle. Cibenzoline (1-128 microM) did not alter the action potential durations at 50 and 90% of repolarization, the effective refractory period or the ratio of effective refractory period to action potential duration at 90% of repolarization. Likewise, the maximum diastolic potential was virtually unaffected. Cibenzoline depressed the maximum rate of rise of phase 0 (dV/dtmax). This effect was dependent on the rate of stimulation and occurred at a relatively low concentration (2 microM). The onset of use-dependent depression was monoexponential and dependent on the drug concentration, as well as the rate of stimulation. The rate of recovery from use-dependent depression also followed a single exponential time course but was independent of drug concentration and stimulation rate. When cibenzoline and lidocaine were combined in the tissue bath, dV/dtmax recovered with a double exponential time course. The first and second components of this recovery corresponded to the time course observed with lidocaine (first) and cibenzoline (second) alone. Also, the magnitude of the second component was less with the combination than with cibenzoline alone, indicating an interaction between the two drugs. In addition, cibenzoline shifted the curve relating normalized dV/dtmax to membrane potential in the hyperpolarizing direction. Finally, cibenzoline did not alter slow-response action potentials induced by elevated [K]o and isoproterenol. The authors conclude that cibenzoline acts as a class la antiarrhythmic agent in guinea pig papillary muscle.

Action Potentials↗

Bombesin receptors as a novel anti-anxiety therapeutic target: BB1 receptor actions on anxiety through alterations of serotonin activity.

The effects of PD 176252 [3-(1H-indol-3-yl)-N-[1-(5-methoxy-pyridin-2-yl)-cyclohexylmethyl]-2-methyl-2-[3-(nitro-phenyl)ureido]propionamide], a nonpeptide bombesin (BB) BB1/BB2 receptor antagonist, were assessed in rats using several ethologically relevant tests of anxiety. Consistent with a role for the bombesin family of peptides in subserving anxiety behaviors, the antagonist increased social interaction (3.75 and 7.5 mg/kg, i.p.), dose-dependently attenuated the number of vocalizations emitted by guinea pig pups separated from their mother (1-30 mg/kg, i.p.), reduced latency to approach a palatable snack in an anxiogenic (unfamiliar) environment, and reduced the fear-potentiated startle response (5 and 10 mg/kg, i.p., and 100-200 ng per rat, i.c.v.). When administered directly to the dorsal raphé nucleus (DRN), PD 176252 (20-500 ng) increased social interaction under aversive conditions, as did the 5-HT1A receptor agonist 8-hydroxy-2(di-n-propylamino)tetralin (50 ng). Furthermore, intra-DRN microinfusion of the peptide antagonist (PD 176252) suppressed, whereas its agonist [neuromedin B (NMB)-30] promoted, the in vivo release of 5-HT in the ventral hippocampus. In parallel, the suppressed social interaction elicited by intra-DRN administration of NMB was attenuated by a systemically administered 5-HT2C (but not 5-HT1A) receptor antagonist. Together, these findings suggest that endogenous BB-like peptides at the DRN evoke the release of 5-HT from the limbic nerve terminals originating from the raphé, specifically at the ventral hippocampus, resulting in anxiogenesis. The finding that this action was attenuated by BB receptor (BB1 and/or BB2) antagonists suggests that these compounds may represent a novel class of anxiolytic agents.

Animals↗

Estrogen receptor 1 polymorphisms are associated with airway hyperresponsiveness and lung function decline, particularly in female subjects with asthma.

BACKGROUND: Sex hormones may contribute to the higher prevalence and severity of adult asthma in women compared with men. OBJECTIVE: Sequence variants in the estrogen receptor alpha gene (ESR1) may alter estrogen action in asthma. METHODS: Two hundred asthma probands and their families (n=1249) were genotyped for 5 single nucleotide polymorphisms (SNPs) in the ESR1 gene (intervening sequence 1 [IVS1]-1505A/G, IVS1-1415T/C, IVS1-397C/T, IVS1-351G/A and exon1+30T/C). Association with asthma and bronchial hyperresponsiveness (BHR) were tested. In the asthma probands, association of SNPs with BHR severity and annual FEV1 decline were determined. RESULTS: No SNP was associated with asthma. IVS1-397 was significantly associated with the presence of BHR (P=.02) and interacted with sex; female subjects with the CT or TT genotype were at risk (P=.01). In asthma probands, all SNPs were associated with FEV1 decline. Exon1+30 CT and TT group had an excess decline of 11.6 mL/y (P=.03) and 15.7 mL/y (P=.01), respectively, compared with the CC group. Of the IVS1 polymorphisms, IVS1-351G/A showed the strongest association, with the AA group having excess decline of 16.1 mL/y (P=.01) compared with the GG group. In subanalyses by sex, these associations were significant only in female subjects. CONCLUSION: ESR1 gene variants may affect development of BHR, particularly in female subjects. They may also lead to a more rapid lung function loss in patients with asthma, and in female subjects specifically. This may result from altered estrogen action, which affects lung development and/or airway remodeling. Further studies on ESR1 gene variations are important to understand better the origin of sex differences in asthma. CLINICAL IMPLICATIONS: Variations in the gene encoding estrogen receptor alpha are associated with BHR and a more rapid annual lung function decline, especially in female subjects. Even though this has no diagnostic or clinical implication, it may open avenues for future sex-specific treatment in asthma.

Adult↗

Insulin-mediated glycogen synthase activity in muscle of spontaneously insulin-resistant and diabetic rhesus monkeys.

Altered insulin action on glycogen synthase activity has been well recognized in non-insulin-dependent diabetes, and some prior evidence has suggested this alteration may be one of the earliest disturbances preceding the development of diabetes. The present study, using the spontaneously insulin-resistant and diabetic rhesus monkey, examined insulin's effect on glycogen synthase at the earliest point of identification of developing diabetes. The normal monkeys (n = 11) had a greater insulin-mediated change in glycogen synthase-independent activity compared with the hyperinsulinemic (n = 8) (P < 0.05) and diabetic (n = 8) (P < 0.01) monkeys. Compared with normal monkeys, the diabetic monkeys had lower basal and insulin-stimulated total glycogen synthase activity (P < 0.05). Monkeys with normal beta-cell responsiveness to intravenous glucose had greater insulin-mediated change in glycogen synthase fractional velocity compared with those with exaggerated (P < 0.01) or absent beta-cell responses to glucose (P < 0.05). We conclude that an alteration in insulin action on glycogen synthase is present as early as beta-cell hyperresponsiveness, one of the earliest detected abnormalities in the progression toward diabetes.

Animals↗