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At least 703 records · Page 39Linked to original sources
PubMed1995

Modulation of calcium currents by G-proteins and adenosine receptors in myenteric neurones cultured from adult guinea-pig small intestine.

1. Whole-cell patch clamp methods were used to analyse voltage-dependent calcium currents in cultured myenteric neurones enzymatically isolated from adult guinea-pig small intestine. 2. Activation of G-proteins by intracellular administration of GTP-gamma-S (100-200 microM in pipette) decreased the amplitude of high voltage activated Ca2+ current (ICa) by more than 50%. Residual ICa was activated more slowly and was non-inactivating during 500 ms test pulses when GTP-gamma-S was included in the pipette solution. 3. Inclusion of 500 microM GDP-beta-S in the patch pipettes increased the amplitude of ICa by over 30% without altering the voltage-dependency. 4. Extracellular application of 2-chloroadenosine suppressed ICa dose-dependently by reducing both transient and sustained components of the current. 5. Pretreatment of the neurones with cholera toxin or forskolin did not alter the actions of GTP-gamma-S or GDP-beta-S or 2-chloroadenosine. 6. The results suggest that high threshold calcium channels in myenteric neurones are influenced by G-proteins and that the inhibitory action of 2-chloroadenosine on ICa involves G-protein coupling of the adenosine receptors to the Ca2+ channel.

Adenosine↗
PubMed1996

Effect of membrane hyperpolarization induced by a K+ channel opener on histamine-induced Ca2+ mobilization in rabbit arterial smooth muscle.

1. The role of membrane hyperpolarization on agonist-induced contraction was investigated in intact and alpha-toxin-skinned smooth muscles of rabbit mesenteric artery by use of the ATP-sensitive K+ channel opener, (-)-(3S,4R)-4-(N-acetyl-N-hydroxyamino)-6-cyano-3,4-dihydro-2,2- dimethyl-2H-1-benzopyran-3-ol (Y-26763), and either histamine (Hist) or noradrenaline (NA). 2. Hist (3 microM) and NA (10 microM) both produced a phasic, followed by a tonic increase in intracellular Ca2+ concentration ([Ca2+]i) and force. Y-26763 (10 microM) potently inhibited the NA-induced phasic and tonic increase in [Ca2+]i and force. In contrast, Y-26763 attenuated the Hist-induced phasic increase in [Ca2+]i and force but had almost no effect on the tonic response. However, ryanodine-treatment of muscles in order to inhibit the function of intracellular Ca2+ storage sites altered the action of Y-26763 which now attenuated the Hist-induced tonic increase in [Ca2+]i and force in a concentration-dependent manner (at concentrations > 1 microM). Glibenclamide (10 microM) attenuated the inhibitory action of Y-26763. 3. Hist (3 microM) depolarized the smooth muscle cells to the same extent as NA (10 microM). In the absence of either agonist, Y-26763 (over 30 nM) hyperpolarized the membrane and glibenclamide inhibited this hyperpolarization. Y-26763 (10 microM) almost abolished the NA-induced membrane depolarization, but only slightly attenuated the Hist-induced membrane depolarization in which the delta (delta) value (the difference before and after application of Hist) was not modified by any concentration of Y-26763. In ryanodine-treated smooth muscle cells, Y-26763 hyperpolarized the membrane and potently inhibited the membrane depolarization induced by Hist. 4. In ryanodine-treated muscle, Y-26763 had no measurable effect on the Hist-induced [Ca2+]i-force relationship. Y-26763 also had no apparent effect on the myofilament Ca(2+)-sensitivity in the presence of Hist in alpha-toxin-skinned smooth muscles. 5. It is concluded that the membrane hyperpolarization induced by Y-26763 may not be enough to inhibit the Hist-activated Ca2+ influx. It is also suggested that Hist prevents the membrane hyperpolarization induced by Y-26763, activating an unknown mechanism which is thought to depend on the function of intracellular Ca2+ storage sites.

Animals↗
PubMed2004

NO pain: potential roles of nitric oxide in neuropathic pain.

The disabling human syndrome of "neuropathic pain" is an intractable complication of peripheral nerve injury or degeneration. A complex interaction between injured peripheral axons, sensory neurons and central nervous system signaling is thought to account for it. In this brief review, we present evidence that the free radical signaling molecule, nitric oxide (NO) may act at several levels of the nervous system during the development of experimental neuropathic pain. For example, NO may directly influence injured axons in the periphery, may indirectly influence pain by its role in the process of Wallerian degeneration, and may signal in the dorsal horn of the spinal cord. While it is premature to argue for therapeutic approaches that alter NO actions, it may be an important player in the cascade of events that generate neuropathic pain.

Journal Article↗
PubMed1989

Bovine pineal tripeptide threonylseryllysine retards puberty in female rats.

When injected into rodents, the bovine pineal tripeptide threonylseryllysine (TSL) elicits diverse antireproductive effects in a number of animal models. Extensive studies of its effects on pubertal development have not been carried out, however. In the present study, 1.0 microgram of T-S-L was administered daily to female Charles River CD rats throughout the peripubertal period, and effects on vaginal opening time, ovarian histology, and serum luteinizing hormone (LH) levels were observed. Since TSL is known to alter the action of luteinizing hormone releasing hormone (LHRH), it was postulated that this antireproductive tripeptide would delay the time of vaginal opening associated with first ovulation. Two hundred eighty-seven weanling females were housed at 22 degrees C under a 14L:10D photoperiod. They were divided into three groups for daily intraperitonal injections of either saline (SAL), 1.0 micrograms TSL, or 5.0 micrograms melatonin (aMT) beginning on the 23rd day of life. Subgroups of nine to ten rats from each treatment group were sacrificed on days 28, 30, 32, 33, 34, 35, 36, 37, 38, and 40. Although the body weights of all animals increased significantly during the course of the study, no significant differences were observed in this parameter among rats treated with saline, aMT, or TSL. Vaginal opening time was significantly delayed by TSL between days 32 and 40, and uterine weights were significantly lower in this group. Prepubertal increases in serum levels of LH were also significantly reduced. At the dose utilized, aMT was without significant effects on these parameters.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Effect of tubulozole, a new synthetic microtubule inhibitor, on the induction of casein gene expression by prolactin.

Colchicine and related drugs are known to inhibit milk secretion. They are also able to prevent stimulation of casein and DNA synthesis by prolactin in the mammary gland. The present report reports data obtained with tubulozole, a new antimitotic drug. Tubulozole C added to culture medium of isolated rabbit epithelial mammary cells strongly inhibited their multiplication. Simultaneously, at a concentration of 1 microM, it prevented almost completely the induction of beta-casein mRNA. Induced cells were rapidly deinduced by addition of the drug to the medium. A similar inhibition was observed when the induction was obtained with prolactin alone or with its two stimulators insulin and glucocorticoids. Tubulozole T, an isomer of tubulozole C which is known to be ineffective in disrupting microtubules, did not alter prolactin actions. These data and those obtained with other tubulin-binding drugs strongly suggest that the integrity of microtubules is required for prolactin to deliver its message to the mammary cell.

Animals↗
PubMed2007

Maternal taurine supplementation in the late pregnant rat stimulates postnatal growth and induces obesity and insulin resistance in adult offspring.

An adequate supply of taurine during fetal life is important for normal beta-cell development and insulin action. An altered availability of taurine may programme glucose metabolism in utero and result in type 2 diabetes in adult age. We examined whether maternal taurine supplementation in late pregnant rats affects postnatal growth, adult body composition, insulin sensitivity and endogenous insulin secretion in intrauterine growth restricted (IUGR) and normal offspring. Uterine artery ligation or sham operations were performed on gestational day (GD) 19. Taurine supplementation was given to half of the dams from GD 18 until term, resulting in four groups of offspring: sham (n = 22), sham/taurine (n = 22), IUGR (n = 22) and IUGR/taurine (n = 24). The offspring were studied at 12 weeks of age. In offspring with normal birth weight, fetal taurine supplementation markedly stimulated postnatal growth. In sham/taurine females, fat depots, plasma free fatty acid and leptin concentrations were increased, and insulin sensitivity was reduced. Insulin sensitivity was unaltered in IUGR and IUGR/taurine offspring. However, whereas IUGR offspring showed little catch-up growth, 50% of IUGR/taurine animals displayed complete catch-up at 12 weeks of age, and these animals had increased fat depots and reduced insulin sensitivity. In conclusion, taurine supplementation in late gestation resulted in accelerated postnatal growth, which was associated with adult obesity and insulin resistance in both IUGR and normal offspring. This effect was particularly evident in females. These data suggest that fetal taurine availability is an important determinant for postnatal growth, insulin sensitivity and fat accumulation.

Adipose Tissue↗
PubMed2002

Modulation of rod photoreceptor potassium Kx current by divalent cations.

Similarities between photoreceptor Kx channels and EAG and KCNQ channels suggest that the Kx channel may be related to one or both of these families of potassium channels. To provide a basis for further comparison of these channels, as well as to reveal the role of zinc (endogenously present in photoreceptors) in Kx channel modulation, we studied the effects of divalent cations on activation and kinetic properties of the noninactivating potassium current, I(Kx), in salamander rod photoreceptors. We found that divalent cations slowed the activation of I(Kx) and shifted its activation curve to positive potentials, effects attributable to surface charge screening. The effect of zinc on I(Kx) kinetics was considerably stronger than that expected from the activation curve shift alone. None of the divalent ions studied changed the monoexponential nature of I(Kx) activation. A simple model of a rod photoreceptor was created using NEURON software. In the model, zinc accelerated and sharpened the light response, broadening the frequency response of rod photoreceptors. Our results show that although the overall effects of divalent cations are in part due to surface charge screening effects, zinc also induced a specific change in I(Kx) activation kinetics, and this action profoundly alters rod response properties.

Ambystoma↗
PubMed2006

Mefloquine enhances nigral gamma-aminobutyric acid release via inhibition of cholinesterase.

Mefloquine, a widely used antimalarial drug, has many neuropsychiatric effects. Although the mechanisms underlying these side effects remain unclear, recent studies show that mefloquine enhances spontaneous transmitter release and inhibits cholinesterases. In this study, we examined the effect of mefloquine on GABA receptor-mediated, spontaneous inhibitory postsynaptic currents (sIPSCs) of dopaminergic neurons, mechanically dissociated from the substantia nigra pars compacta of rats aged 6 to 17 postnatal days. Mefloquine (0.1-10 microM) robustly and reversibly increased the frequency of sIPSCs with an EC50 of 1.3 microM. Mefloquine also enhanced the frequency of miniature inhibitory postsynaptic currents in the presence of tetrodotoxin but without changing their mean amplitude. This suggests that mefloquine acts presynaptically to increase GABA release. Mefloquine-induced enhancement of sIPSCs was significantly attenuated in medium containing low Ca2+ (0.5 mM) or following pretreatment with 1,2-bis (2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetrakis(acetoxymethyl ester (30 microM), a membrane-permeable Ca2+ chelator. In contrast, 100 microM Cd2+ did not alter the action of mefloquine. This suggests that mefloquine-induced facilitation of GABA release depends on extracellular and intraterminal Ca2+ but not on voltage-gated Ca2+ channels. Mefloquine-induced enhancement of sIPSCs was significantly attenuated in the presence of the anticholinesterase agent physostigmine or blockers of non-alpha7 nicotinic acetylcholine receptors. Taken together, these data suggest that mefloquine enhances GABA release through its inhibition of cholinesterase. This allows accumulation of endogenously released acetylcholine, which activates neuronal nicotinic receptors on GABAergic nerve terminals. The resultant increase of Ca2+ entry into these terminals enhances vesicular release of GABA. This action may contribute to the neurobehavioral effects of mefloquine.

Animals↗
PubMed2004

Identification of amino acid residues in the insect sodium channel critical for pyrethroid binding.

The voltage-gated sodium channel is the primary target site of pyrethroids, which constitute a major class of insecticides used worldwide. Pyrethroids prolong the opening of sodium channels by inhibiting deactivation and inactivation. Despite numerous attempts to characterize pyrethroid binding to sodium channels in the past several decades, the molecular determinants of the pyrethroid binding site on the sodium channel remain elusive. Here, we show that an F-to-I substitution at 1519 (F1519I) in segment 6 of domain III (IIIS6) abolished the sensitivity of the cockroach sodium channel expressed in Xenopus laevis oocytes to all eight structurally diverse pyrethroids examined, including permethrin and deltamethrin. In contrast, substitution by tyrosine or tryptophan reduced the channel sensitivity to deltamethrin only by 3- to 10-fold, indicating that an aromatic residue at this position is critical for the interaction of pyrethroids with sodium channels. The F1519I mutation, however, did not alter the action of two other classes of sodium channel toxins, batrachotoxin (a site 2 toxin) and Lqhalpha-IT (a site 3 toxin). Schild analysis using competitive interaction of pyrethroid-stereospecific isomers demonstrated that the F1519W mutation and a previously known pyrethroid-resistance mutation, L993F in IIS6, reduced the binding affinity of 1S-cis-permethrin, an inactive isomer that shares the same binding site with the active isomer 1R-cis-permethrin. Our results provide the first direct proof that Leu993 and Phe1519 are part of the pyrethroid receptor site on an insect sodium channel.

Amino Acid Substitution↗
PubMed1973

Further studies on the influence of steroids on viral infection in mice.

Certain steroids have been reported to enhance experimental viral infections, whereas others have little or no effect. Interference with the interferon system has been suggested as a possible mechanism for the viral infection-enhancing (VIE) activity of hormones. In the present study, steroids (prednisolone, progesterone, testosterone) which had no effect on MM virus infection demonstrated VIE activity against Mayaro virus infection. It is suggested that the VIE activity of a hormone may be dependent on the viral agent used for challenge. Data are also presented which suggest that, in addition to interference with the interferon system, the VIE activity of steroid hormones may be the result of at least two other actions: (i) alteration of cell membranes; (ii) stimulation of initial viral replication.

Animals↗
PubMed1975

dnaB gene of Escherichia coli K-12 affects superinfection inhibition between F' plasmids.

F' Escherichia coli K-12 strains bearing the chromosomal mutation dnaB43 offer significantly less resistance to the conjugational introduction of a second F' plasmid than do nonmutant strains. Both the entry exclusion and incompatibility components of superinfection inhibition are altered. This action of dnaB43 occurs regardless of the presence of a recA-minus mutation in matings in liquid cultures and on membrane filters and is not limited to a particular set of F' plasmids. These effects are co-transducible by phage P1 with the temperature sensitivity conferred by dnaB43. The effects also occur with a strain carrying dnaB107. In the double F' strains that arise, the two plasmids exist as units autonomous of one another and the chromosome.

Chromosomes, Bacterial↗
PubMed2004

The binding of histone deacetylases and the integrity of zinc finger-like motifs of the E7 protein are essential for the life cycle of human papillomavirus type 31.

The E7 oncoprotein of high-risk human papillomaviruses (HPVs) binds to and alters the action of cell cycle regulatory proteins such as members of the retinoblastoma (Rb) family of proteins as well as the histone deacetylases (HDACs). To examine the significance of the binding of E7 to HDACs in the viral life cycle, a mutational analysis of the E7 open reading frame was performed in the context of the complete HPV type 31 (HPV-31) genome. Human foreskin keratinocytes were transfected with wild-type HPV-31 genomes or HPV-31 genomes containing mutations in HDAC binding sequences as well as in the C-terminal zinc finger-like domain, and stable cell lines were isolated. All mutant genomes, except those with E7 mutations in the HDAC binding site, were found to be stably maintained extrachromosomally at an early passage following transfection. Upon further passage in culture, genomes containing mutations to the Rb binding domain as well as the zinc finger-like region quickly lost the ability to maintain episomal genomes. Genomes containing mutations abolishing E7 binding to HDACs or to Rb or mutations to the zinc finger-like motifs failed to extend the life span of transfected keratinocytes and caused cells to arrest at the same time as the untransfected keratinocytes. When induced to differentiate by suspension in methylcellulose, cells maintaining genomes with mutations in the Rb binding domain or the zinc finger-like motifs were impaired in their abilities to activate late viral functions. This study demonstrates that the interaction of E7 with HDACs and the integrity of the zinc finger-like motifs are essential for extending the life span of keratinocytes and for stable maintenance of viral genomes.

Binding Sites↗
PubMed1989

Pathogenesis and immunity in murine salmonellosis.

Salmonella is traditionally described as a facultative intracellular parasite, and host macrophages are regarded as the primary effector cells in both native and acquired immunity in mouse typhoid. This concept has not been unanimously accepted in the literature. Based on cell culture experiments and electron microscopic examinations of infected tissues, we observed that virulent Salmonella typhimurium is killed within polymorphs and macrophages of guinea pigs and mice. In a systemic disease, the organism propagates primarily in the extracellular locations of sinusoids and tissue lesions and within hepatocytes. Hence, it is more likely to be an extracellular pathogen and its virulence is directly related to its antiphagocytic property. The conspicuous absence of macrophages in the primary lesions of murine salmonellosis disputes the likelihood of their significant role in native resistance to the disease. Acquired cellular immunity is expressed as an enhanced antibacterial activity of macrophages facilitated by cytophilic antibodies rather than as an altered antibacterial action of immune macrophages. It is proposed that acquired immunity in murine salmonellosis is a synergistic manifestation of the innate capacity of polymorphs and macrophages to destroy ingested salmonellae, the activated antibacterial functions of macrophages mediated by cytophilic antibodies, the opsonic and agglutinating actions of antiserum, and the accelerated inflammation associated with delayed hypersensitivity to bacterial antigens. Unlike live attenuated vaccines, nonviable vaccines offer a significant, though not a solid, protection against subsequent challenges.

Animals↗
PubMed1995

Clinical ethics committee.

An informal clinical ethics committee was set up to advise on ethical problems in prenatal diagnosis in Leeds. It was used twice in six months but was not called on again in the subsequent year, and we describe this experience. In North America similar committees are often used to advise on clinical moral dilemmas, and we review the published evidence from there and discuss some of the advantages and problems. Our committee's advice may have altered clinicians' actions considerably, but perhaps doctors in Britain are not yet ready to surrender this aspect of clinical autonomy.

Abortion, Induced↗
PubMed1978

Effect of the external concentrations of potassium and sodium on the release of (--)-[3H]noradrenaline from the adrenergic nerves of the rat vas deferens.

The effect of the external concentrations of sodium and potassium on the nerve-induced release of (--)-[3H]noradrenaline from the adrenergic nerves of the rat vas deferens has been investigated. Increasing the external potassium concentration above 5 mM decreased the amount of noradrenaline released, while reducing the external potassium concentration below 5 mM had no significant effect on the induced release of noradrenaline. Decreasing the external sodium concentration below 75 mM progressively decreased the release of noradrenaline. It is concluded that the amplitude of the action potential is optimum for release at the normal resting membrane potential, and only decreasing the amplitude of the action potential alters the amount of transmitter released per nerve impulse.

Animals↗
PubMed1979

Electrical activity of rat myocardial cells in culture: La3+-induced alterations.

Intracellular analysis of neonatal rat (1-2 day old) ventricular cells in culture shows that contracting myocardial cells exhibit an array of different patterns of spontaneous electrical activity. Resting membrane potentials varied between -40 mV and -98 mV. Our results indicate that some cultured cells show resting membrane potentials, overshoot, and total spike amplitude values comparable to those normally found in neonatal and adult rat heart. A low ratio of pacemaker (40%) to nonpacemaker cells (60%) and low incidence of hyperpolarizing after-potentials (35%) were found. La3+ application (0.1-4.0 mM) induced progressive cell depolarization, concomitant diminution in discharge frequency, and marked alteration of action potential configuration. A parallel decline in frequency and strength of rhythmic contractions was observed. Abolition of contractility occurred only in association with depolarization and complete disappearance of action potentials. Recovery of electrical and contractile activity followed medium replacement. Our results indicate that La3+ does not act as a specific excitation-contraction (E-C) uncoupler in the cultured cells but has multiple effects upon their normal electrical characteristics.

Action Potentials↗
PubMed2004

Short-term resistance to diet-induced obesity in A/J mice is not associated with regulation of hypothalamic neuropeptides.

To investigate the mechanisms underlying long-term resistance of the A/J mouse strain to diet-induced obesity, we studied, over a period of 4 wk, the expression of uncoupling proteins in brown adipose tissue and the expression of hypothalamic neuropeptides known to regulate energy homeostasis and then used microarray analysis to identify other potentially important hypothalamic peptides. Despite increased caloric intake after 2 days of high-fat feeding, body weights of A/J mice remained stable. On and after 1 wk of high-fat feeding, A/J mice adjusted their food intake to consume the same amount of calories as mice fed a low-fat diet; thus their body weight and insulin, corticosterone, free fatty acid, and glucose levels remained unchanged for 4 wk. We found no changes in hypothalamic expression of several orexigenic and/or anorexigenic neuropeptides known to play an important role in energy homeostasis for the duration of the study. Uncoupling protein-2 mRNA expression in brown adipose tissue, however, was significantly upregulated after 2 days of high-fat feeding and tended to remain elevated for the duration of the 4-wk study. Gene array analysis revealed that several genes are up- or downregulated in response to 2 days and 1 wk of high-fat feeding. Real-time PCR analysis confirmed that expression of the hypothalamic IL-1 pathway (IL-1beta, IL-1 type 1 and 2 receptors, and PPM1b/PP2C-beta, a molecule that has been implicated in the inhibition of transforming growth factor-beta-activated kinase-1-mediated IL-1 action) is altered after 2 days, but not 1 wk, of high-fat feeding. The role of additional molecules discovered by microarray analysis needs to be further explored in the future.

Adipose Tissue, Brown↗
PubMed1977

Effect of serotonin treatment on intestinal transport in the rabbit.

The hormone serotonin (5-hydroxytryptamine) has been implicated as the cause of the diarrhea seen in many patients with the carcinoid syndrome. To determine whether serotonin is an intestinal secretagogue, the effect of serotonin on intestinal water and electrolyte transport was evaluated in the rabbit. Two weeks of daily subcutaneous injection of serotonin suspended in oil resulted in a blood serotonin level elevated to twice that of controls. Intestinal transport was studied in vivo by a perfusion technique. Serotonin treatment resulted in ileal secretion and decreased mid-jejunal absorption of water and electrolytes but did not effect water absorption in the proximal jejunum or colon. Intestinal absorption of D-glucose and the amino acid L-tryptophan and glucose-dependent water and electrolyte absorption were normal in serotonin-treated animals. Serotonin-induced ileal secretion was reversed by methysergide, a peripheral antagonist of serotonin action. No alterations in intestinal histology or permeability occurred in serotonin-treated animals. Serotonin-induced intestinal secretion was not associated with alterations in the activities of intestinal mucosal adenylate cyclase, cyclic nucleotide phosphodiesterase, or Na-K-ATPase.

Animals↗