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PubMed1985

Subcellular translocation of glucose transporters: role in insulin action and its perturbation in altered metabolic states.

In this article we have described the hypothesis that insulin stimulates glucose transport through glucose transporter translocation from an intracellular pool to the plasma membrane. In addition, we have shown that changes in the numbers and subcellular distributions of glucose transporters correlate with alterations in insulin-stimulated glucose transport activity in several experimental models of insulin resistance and hyperresponsiveness. However, in experiments with counterregulatory hormones and with hyperresponsive states induced by nutritional repletion following deprivation, changes in insulin responsiveness cannot be fully explained by such alterations in the numbers and/or subcellular distribution of glucose transporters. Thus, evidence has been presented for changes in glucose transporter intrinsic activity that both inhibit and augment insulin-stimulated glucose transport rates. Finally, we have discussed data suggesting that the translocation process is applicable to human tissue and that significant changes in adipose cell glucose transport activity have been correlated with total glucose disposal in various metabolic states in humans. Determining the physiologic factors involved in modulating these events at the cellular level is an important area for further investigation.

Adipose Tissue↗
PubMedDate not supplied

Insulin resistance and endothelial dysfunction: the road map to cardiovascular diseases.

Cardiovascular disease affects approximately 60% of the adult population over the age of 65 and represents the number one cause of death in the United States. Coronary atherosclerosis is responsible for the vast majority of the cardiovascular events, and a number of cardiovascular risk factors have been identified. In recent years, it has become clear that insulin resistance and endothelial dysfunction play a central role in the pathogenesis of atherosclerosis. Much evidence supports the presence of insulin resistance as the fundamental pathophysiologic disturbance responsible for the cluster of metabolic and cardiovascular disorders, known collectively as the metabolic syndrome. Endothelial dysfunction is an important component of the metabolic or insulin resistance syndrome and this is demonstrated by inadequate vasodilation and/or paradoxical vasoconstriction in coronary and peripheral arteries in response to stimuli that release nitric oxide (NO). Deficiency of endothelial-derived NO is believed to be the primary defect that links insulin resistance and endothelial dysfunction. NO deficiency results from decreased synthesis and/or release, in combination with exaggerated consumption in tissues by high levels of reactive oxygen (ROS) and nitrogen (RNS) species, which are produced by cellular disturbances in glucose and lipid metabolism. Endothelial dysfunction contributes to impaired insulin action, by altering the transcapillary passage of insulin to target tissues. Reduced expansion of the capillary network, with attenuation of microcirculatory blood flow to metabolically active tissues, contributes to the impairment of insulin-stimulated glucose and lipid metabolism. This establishes a reverberating negative feedback cycle in which progressive endothelial dysfunction and disturbances in glucose and lipid metabolism develop secondary to the insulin resistance. Vascular damage, which results from lipid deposition and oxidative stress to the vessel wall, triggers an inflammatory reaction, and the release of chemoattractants and cytokines worsens the insulin resistance and endothelial dysfunction.From the clinical standpoint, much experimental evidence supports the concept that therapies that improve insulin resistance and endothelial dysfunction reduce cardiovascular morbidity and mortality. Moreover, interventional strategies that reduce insulin resistance ameliorate endothelial dysfunction, while interventions that improve tissue sensitivity to insulin enhance vascular endothelial function. There is general agreement that aggressive therapy aimed simultaneously at improving insulin-mediated glucose/lipid metabolism and endothelial dysfunction represents an important strategy in preventing/delaying the appearance of atherosclerosis. Interventions that 1 correct carbohydrate and lipid metabolism, 2 improve insulin resistance, 3 reduce blood pressure and restore vascular reactivity, and 4 attenuate procoagulant and inflammatory responses in adults with a high risk of developing cardiovascular disease reduce cardiovascular morbidity and mortality. Whether these benefits hold when the same prevention strategies are applied to younger, high-risk individuals remains to be determined.

Aged↗
PubMed1993

Possible autocrine/paracrine actions of insulin-like growth factors during embryonic development: expression and action of IGFs in undifferentiated P19 cells.

The insulin-like growth factors I and II (IGF I and II) and their cell surface receptors are expressed in the mammalian embryo and may function as autocrine or paracrine growth factors during early development. P19 embryonic carcinoma cells, derived from a 7.5 day mouse embryo, were used as a model for a functional study of the IGF system in post-implantation embryogenesis. Undifferentiated P19 cells synthesized IGF I and II, the type I and II IGF receptors, and IGF binding proteins (IGF BP2, IGF BP3, and IGF BP4). P19 cells showed an increase in thymidine incorporation of 150% of control with a 4 hour incubation of IGF I (10 ng/ml) or IGF II (100 ng/ml) and an increase in cell viability compared to control cells during 24 hours of serum starvation. In both experiments IGF I was more potent than IGF II. Endogenous concentrations of IGF I and II in conditioned media were low compared to the doses of exogenous IGFs required for biologic effect, but nonetheless contributed significantly to baseline DNA synthesis, as demonstrated by inhibition of IGF actions with specific antibodies. Cell surface associated IGF BPs bound more radiolabeled IGF than IGF receptors, as determined by binding studies and affinity cross-linking. IGF I and IGF II appeared to regulate production of IGF BP2, suggesting that the IGFs may regulate their own actions by altering the abundance of their binding proteins.

Animals↗
PubMed2003

Proteoglycans are potent modulators of the biological responses of eosinophils to chemokines.

Chemokines play critical roles in governing the recruitment and activation of eosinophils at sites of allergic inflammation, particularly the asthmatic lung. However, we know little of how chemokine function is regulated post-translationally. Proteoglycans, consisting of a core protein and glycosaminoglycan (GAG) side chains, are cell surface molecules and components of the extracellular matrix that are able to bind chemokines, whilst heparin is a GAG with therapeutic value in asthma. We examined whether soluble GAG could alter the actions of chemokines in assays of eosinophil activation. Heparin inhibited intracellular calcium flux, respiratory burst and chemotactic responses of eosinophils to CCL11, but not to the chemoattractant C5a, and inhibited binding of CCL11 to CCR3. Heparin also inhibited eosinophil stimulation by CCL11, CCL24, CCL7, CCL13 and CCL5 to differing degrees, which broadly correlated with their relative affinities for heparin. Heparan sulfate and dermatan sulfate, but not chondroitin sulfate, also inhibited the actions of CCL11 and CCL13 in assays of cellular shape change and chemotaxis. Following treatment with the sulfation inhibitor chlorate or proteoglycanases, no inhibition of CCL11-induced activity was observed using either eosinophils or a CCR3-expressing transfectant cell line. This suggests that cell surface proteoglycans are not necessary for signaling via CCR3. However, the GAG context in which chemokines are expressed is likely to represent an important level of regulation of allergic inflammation.

Calcium↗
PubMedDate not supplied

Circulatory effects of diazepam in heart disease.

Diazepam was administered to ten patients with heart disease during diagnostic cardiac catheterization, in order to determine whether or not this drug's circulatory actions could alter results obtained during the procedure. Diazepam produced no change in baroreceptor sensitivity; however, there was a significant rise in heart rate and a significant fall in aortic systolic and left ventricular end-diastolic pressures. Cardiac index was unchanged, whereas stroke volume fell significantly. Systemic vascular resistance and peak left ventricular dp/dt did not change throughout the study. Clinical response in terms of sedation was judged to be satisfactory in eight patients, and no adverse effect on respiration was noted. Diazepam has little effect on basal circulatory and respiratory parameters when changes in these parameters are averaged for our ten patients. However, substantial changes in hemodynamic parameters did occur in several individuals, and such alteration in circulatory function must be considered when this agent is used routinely in patients having diagnostic cardiac catheterization.

Blood Pressure↗
PubMed1989

Regulation of tissue transglutaminase gene expression as a molecular model for retinoid effects on proliferation and differentiation.

Retinoids (structural and functional analogs of vitamin A) are potent antiproliferative agents whose mode of action is poorly understood. It has been suggested that the molecular events that underscore their action involve alterations in gene expression, but no gene has yet been shown to be directly regulated by these molecules. Several years ago, we found that retinoic acid caused an accumulation of the enzyme tissue transglutaminase in murine peritoneal macrophages and in human promyelocytic leukemia (HL-60) cells. We now report that this induction is caused by an increase in the mRNA for this enzyme. Retinoic acid is the only mediator of this induction, since its effects do not depend on the presence of serum proteins. The induction of tissue transglutaminase mRNA is not due to an increase in its stability but to an increase in the relative transcription rate of its gene. We present a model to correlate the retinoid induction of tissue transglutaminase with retinoid effects on cellular growth and differentiation.

Animals↗
PubMed2006

Biological activity of the functional epitope of ciguatoxin fragment AB on the neuroblastoma sodium channel in tissue culture.

It is well established that the targeted receptor for ciguatoxin (CTX) in mammalian tissues is the sodium channel, affecting the influx of sodium into cells and altering the action potential and function of the cell. Since the syntheses of fragments of CTX has become available, our focus has been on the receptor functions of the west sphere AB and east sphere JKLM fragments using the neuroblastoma cell assay, guinea pig atrium assay, and the membrane immunobead assay (MIA). The data presented here suggest that the west sphere AB of the ciguatoxin molecule is the active portion and is responsible for the activation of the sodium channels.

Animals↗
PubMed1984

Metabolic epidemiology of prostatic cancer.

A review of the epidemiological evidence indicates that dietary fat very likely has an etiologic role in the development of prostatic carcinoma. While this effect may be mediated by way of altered hormonal action on the prostate, there is little supporting evidence from assays of plasma or urinary hormones in case-control studies or the investigation of high-risk and low-risk groups. The application of metabolic epidemiology to this problem is most likely to succeed by direct studies of the prostate gland, and the performance of relevant assays on prostatic fluid. Estradiol and estrone levels were found to be higher in prostatic fluid than in serum, whereas for prolactin the reverse was true. Testosterone concentrations were very low in prostatic fluid, perhaps because of the high degree of plasma protein binding. Preliminary data indicated that prostatic fluid estradiol and prolactin levels are elevated in some prostate cancer patients; estrone levels appear to be normal.

Androgens↗
PubMed1994

Stimulation of follistatin production by epidermal growth factor in cultured rat hepatocytes.

Production of follistatin in cultured rat hepatocytes was studied by measuring follistatin release with a protein-binding assay using [125I]activin A. Follistatin was detected in conditioned medium of cultured hepatocytes. Ligand blotting using [125I]activin revealed that follistatin released into the medium consisted of two different forms with molecular weight of approximately 40 K-Da. Epidermal growth factor (EGF) elicited dose-dependent increases in DNA synthesis and follistatin release. Dose-response relationship for EGF-induced follistatin release correlated well with that for EGF-induced DNA synthesis. In EGF-stimulated cells, a marked increase in DNA synthesis occurred after 48 hrs. Similarly, follistatin release was markedly augmented after 48 hrs. Amount of cell-bound follistatin was not changed by the treatment with EGF. These results indicate that cultured hepatocytes synthesize and release follistatin. The activin-follistatin system operates in cultured rat hepatocytes and may modulate DNA synthesis by altering the action of activin A.

Activins↗
PubMed2000

Human chorionic gonadotropin-induced spermiation in Bufo arenarum is not mediated by steroid biosynthesis.

This study employed an in vitro system to identify potential steroidal mediators of spermiation in Bufo arenarum. Testicular fragments were incubated for 2 h at 28 degrees. Spermiation was induced by 10 IU human chorionic gonadotropin (hCG) and the effect of different inhibitors of steroid biosynthesis was analyzed. Cyanoketone (10(-5)-10(-6) M), an inhibitor of 3-oxo-4-ene steroid biosynthesis, did not block hCG-inducing activity even when biosynthesis of 3-oxo-4-ene steroids and its reduced metabolites was inhibited by 95%. Aminogluthetimide at a concentration that inhibited testosterone biosynthesis (10(-4) and 10(-5) M) did not alter hCG actions. Similar results were obtained with spironolactone, an inhibitor of 17alpha-hydroxylase/17-20 lyase activity. No spermiation-inducing activity was found with different steroids (progesterone, 17-hydroxypregnenolone, 17, 20alpha/beta-dihydroxy-4-pregnene-3-one, estradiol, testosterone, etc.). It is concluded that spermiation induced by hCG is not steroid mediated in B. arenarum.

3-Hydroxysteroid Dehydrogenases↗
PubMed1999

Lysophosphatidylcholine, a metabolite which accumulates early in myocardium during ischemia, reduces gap junctional coupling in cardiac cells.

Lysophosphatidylcholine (LPC) is a metabolite that accumulates rapidly during cardiac ischemia in animal and human hearts. LPC induces electrophysiological changes including action potential alterations and cardiac arrhythmias. Since there is increasing evidence that disrupted cell coupling can contribute to the generation of cardiac arrhythmias under ischemic conditions, this study was designed to assess the effects of LPC on gap junction coupling between cardiac cell pairs using the dual whole-cell voltage-clamp technique. To measure gap junction resistance (r(j)), both cells of a pair were first clamped to a common holding potential and then, one cell was stepped to various voltages (20 mV steps from -50 to +50 mV). Junctional conductance (g(j)=1/r(j)) was derived from the junctional current recorded in the non-stimulated cell divided by the trans-junctional voltage. Extracellular medium was set to minimize non-junctional membrane conductance. LPC induced a decrease in g(j)after about 3, 8 and 12 min superfusion, respectively, for 50, 10 and 5 micromol/l. When LPC was continuously superfused (no washout), no steady-state was observed but a complete uncoupling (i.e. when the junctional resistance is infinitely high) after a delay of 7.3+/-1.2 min, 11.3+/-6.0 min, 15. 2+/-5.5 min and 23.3+/-6.0 min, respectively, for LPC 50 (n=5), 20 (n=4), 10 (n=5) and 5 (n=3) micromol/l. Mg(2+(out))at a concentration of 5 mmol/l exerted protective effects against LPC-induced uncoupling. In conclusion, LPC, at concentrations measured in situ during cardiac ischemia, is a potent inhibitor of gap junction communications between cardiac cells. Impaired junctional communications due to LPC accumulation early during ischemia could decrease electrical conduction and contribute to the genesis of malignant arrhythmias.

Animals↗
PubMedDate not supplied

The cyclic AMP system and Drosophila learning.

The cyclic AMP (cAMP) system plays a critical role in olfactory learning in the fruit fly, Drosophila melanogaster, as evidenced by the following: [1] The dunce gene encodes a form of cAMP phosphodiesterase (PDE). Flies carrying mutations at this gene show reduced PDE activity, high cAMP levels, and deficits in olfactory learning and memory [2]. The rutabaga gene encodes one type of adenylyl cyclase (AC) similar in properties to the Type I AC characterized from vertebrate brain. This enzyme is activated by G-protein and Ca++ and has been postulated to be a molecular coincidence detector, capable of integrating information from two independent sources such as the conditioned stimulus (CS) and the unconditioned stimulus (US) delivered to animals during Pavlovian conditioning. Rutabaga mutant flies are deficient in AC activity and show behavioral defects similar to those exhibited by dunce mutants [3]. Flies carrying mutations in the gene (DC0) that encodes the catalytic subunit of protein kinase A (PKA), the major mediator of cAMP actions, show alterations in learning performance and a loss in PKA activity. All three genes are expressed preferentially in mushroom bodies, neuroanatomical sites that mediate olfactory learning. Interestingly, the PDE and the catalytic subunit of PKA are found primarily in axonal and dendritic compartments of the mushroom body cells, whereas the AC is found primarily in the axonal compartment. The reason for this differential compartmentalization is unclear, although the hypothetical role of AC as coincidence detector would predict that CS and US stimuli are integrated in the axonal compartment. These observations suggest that cAMP is a dominant second messenger utilized by mushroom body cells to modulate their physiology while the animal is learning and consolidating memory. However, many other types of molecules are likely involved in the physiological alterations that occur in these cells during learning, including cell surface proteins, transcription factors, and synaptic proteins.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1995

Calmodulin: effects of cell stimuli and drugs on cellular activation.

The activity, localization and cellular content of CaM can be regulated by drugs, hormones and neurotransmitters. Regulation of physiological responses of CaM can depend upon local Ca(2+)-entry domains in the cells and phosphorylation of CaM target proteins, which would either decrease responsiveness of CaM target enzymes or increase CaM availability for binding to other target proteins. Despite the abundance of CaM in many cells, persistent cellular activation by a variety of substances can lead to an increase in CaM, reflected both in the nucleus and other cellular compartments. Increases in CaM-binding proteins can accompany stimuli-induced increases in CaM. A role for CaM in vesicular or protein transport, cell morphology, secretion and other cytoskeletal processes is emerging through its binding to cytoskeletal proteins and myosins in addition to the more often investigated activation of target enzymes. More complete knowledge of the physiological regulation of CaM can lead to a greater understanding of its role in physiological processes and ways to alter its actions through pharmacology.

Amino Acid Sequence↗
PubMed1986

Effects of low-level microwave irradiation on amphetamine hyperthermia are blockable by naloxone and classically conditionable.

In a series of experiments, we investigated the effects of pulsed low-level microwave irradiation on amphetamine-induced hyperthermia in the rat. Rats were irradiated in a 2,450-MHz cylindrical waveguide exposure system at 1 mW/cm2, 2 mus pulses, 500 pps, average SAR of 0.6 W/kg. Acute (45 min) exposure to microwaves attenuated amphetamine-induced hyperthermia. This effect was blocked by pretreatment of the animals with the narcotic antagonist naloxone. In another experiment, rats were subjected to ten daily sessions of microwave exposure (45 min/session). On day 11, amphetamine-induced hyperthermia was studied in the animals immediately after a session of either microwave or sham exposure. Similar to the acute effect, amphetamine-induced hyperthermia was attenuated in rats irradiated with microwaves (unconditioned effect). In the sham-irradiated animals we observed a potentiation of the amphetamine-induced hyperthermia, which was a conditioned effect of microwaves. Thus, the conditioned effect (potentiation) was opposite in direction to the unconditioned effect (attenuation). No tolerance developed to the unconditioned effect after subchronic exposure. Furthermore, both conditioned and unconditioned effects of microwaves on amphetamine-induced hyperthermia could be blocked by treatment with naloxone. These data suggest that microwave irradiation may activate endogenous opioids, which in turn alter the actions of psychoactive drugs, and the effect of microwaves on drug action can be classically conditioned.

Amphetamine↗
PubMed1992

Phosphorylation of atrial natriuretic factor R1 receptor by serine/threonine protein kinases: evidences for receptor regulation.

The 130 kDa atrial natriuretic factor receptor (ANF-R1) purified from bovine adrenal zona glomerulosa is phosphorylated in vitro by serine/threonine protein kinases such as cAMP-, cGMP-dependent and protein kinase C. This phosphorylation is independent of the presence of ANF (99-126) and there is no detectable intrinsic kinase activity associated with the ANF-R1 receptor or with its activated form. In bovine adrenal zona glomerulosa cells, TPA (phorbol ester) induces a marked inhibition of the ANF-stimulated cGMP accumulation as well as of the membrane ANF-sensitive guanylate cyclase catalytic activity without any change in the binding capacity or affinity for 125I-ANF. However, we have demonstrated a significant 32P incorporation in the ANF-R1 receptor of the TPA-treated cells. The effect of TPA on the zona glomerulosa ANF-R1 receptors was abolished by calphostin C, a specific protein kinase C inhibitor. Altered ANF actions due to blunted response of guanylate cyclase to ANF could be a consequence of the ANF receptor phosphorylation by excessive activity of protein kinase C and might be involved in the pathogenesis of hypertension.

Amino Acid Sequence↗
PubMed1983

Analysis of the anticholinergic and musculotropic effects of desmethylimipramine on the rabbit urinary bladder.

The anticholinergic and musculotropic relaxant properties of desmethylimipramine (DMI) on smooth muscle were investigated utilizing cholinergic radioligand receptor binding and in-vitro muscle bath techniques. Receptor binding studies revealed the direct antimuscarinic potency of DMI to be 1/480th that of atropine. Muscle bath studies characterized discrete antimuscarinic and musculotropic actions. An initial, competitive antimuscarinic action could be separated from a delayed onset, noncompetitive musculotropic action by altering the time between the addition of DMI and the addition of bethanechol to the smooth muscle bath.

Animals↗
PubMed1980

Effects of some alpha-adrenoceptor agonists and antagonists on the guinea-pig ileum.

The purpose of the present study was to further characterize the alpha-adrenoceptors located on parasympathetic fibres. Segments of guinea-pig ileum were stimulated by transmural electrical pulses, and the ensuing contractions, which are due to the release of acetylcholine from postganglionic parasympathetic fibres, were monitored. Clonidine and tramazoline, which are thought to act preferentially on presynaptic alpha-adrenoceptors, reduced the contractions, whereas phenylephrine and methoxamine, postsynaptic alpha-adrenoceptor agonists, were ineffective. Contractions induced by acetylcholine were not changed by clonidine but were abolished by atropine. Yohimbine, piperoxan, phentolamine and the thymoxamine reversed or prevented the inhibitory effect of clonidine. Prazosin and AR-C239 did not antagonize this effect. The inhibitory effect of tramazoline was antagonized by piperoxan but not AR-C239 or by prazosin. Naloxone did not alter the action of clonidine, and piperoxan did not change the inhibitory effect of morphine. In conclusion, these experiments suggest the presence on cholinergic postganglionic fibres of both opiate receptors and alpha-adrenoceptors.. The latter appear to resemble more closely alpha 2-adrenoceptors than alpha 1-adrenoceptors.

Acetylcholine↗