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PubMedDate not supplied

E-1020, a water soluble imidazopyridine, has direct effects on Ca(2+)-dependent force and ATP hydrolysis of canine and bovine cardiac myofilaments.

E-1020 is a cardiotonic agent that acts as a cyclic-AMP phosphodiesterase inhibitor but also may have actions which alter myofilament response to Ca2+. To identify direct actions of E-1020 on cardiac contractile proteins, effects of E-1020 on myofibrillar Ca2+ dependent MgATPase and force generation in chemically skinned fiber bundles were measured. In bovine cardiac myofibrils, E-1020 (100 microM) significantly increased myofilament Ca2+ sensitivity and Ca(2+)-dependent ATPase activity at submaximal pCa values. At pCa 6.75, E-1020 significantly increased ATPase activity in bovine (10-100 microM) and canine (1-100 microM) cardiac myofibrils but had no effect on rat cardiac myofibrils. Moreover, in one population of canine ventricular fiber bundles, E-1020 (0.01-10 microM) significantly increased isometric tension at pCa 6.5 and 6.0, whereas in another population of bundles E-1020 had no effect on tension. In no case was resting (pCa 8.0) or maximal tension (pCa 4.5) increased by E-1020. Measurements of Ca2+ binding to canine ventricular skinned fiber preparations demonstrated that E-1020 does not alter the affinity of myofilament troponin C for Ca2+. We conclude that part of the mechanism by which E-1020 acts as an inotropic agent may involve alterations in the responsiveness of contractile proteins to Ca2+. The lack of effect of E-1020 on some preparations may be dependent on isoform populations of myofilament proteins.

Actin Cytoskeleton↗
PubMed1977

The change of erythrocyte shape following action of different substances altering mg++-dependent ATPase activity (actomyosin-like protein).

It was found that some substances as aspartate, glutamate, atropine, physostigmine, ephedrine, caffeine and theophylline tended to alter the erythrocyte shape in the same concentration in which also the Mg++-dependent ATPase activity had been changed. The employment of various concentrations of barbiturate revealed that changes of the erythrocyte shape were dependent on its concentration. In the present study the relationship between Mg++-dependent ATPase and biconcave erythrocyte shape is discussed.

Adenosine Triphosphatases↗
PubMed1990

The role of altered sodium currents in action potential abnormalities of cultured dorsal root ganglion neurons from trisomy 21 (Down syndrome) human fetuses.

Trisomy 21 (Down syndrome) results in abnormalities in electrical membrane properties of cultured human fetal dorsal root ganglion (DRG) neurons. Action potentials have faster rates of depolarization and repolarization, with decreased spike duration, compared to diploid neurons. In order to analyze the faster depolarization rate observed in trisomic neurons, we examined sodium currents of cultured human fetal DRG neurons from trisomy 21 and control subjects, using the whole-cell patch-clamp technique. The neurons were replated in culture to reduce dendritic spines. Two components of the sodium current were identified: (1) a fast, tetrodotoxin (TTX)-sensitive current; and (2) a slow, TTX-resistant component. The inactivation curves of both current types in trisomic neurons showed a shift of approximately 10 mV towards more depolarized potentials compared to control neurons. Thus, whereas essentially all of the fast sodium channels were inactivated at normal resting potentials in control neurons, approximately 10% of these channels were available for activation in trisomy 21 cells. Furthermore, the fast current showed accelerated activation kinetics in trisomic neurons. The slow sodium current of trisomic neurons showed slower deactivation kinetics than control cells. No differences were observed between trisomic and control neurons in the maximal conductance or current densities of either fast or slow current components. These data indicate that the greater rate of depolarization in trisomy 21 neurons at resting potentials is primarily due to activation of residual fast sodium channels that also have a faster time course of activation.

Action Potentials↗
PubMed1987

myo-inositol action on gerbil intestine: alterations in alkaline phosphatase activity upon phosphatidylinositol depletion and repletion in vivo.

The influence of phosphatidylinositol (PI) on intestinal alkaline phosphatase activity was studied in myo-inositol deficient gerbils. A reduction of membrane PI in intestinal mucosa to 30-40% of the control was produced by feeding female gerbils a myo-inositol-deficient diet containing coconut oil for 2 weeks. As expected, the animals developed typical intestinal lipodystrophy with abnormal fat accumulation. In the PI-depleted animal, intestinal alkaline phosphatase activity was reduced to 20-30% of the control group. The levels of both membranous and soluble enzymes in intestinal mucosa were affected, but there were no changes in liver, kidney and plasma levels. When the lipodystrophic gerbils were given dietary myo-inositol, the complete repletion of intestinal membrane PI to the control level occurred 36 h later, whereas membrane-bound alkaline phosphatase activity in intestine was not restored to the control level until 72 h later. Administration of cycloheximide or actinomycin D did not block this enzyme induction. Lymphatic output of triacylglycerol into the bloodstream was stimulated 10-fold at 18 h of myo-inositol repletion, but there was no parallel increase in the activity of alkaline phosphatase in plasma during this early phase of intestinal recovery. Thus, these data suggest a possible regulatory role of PI in the processing and/or turnover of alkaline phosphatase in vivo, but a negative role of alkaline phosphatase in lipid transport across gerbil intestine.

Alkaline Phosphatase↗
PubMed1997

Electrophysiologic effects of acute myocardial ischemia: a theoretical study of altered cell excitability and action potential duration.

OBJECTIVE: To study the ionic mechanisms of electrophysiologic changes in cell excitability and action potential duration during the acute phase of myocardial ischemia. METHODS: Using an ionic-based theoretical model of the cardiac ventricular cell, the dynamic LRd model, we have simulated the three major component conditions of acute ischemia (elevated [K]o, acidosis and anoxia) at the level of individual ionic currents and ionic concentrations. The conditions were applied individually and in combination to identify ionic mechanisms responsible for reduced excitability at rest potentials, delayed recovery of excitability, and shortened action potential duration. RESULTS: Increased extracellular potassium ([K]o) had the major effect on cell excitability by depolarizing resting membrane potential (Vrest), causing reduction in sodium channel availability. Acidosis caused a [K]o-independent reduction in maximum upstroke velocity, (dVm/dt)max. A transition from sodium-current dominated to calcium-current dominated upstroke occurred, and calcium current alone was able to sustain the upstroke, but only after sodium channels were almost completely (97%) inactivated. Acidic conditions prevented the transition to calcium dominated upstroke by acidic reduction of both sodium and calcium currents. Anoxia, simulated by lowering [ATP]i and activating the APT-dependent potassium current, IK(ATP), was the only process that could decrease action potential duration by more than 50% and reproduce AP shape changes that are observed experimentally. Acidic or anoxic depression of the L-type calcium current could not reproduce the observed action potential shape changes and APD shortening. Delayed recovery of excitability, known as 'post-repolarization refractoriness', was determined by the voltage-dependent kinetics of sodium channel recovery; Vrest depolarization caused by elevated [K]o increased the time constant of (dVm/dt)max recovery from tau = 10.3 ms at [K]o = 4.5 mM to tau = 81.4 ms at [K]o = 12 mM, reflecting major slowing of sodium-channel recovery. Anoxia and acidosis had little affect on tau. CONCLUSIONS: The major conditions of acute ischemia, namely elevated [K]o, acidosis and anoxia, applied at the ionic channel level are sufficient to simulate the major electrical changes associated with ischemia. Depression of membrane excitability and delayed recovery of excitability in the single, unloaded cell are caused by elevated [K]o with additional excitability depression by acidosis. Major changes in action potential duration and shape can only be accounted for by anoxia-dependent opening of IK(ATP).

Acidosis↗
PubMed2001

Glibenclamide's action in the hypothalamus alters peripheral glucose homeostasis.

Bilateral injections of 0.2 nmol of glibenclamide, targeted at the ventromedial hypothalamus of albino rats, significantly impaired recovery of blood glucose levels following insulin-induced hypoglycemia (P=0.0026). Similar injections of 0.2 and 2.0 nmol glibenclamide reduced blood glucose by 23.6 and 40.8 mg%, respectively, in otherwise untreated rats (P<0.01 and P<0.001). Intravenous injection of these doses of the drug did not lower blood glucose. The results support the hypothesis that K(ATP)(+) channels within the hypothalamus serve a counterregulatory function in the maintenance of peripheral glucose levels.

Animals↗
PubMed1999

Can insulin action induce myocardial texture alterations in essential hypertension?

The prevalence of hyperinsulinemia/insulin resistance in hypertensive individuals, as well as the effects of insulin on myocytic and fibroblastic growth, are well known in both epidemiologic and animal models. To check whether there are any links between ultrasonic myocardial texture parameters and insulin level in essential hypertensives, we compared 18 essential hypertensive men (Group 1, H) with 18 age- and gender-matched healthy controls (Group 2, C) (age, 57 +/- 10 years). For all study subjects we performed ambulatory blood pressure monitoring (ABPM); conventional 2-D Doppler echocardiography for the assessment of the left ventricular mass index (LVMi) and function; quantitative analysis of digitized echocardiographic images for evaluation of cyclic variation (CVI) of mean gray level (MGL) at the septum and posterior wall levels; and 75-g 3-h oral glucose tolerance test (OGTT) for analysis of area under glycemic curve (AUGC, g/min/dL) and insulinemic curve (AUIC, mU/min/mL), as well as serum glucose and insulin peaks. Both the daily mean blood pressure (H: 109 +/- 4.6 v C: 94.6 +/- 4.6, P < .0001) and LVMi (adjusted for body surface) (H: 133 +/- 24 v C: 97 +/- 21 g/m2, P < .0001) were significantly higher in hypertensives. Values for AUIC were significantly higher in hypertensives (10.37 +/- 5.53 v 6.33 +/- 5.28), P < .032); CVI was also significantly higher in group C, for both septum (C: 40.2 +/- 16.9 v H: 15.9 +/- 18.1, P < .0001) and posterior wall (C: 44.5 +/- 19.6 v H: 20 +/- 17.5; P < .0001). There was a significant inverse correlation between AUIC and CVI for both septum (r: -0.57, P < .001) and posterior wall (r: -0.50, P < .002). The significantly higher impairment of myocardial ultrasonic texture and the higher level of the AUIC insulinemia in hypertensives, as well as the significant inverse relationship between CVI and hyperinsulinemia, are our major findings. Hyperinsulinemia/insulin resistance could cause an altered collagen/muscular ratio, which could potentially explain, at least in part, the CVI alterations detected in hypertensive patients.

Adolescent↗
PubMed2003

Altered awareness of voluntary action after damage to the parietal cortex.

A central question in the study of human behavior is the origin of willed action. EEG recordings of surface brain activity from human subjects performing a self-initiated movement show that the subjective experience of wanting to move follows, rather than precedes, the 'readiness potential'--an electrophysiological mark of motor preparation. This raises the issue of how conscious experience of willed action is generated. Here we show that patients with parietal lesions can report when they started moving, but not when they first became aware of their intention to move. This stands in contrast with the performance of cerebellar patients who behaved as normal subjects. We thus propose that when a movement is planned, activity in the parietal cortex, as part of a cortico-cortical sensorimotor processing loop, generates a predictive internal model of the upcoming movement. This model might form the neural correlate of motor awareness.

Adult↗
PubMed1972

Alteration of the cytotoxic action of sensitized lymphocytes by cholinergic agents and activators of adenylate cyclase.

The cytotoxic action of lymphocytes upon cells bearing alloantigens to which they are sensitized is inhibited by agents that elevate intracellular amounts of 3':5'-cyclic AMP: prostaglandin E(1), cholera toxin, and theophylline. Cholinergic agents, added in the range of 1 to 100 pM, enhance cytotoxicity, an effect that is blocked by atropine. Because cholinergic agents elevate cyclic GMP in other in vitro systems, these findings suggest that the cytotoxic process effected by sensitized lymphocytes is a secretory phenomenon modulated by cyclic AMP and cyclic GMP.

Acetylcholine↗
PubMed1983

Estrogen action at endometrial membranes: alterations in luminal surface detectable within seconds.

The morphological effects of estrogen on the luminal surfaces of rat endometrial cells were investigated by scanning electron microscopy. Ovariectomized rats were injected intravenously with estradiol-17 beta (E2 beta), 0.5 micrograms/0.25 ml per 100 g body wt. At various intervals thereafter, the lumen of a uterine horn was flushed with buffered 2% glutaraldehyde and then prepared for scanning electron microscopy by conventional methods. In control rats that had received an equivalent volume of placebo vehicle, the luminal cell surface was characterized by short, sparse microvilli (MV) and, in most cells, a single, central cilium. At 30 s after E2 beta injection, the number of MV was significantly increased. By 1 min, MV density was further increased and MV were frequently clustered; also, the central cilium of many cells was no longer evident. Similar results were obtained after exposure to diethylstilbestrol for 30 s to 1 min, whereas neither a subthreshold dose of E2 beta nor a dose of the relatively inactive congener E2 alpha equivalent to a saturating concentration of E2 beta gave statistically significant responses in surface changes by the present criteria. After 3-7 min of E2 beta exposure, MV had increased greatly in length and density. These effects underwent dramatic regression by 15-30 min after E2 beta treatment, with distinct diminution of microvillar lengths and numbers, reduction of clustering, and reappearance of the central cilium in many cells. This was succeeded at 1 h by a renewed surge of surface activity. These results are consistent with cumulative evidence for rapid alterations of the surface membrane of estrogen-sensitive cells in response to physiological levels of active hormone. Whether these responses in the luminal surfaces are primary, or are secondary reflections of receptor-mediated membrane alterations at the basolateral blood-front, remains to be determined.

Animals↗
PubMed2006

Influence of adiposity in the blunted whole-body protein anabolic response to insulin with aging.

BACKGROUND: Although insulin resistance of glucose is often reported with aging, that of protein metabolism is still debated. We tested if the insulin sensitivity of protein metabolism parallels that of glucose and is altered with aging. METHODS: Whole-body (13)C-leucine and (3)H-glucose kinetics were measured in the postabsorptive state and during an hyperinsulinemic, euglycemic, isoaminoacidemic clamp in 12 young men (age: 27 +/- 1 years; body mass index [BMI]: 23 +/- 1 kg/m(2)), 11 young women (age: 25 +/- 1 years; BMI: 21 +/- 1 kg/m(2)), 9 elderly men (age: 70 +/- 1 years; BMI: 26 +/- 1 kg/m(2)), and 10 elderly women (age: 69 +/- 2 years; BMI: 23 +/- 1 kg/m(2)). RESULTS: Postabsorptive leucine flux rates adjusted for fat-free mass (FFM) were not different between elderly and young participants. During the clamp, leucine flux and protein synthesis rates increased less in the elderly participants, and protein breakdown decreased equally. Thus, the net anabolic (protein balance) response to hyperinsulinemia was lower in elderly versus young participants (p =.007) and was highly correlated with the clamp glucose rate of disposal (r = 0.671, p <.001), indicating insulin resistance of protein concurrent with that of glucose. From regression analysis, FFM explained 73% of the variance in the anabolic response. Age explained an additional 3%, but was accounted for by markers of adiposity. FFM and percent body fat collectively explained 79% of the variance. CONCLUSION: Both reduction in absolute FFM and increased adiposity, intrinsic to the aging process, are associated with an altered anabolic action of insulin in stimulating protein synthesis. This alteration may contribute to the progressive muscle loss with aging.

Adiposity↗
PubMed2002

An alteration in the hypothalamic action of estradiol due to lack of progesterone exposure can cause follicular cysts in cattle.

Many mammals, including cattle, can develop ovarian follicular cysts, but the physiological mechanisms leading to this condition remain undefined. We hypothesized that follicular cysts can develop because estradiol will induce a GnRH/LH surge on one occasion but progesterone exposure is required before another GnRH/LH surge can be induced by estradiol. In experiment 1, 14 cows were synchronized with an intravaginal progesterone insert (IPI) for 7 days, and prostaglandin F(2alpha) was given on the day of IPI removal. Estradiol benzoate (EB; 5 mg i.m.) was given 3 days before IPI removal to induce atresia of follicles. Cows were given a second EB treatment 1 day after IPI removal to induce a GnRH/LH surge in the absence of an ovulatory follicle. All cows had an LH surge following the second EB treatment, and 10 of 14 cows developed a large-follicle anovulatory condition (LFAC) that resembled follicular cysts. These LFAC cows were given a third EB treatment 15 days later, and none of the cows had an LH surge or ovulation. Cows were then either not treated (control, n = 5) or treated for 7 days with an IPI (n = 5) starting 7 days after the third EB injection. Cows were treated for a fourth time with 5 mg of EB 12 h after IPI removal. All IPI-treated, but no control, cows had an LH surge and ovulated in response to the estradiol challenge. In experiment 2, cows were induced to LFAC as in experiment 1 and were then randomly assigned to one of four treatments 1) IPI + EB, 2) IPI + GnRH (100 microg), 3) control + EB, and 4) control + GnRH. Control and IPI-treated cows had a similar LH surge and ovulation when treated with GnRH. In contrast, only IPI-treated cows had an LH surge following EB treatment. Thus, an initial GnRH/LH surge can be induced with high estradiol, but estradiol induction of a subsequent GnRH/LH surge requires exposure to progesterone. This effect is mediated by the hypothalamus, as evidenced by similar LH release in response to exogenous GnRH. This may represent the physiological condition that underlies ovarian follicular cysts.

Administration, Intravaginal↗
PubMed2006

Modulation of cardiac Na(+) and Ca(2+) currents by CaM and CaMKII.

Sarcolemmal sodium (Na) and calcium (Ca) currents are fundamentally involved in shaping the cardiac action potential. Alterations in Na or Ca currents can change action potential characteristics and therefore might result in cardiac arrhythmias. Also, these ions contribute to excitation-contraction coupling and therefore are important in myocyte shortening and contractility of the heart. This review article summarizes how sarcolemmal Na and Ca channels are regulated with an emphasis on the novel role of Ca-dependent proteins Calmodulin (CaM) and especially Ca/CaM-dependent protein kinase II (CaMKII) to modulate sarcolemmal Na and Ca channels in the heart.

Action Potentials↗