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PubMed2001

Large-conductance calcium-activated potassium channels in neonatal rat intracardiac ganglion neurons.

The properties of single Ca2+-activated K+ (BK) channels in neonatal rat intracardiac neurons were investigated using the patch-clamp recording technique. In symmetrical 140 mM K+, the single-channel slope conductance was linear in the voltage range -60/+60 mV, and was 207+/-19 pS. Na+ ions were not measurably permeant through the open channel. Channel activity increased with the cytoplasmic free Ca2+ concentration ([Ca2+]i) with a Hill plot giving a half-saturating [Ca2+] (K0.5) of 1.35 microM and slope of approximately equals 3. The BK channel was inhibited reversibly by external tetraethylammonium (TEA) ions, charybdotoxin, and quinine and was resistant to block by 4-aminopyridine and apamin. Ionomycin (1-10 microM) increased BK channel activity in the cell-attached recording configuration. The resting activity was consistent with a [Ca2+]i <100 nM and the increased channel activity evoked by ionomycin was consistent with a rise in [Ca2+]i to > or =0.3 microM. TEA (0.2-1 mM) increased the action potential duration approximately equals 1.5-fold and reduced the amplitude and duration of the afterhyperpolarization (AHP) by 26%. Charybdotoxin (100 nM) did not significantly alter the action potential duration or AHP amplitude but reduced the AHP duration by approximately equals 40%. Taken together, these data indicate that BK channel activation contributes to the action potential and AHP duration in rat intracardiac neurons.

Action Potentials↗
PubMed1981

Corticosterone secretion after inhibition of prostaglandin synthesis by indomethacin.

Systemic indomethacin (Ind) administration decreased prostaglandin F (PGF) content of the rat adrenal to less than 1.4 pg/mg. This was less than 5% of the adrenal PGF content in the gelatin-treated (Gel) control group (34 pg/mg). Basal plasma corticosterone levels were increased by the Ind treatment. Since the calculated metabolic clearance rate for corticosterone was unchanged, this increase was attributed to an enhanced adrenal secretion rate that was secondary to elevated plasma ACTH concentration. Ether exposure in the presence of Ind did not stimulate a normal rise in plasma corticosterone or adrenal corticosteroidogenesis. Adrenal responsiveness to exogenous ACTH was reduced after Ind treatment. There was a normal rise in plasma ACTH levels following ether exposure confirming the adrenal as the site of inhibition. Systemic Ind treatment thus appears to have two sites of action in altering plasma corticosterone levels: 1) a direct effect on the adrenal, inhibiting normal secretion in response to acute elevations of plasma ACTH, and 2) an action at the pituitary or hypothalamic level, eliciting an increase in basal ACTH secretion.

Adrenal Cortex↗
PubMed1984

Inhibition of sodium-independent amino acid transport by dexamethasone in rat hepatoma cells.

We studied the uptake of leucine, phenylalanine, and the amino acid analog, 2-aminonorborane-2-carboxylic acid, by rat hepatoma cells in tissue culture. The uptake of these amino acids was partially mediated by a plasma membrane transport system similar to the L agency described in other cell types in that it does not require extracellular sodium and is subject to trans-stimulation. Initial rates of sodium-independent transport of these amino acids were calculated using mathematical transformations of the uptake time course curves. The glucocorticoid dexamethasone inhibits the activity of this transport system; the initial rates of sodium-independent uptake of leucine, phenylalanine, and 2-aminonorborane-2-carboxylic acid are decreased by approximately one-third (average = 30%, n = 19) after incubation of HTC cells with 0.1 microM dexamethasone. This inhibition requires at least 15 h, reaching a maximum at 24 h of exposure of the cells to the hormone. Dexamethasone has an asymmetrical effect on sodium-independent amino acid transport in that exposure of the cells to the hormone does not inhibit the rates of outflow of leucine or phenylalanine from preloaded cells into medium without sodium. Inhibition of uptake is blocked by 0.1 mM cycloheximide and 4 microM actinomycin D, indicating the need for continuous protein synthesis for dexamethasone action. Insulin, which is known to partially reverse the inhibitory effect of dexamethasone on the A amino acid transport system in HTC cells, does not alter the action of dexamethasone on the L system. Previous investigations have demonstrated inhibition by dexamethasone of at least two distinct sodium-dependent amino acid transport activities in HTC cells. The data presented here, showing inhibition by the glucocorticoid of a sodium-independent transport activity, indicate that the effect of the hormone is independent of the energy source of the amino acid transport systems affected.

Amino Acids↗
PubMed2004

Insulin signaling in heart muscle: lessons from genetically engineered mouse models.

The heart is an insulin-responsive organ, and disorders of insulin action, such as diabetes and obesity, can have profound effects on cardiac performance. Insulin signaling influences numerous functions within the heart, such as metabolic substrate preference, cell size, and the response of the heart to ischemia and hypertrophy. Because the systemic consequences of altered insulin action can have significant but indirect effects on the heart, the generation of mice with altered expression of insulin receptors and key components of the insulin-signal transduction pathways in cardiomyocytes have led to interesting and occasionally surprising new insights into the regulation of cardiac biology by insulin.

Animals↗
PubMed1983

Structure-function studies of N-acyl derivatives of tryptophan that function as specific cholecystokinin receptor antagonists.

Benzotript, N-p-chlorobenzoyl-L-tryptophan, is a specific cholecystokinin receptor antagonist. In the present study we used dispersed pancreatic acini to examine tryptophan as well as several different N-acyl derivatives of tryptophan for their abilities to function as cholecystokinin receptor antagonists. L-Tryptophan, D-tryptophan as well as each acyl derivative tested inhibited cholecystokinin-stimulated amylase secretion and outflux of 45Ca and there was a good correlation between the ability of a particular agent to inhibit the action of cholecystokinin on acinar function and its ability to inhibit binding of 125I-labeled cholecystokinin to pancreatic acini. Results with butyloxycarbonyl-L-tryptophan indicated that the inhibition of the action of cholecystokinin caused by L-tryptophan and various acyl derivatives is specific, competitive and fully reversible. In functioning as a cholecystokinin receptor antagonist the relative potencies of the agents tested were: carbobenzoxy-L-tryptophan greater than benzotript greater than benzoyl-L-tryptophan = butyloxycarbonyl-L-tryptophan greater than acetyl-L-tryptophan greater than L-tryptophan. In inhibiting the actions of cholecystokinin, native as well as N-acyl derivatives of D-tryptophan were equipotent with the corresponding compound containing L-tryptophan. Although L-tryptophan inhibited the actions of cholecystokinin, L-phenylalanine, L-methionine or L-aspartic acid, even when tested at concentrations as high as 3 mM, did not alter the action of cholecystokinin on pancreatic acini. The antagonism of the actions of cholecystokinin was not restricted to N-acyl derivatives of L-tryptophan because butyloxycarbonyl-L-methionine and butyloxycarbonyl-L-phenylalanine but not butyloxycarbonyl-L-aspartic acid also antagonized the actions of cholecystokinin. These results demonstrate that both the nature of the N-acyl group and the amino acid residue are important determinants of the affinity of the antagonist for the cholecystokinin receptor. For derivatives of L-tryptophan, the more hydrophobic the N-acyl moiety, the greater the affinity of the derivative for the cholecystokinin receptor.

Animals↗
PubMed2000

Tryptophan scanning mutagenesis in TM2 of the GABA(A) receptor alpha subunit: effects on channel gating and regulation by ethanol.

1. Each residue in the second transmembrane segment (TM2) of the human GABA(A) receptor alpha(2) subunit was individually mutated to tryptophan. The wild-type or mutant alpha(2) subunits were expressed with the wild-type human GABA(A) receptor beta(2) subunit in Xenopus oocytes, and the effects of these mutations were investigated using two-electrode voltage-clamp recording. 2. Four mutations (V257W, T262W, T265W and S270W) produced receptors which were active in the absence of agonist, and this spontaneous open channel activity was blocked by both picrotoxin and bicuculline, except in the alpha(2)(V257W)beta(2) mutant receptor, which was not sensitive to picrotoxin. 3. Six mutations (V257W, V260W, T262W, T267W, S270W and A273W) enhanced the agonist sensitivity of the receptor, by 10 - 100 times compared with the wild-type alpha(2)beta(2) receptor. Other mutations (T261W, V263W, L269W, I271W and S272W) had little or no effect on the apparent affinity of the receptor to GABA. Eight of the tryptophan mutations (R255, T256, F258, G259, L264, T265, M266 or T268) resulted in undetectable GABA-induced currents. 4. The S270W mutation eliminated potentiation of GABA by ethanol, whereas T261W markedly increased the action of ethanol. The T262W mutation produced direct activation (10% of maximal GABA response) by ethanol in the absence of GABA, while other mutations did not alter the action of ethanol significantly. 5. These results are consistent with a unique role for S270 in the action of ethanol within the TM2 region, and with models of GABA(A) receptor channel function, in which specific residues within TM2 are critical for the regulation of channel gating (S270, L264), while other residues (L269, I271 and S272) have little effect on these functions and may be non-critical structural residues.

Amino Acid Sequence↗
PubMed1985

New perspectives on the role of magnesium in the pathophysiology of the cardiovascular system. II. Experimental aspects.

It has generally been believed that the physiological roles for magnesium ions (Mg2+) in cardiac and vascular smooth muscle are limited to regulation of contractile proteins, sarcoplasmic reticular membrane transport of calcium ions (Ca2+), cofactor in ATPase activities and metabolic regulation of energy-dependent cytoplasmic and mitochondrial pathways. In addition, up until recently, it was not thought that small changes in free external ([Mg2+]0) or cytoplasmic Mg2+ could exert any significant effects on cardiac or vascular smooth muscle contractility. It is clear, however, from the newer studies that [Mg2+]0 can affect tension and contractility of these muscle cells by altering membrane and intracellular organelle binding and transport of Ca2+, affecting hormone-receptor interactions, regulating electrolyte content and transport, affecting resting membrane-generated and action potentials, altering excitation-contraction coupling events, and regulate peripheral and cerebral vascular tone and blood flow. In addition, it is also now clear that small changes of free [Mg2+] at the cardiac and vascular muscle membranes can exert significant effects on mechanical and electrical activities of these cells. Considerable new data lend support to the idea that [Mg2+]0 is fundamental in the regulation of cardiovascular homeostasis. Dietary, metabolic or drug-induced changes in Mg2+ levels appear to play important roles in the etiology of cardiac and vascular disorders. Evidence is reviewed and presented to indicate that Mg2+ is important in the pathophysiology and treatment of certain forms of experimental and genetic types of hypertension. This divalent cation may also be important in the etiology of a variety of disorders which have vasospasm in common. Evidence is reviewed to support the concept that Mg2+ is a naturally occurring or mimic weak Ca2+ antagonist, which should be useful in the treatment of several types of cardiac and vascular disorders.

Animals↗
PubMed1991

[The effect of diabetogenic substances on the zinc and calcium content in the pancreatic islet cells of rabbits].

The injections of diabetogenic drugs to rabbits induced a decrease in zinc and calcium content in B insulocytes dependent on the degree of these cells damage and hyperglycemia. The content of these metals in A insulocytes was not significantly altered due to a light injury of these cells. A high concentration of calcium in islet A cells is suggested to be a protective factor to the action of alteration agents.

Aminoquinolines↗
PubMed1986

Differential effects of methylmercuric chloride and mercuric chloride on the L-glutamate and potassium evoked release of [3H]dopamine from mouse striatal slices.

The effects of CH3HgCl and HgCl2 on the evoked release of 3H from mouse striatal slices prelabelled with [3H]dopamine have been examined. CH3HgCl (10 microM) was observed to increase the L-glutamate-evoked release of [3H]dopamine, while HgCl2 (10 microM) had no effect. In contrast, CH3HgCl at concentrations up to 100 microM had no effect on the 25 mM K+-stimulated release of [3H]dopamine, whereas HgCl2 (100 microM) significantly reduced the 25 mM K+-stimulated release of [3H]dopamine. Thus CH3HgCl and HgCl2 have differential effects on the L-glutamate- and K+-stimulated release of [3H]dopamine from mouse striatal slices, suggesting that these compounds may have different sites and (or) mechanisms of action in altering neurotransmitter release. It is suggested that CH3HgCl may act predominantly at intracellular sites or at the level of the L-glutamate receptor, whereas the major site of action of HgCl2 may be the voltage-operated calcium channel.

Animals↗
PubMed1987

[Cellular electrophysiological effects of fulguration by low energy shock].

In spite of the increasing use of catheter ablation in the treatment of refractory ventricular and supraventricular arrhythmias, little information is available on the basic electrophysiological effects of the treatment. Although high-energy shocks are still usually delivered, the current trend is toward lower energies. We studied the electrophysiological effects of non-deflagrating anodic shocks of 2 joules on preparations of sheep ventricular myocardium and Purkinje's fibers. The shocks were delivered by a standard defibrillator between a small-area catheter electrode and a wide-area inert electrode. Action potentials were recorded by the standard microelectrode technique. After the shocks were delivered, the Purkinje's cells that were 5 mm distant from the shocked area on either side were depolarized in the -30 to -40 mV zone, but they progressively reverted to an almost normal resting potential. Recovery was bi-exponential, with time constants of about 1 min and 10 min respectively. Similarly, the conduction block induced by the electric shock in 100% of the cases was reversible in 50%. It must be noted that at the time of conduction recovery the pattern observed was that of electrotonic conduction where the distal action potential conducted was preceded by a pre-potential. This pattern always regressed progressively, with gradual disappearance of the pre-potential in the distal cells, suggesting that the unexcitable area had vanished or become smaller. Although a normal 1/1 conduction and normal action potentials returned in the cells that were 5 mm distant from the shocked area, recordings performed at a distance of 1 to 4 mm from that area disclosed alterations of action potentials that were usually irreversible.(ABSTRACT TRUNCATED AT 250 WORDS)

Action Potentials↗
PubMed1980

Cardiac arrhythmias induced by guanethidine in cats anesthetized with halothane.

Rapid i.v. administration of guanethidine provokes severe and sustained ventricular arrhythmias in cats anesthetized with halothane. The arrhythmias include premature ventricular excitations, multifocal ventricular rhythm, bigeminy, trigeminy and ventricular tachycardia. They begin in about 20 sec and last from 4 to 100 min. By comparison, a standard dose of noradrenaline (10 micrograms/kg) induces ventricular arrhythmias which develop in about 12 sec and continue for 1-2.5 min. Pretreatment with beta-adrenoceptor blocking drugs prevents arrhythmias from both drugs, and pretreatment with imipramine or reserpine prevents arrhythmias for guanethidine but not noradrenaline. The adrenergic neuron blocking action of guanethidine does not alter the arrhythmogenic action of guanethidine since arrhythmias can still be produced after adrenergic neuron blockade. These results indicate that guanethidine causes arrhythmias by releasing noradrenaline from cardiac adrenergic neuron storage sites and, therefore, point out the vulnerability of the heart to arrhythmias when noradrenaline-releasing drugs interact with halogenated hydrocarbon anesthetics.

Anesthesia↗
PubMedDate not supplied

Pharmacological manipulation of sincalide (CCK-8)-induced suppression of feeding.

The current study involves an investigation of the possible neurotransmitter systems involved in the ability of exogenously administered sincalide (cholecystokinin octapeptide, CCK-8) to suppress feeding. Male rats previously trained to obtain food either during a daily 3-hr session, or conditioned to obtain food pellets on a fixed-ratio or fixed-interval schedule of reinforcement, were treated IP with CCK-8, following pretreatment with representative drugs of several pharmacological classes. Pretreatment with phenoxybenzamine, tolazoline, yohimbine, morphine, haloperidol or picrotoxin reduced the efficacy of CCK-8. However, pretreatment with naloxone or clonidine potentiated the suppressant action of CCK-8 on feeding. Propranolol, diphenhydramine, cimetidine, atropine, d-amphetamine, fenfluramine or diazepam pretreatment either had no effect or no consistent action in altering the activity of CCK-8. The ability of CCK-8 to suppress feeding was not altered by subacute treatment with the anorectics, d-amphetamine or fenfluramine, using a regimen known to induce tolerance. These data indicate that CCK-8 exerts a different mechanism of action than that of fenfluramine or d-amphetamine, and furthermore, that noradrenergic, dopaminergic, GABAergic or endogenous opioid systems either mediate or can modify the effect of CCK-8 on feeding.

Animals↗
PubMed2001

Is there nicotinic modulation of nerve growth factor? Implications for cholinergic therapies in Alzheimer's disease.

Studies on the neurobiology of nerve growth factor (NGF) reveal a diverse range of actions. Through alterations in gene expression, NGF is important in maintaining and regulating the phenotype of neurons that express the high-affinity receptor, trkA. Nerve growth factor also has a rapid action, revealed by its role in pain signaling in bladder and in skin. In the central nervous system (CNS), NGF has an intimate relationship with the cholinergic system. It promotes cholinergic neuron survival after experimental injury but also maintains and regulates the phenotype of uninjured cholinergic neurons. In addition to these effects mediated by gene expression, NGF has a rapid neurotransmitter-like action to regulate cholinergic neurotransmission and neuronal excitability. Consistent with its actions on the cholinergic system, NGF can enhance function in animals with cholinergic lesions and has been proposed to be useful in humans with Alzheimer's disease (AD); however, the problems of CNS delivery and of side effects (particularly pain) limit the clinical efficacy of NGF. Drug treatment strategies to enhance production of NGF in the CNS may be useful in the treatment of AD. Nicotine is one such agent, which, when administered directly to the hippocampus in rats, produces long-lasting elevation of NGF production.

Acetylcholine↗
PubMed1997

Expression of a luteoviral movement protein in transgenic plants leads to carbohydrate accumulation and reduced photosynthetic capacity in source leaves.

Elucidating the role of viral genes in transgenic plants revealed that the movement protein (MP) from tobacco mosaic virus is responsible for altered carbohydrate allocation in tobacco and potato plants. To study whether this is a general feature of viral MPs, the movement protein MP17 of potato leafroll virus (PLRV), a phloem-restricted luteovirus, was constitutively expressed in tobacco plants. Transgenic lines were strongly reduced in height and developed bleached and sometimes even necrotic areas on their source leaves. Levels of soluble sugars and starch were significantly increased in source leaves. Yet, in leaf laminae the hexose-phosphate content was unaltered and ATP reduced to only a small extent, indicating that these leaves were able to maintain homeostatic conditions by compartmentalization of soluble sugars, probably in the vacuole. On the contrary, midribs contained lower levels of soluble sugars, ATP, hexose-phosphates and UDP-glucose supporting the concept of limited uptake and catabolism of sucrose in the phloem. The accumulation of carbohydrates led to a decreased photosynthetic capacity and carboxylation efficiency of ribulose-1,5-bisphosphate carboxylase/oxygenase (rubisco) probably owing to decreased expression of photosynthetic proteins. In parallel, levels of pathogenesis-related proteins were elevated which may be the reason for the obtained limited resistance against the unrelated potato virus Y (PVY)N in the transgenic tobacco plants. Ultrathin sections of affected leaves harvested from 2-week-old plants revealed plasmodesmal alterations in the phloem tissue while plasmodesmata between mesophyll cells were indistinguishable from wild-type. These data favour the phloem tissue to be the primary site of PLRV MP17 action in altering carbohydrate metabolism.

Carbohydrate Metabolism↗
PubMed1997

Actions of phenylephrine, isoproterenol, and epinephrine with halothane on endocardial conduction and activation in canine left ventricular papillary muscles.

BACKGROUND: Myocardial sensitization by halothane to the arrhythmogenic effects of epinephrine involves synergistic actions mediated by alpha 1- and beta-adrenoceptors. Halothane potentiates a transient a1-adrenoceptor-mediated negative dromotropic effect of epinephrine on Purkinje fibers. This study examines how halothane alters the actions of alpha 1- and beta-agonists and epinephrine on endocardial conduction. METHODS: Superfused canine papillary muscles were mapped to locate a Purkinje-ventricular muscle junction (PVJ), and bipolar electrodes were placed to measure Purkinje and endocardial conduction velocity and PVJ conduction time during stimulation of the Purkinje layer. The effects of exposure to 5 microM phenylephrine, 1 microM isoproterenol, or 5 microM epinephrine on conduction were determined in the absence and presence of 0.4 mM halothane in three groups of 10 preparations. RESULTS: Isoproterenol slightly increased Purkinje conduction velocity and markedly improved conduction at the PVJ and in the endocardium similarly in the presence or absence of halothane. Phenylephrine depressed Purkinje velocity (-12%) only in the presence of halothane and did not slow conduction at the PVJ or in the myocardium. Epinephrine transiently depressed Purkinje velocity, more so with (-22%) than without (-12%) halothane (P < or = 0.01), and simultaneously facilitated conduction at the PVJ and in the myocardium. CONCLUSIONS: The prodysrhythmic actions of epinephrine with halothane may involve disparate effects on conduction, including speeding on conduction at the PVJ and in the myocardium, similar to that produced by isoproterenol, accompanied by simultaneous but transient alpha 1-mediated depression of conduction in the Purkinje system.

Adrenergic alpha-Agonists↗
PubMed1983

[Changes in glycoprotein composition of the tracheal submucosal glands caused by S-carboxymethylcysteine treatment].

The mechanism for the expectorant effect of S-carboxymethylcysteine (S-CMC) was investigated histologically and histochemically using isolated canine trachea. Following S-CMC treatment, the number of total glycoprotein-containing goblet cells (GC) did not change. The numbers of acid glycoprotein (AGP)-, neutral glycoprotein (NGP)-, and sulphated glycoprotein (SGP)-containing GC were also unaltered in a concentration range of 10(-7) to 10(-4) M. On the other hand, the ratio of the acinar inner diameter of submucosal glands (SG) to the tracheal wall thickness significantly increased with 10(-5) and 10(-4) M S-CMC, and the thickness of the acini of SG significantly decreased with 10(-4) M S-CMC. Although the ratio of the numbers of AGP-to NGP-containing glandular cells and AGP content in the cells did not change, the number of SGP-containing glandular cells significantly decreased with 10(-4) M S-CMC, and SGP content in the cells significantly decreased concentration-dependently High concentrations (10(-5) and 10(-4) M) of S-CMC produced increases in total saccharide, protein and N-acetylhexosamine concentrations in the incubation fluid. These findings suggest that S-CMC has a selective secretagogic action on SG, and an action which alters the composition of AGP, a chief viscous factor, in the mucous granules of SG. The expectorant effect of this agent may, at least in part, be ascribable to these actions.

Animals↗
PubMed1984

Modification of drug action by hyperammonemia.

Pretreatment with ammonium acetate (NH4Ac) (6 mmol/kg s.c.) approximately doubled the time morphine-treated mice remained on a hot surface and similarly increased muscular incoordination by diazepam, but NH4Ac treatment alone had no effect. Thus, hyperammonemia is capable of altering drug action and must be considered along with impaired drug metabolism in enhanced drug responses associated with liver disease. Experiments in vitro showed that acetylcholine-induced catecholamine release from bovine adrenal medulla is depressed as much as 50% by 0.3 mM NH4Ac and KCl-induced contractions of guinea-pig ileum were inhibited 20% by 5 mM NH4Ac. Addition of excess calcium reversed the depression in both tissues, but calcium-independent catecholamine release by acetaldehyde was not blocked by NH4Ac. These results suggested that ammonia blocks calcium channels. Parallels in the actions of NH4Ac and the calcium channel blocker verapamil support this concept. Both verapamil (10 mg/kg i.p.) and NH4Ac pretreatment enhanced morphine analgesia- and diazepam-induced muscular incoordination and antagonized amphetamine-induced motor activity, and neither verapamil nor NH4Ac affected the convulsant action of metrazol. The data suggest that hyperammonemia exerts a calcium channel blocking action which enhances the effects of central nervous system depressants and certain opioid analgesics.

Acetates↗
PubMed1989

Persistent alterations in GABAA receptor binding and function after prenatal lorazepam administration in the chick.

Behavioral abnormalities have been reported in young and adult animals exposed to benzodiazepines prenatally. The presence of neurochemical alterations in the GABAergic system after prenatal benzodiazepine exposure was assessed in a chick model which avoids prenatal and postnatal maternal effects. The GABAA receptor complex, the presumed site of benzodiazepine action, was altered in adult chickens previously exposed to lorazepam for 10 days in ovo. Binding was decreased at the putative chloride channel site labeled by [35S]TBPS, coupling was decreased between this site and the GABA binding site, and function of the GABAA receptor in chloride uptake was diminished in animals exposed to prenatal lorazepam. Persistent neurochemical alterations in the GABAergic system accompany prenatal benzodiazepine exposure, and may influence subsequent behavior and development.

Animals↗