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Biomedical subjects

A A Grace

Publications and source records attributed to A A Grace.

At least 37 records · Page 2Linked to original sources
PubMed2001

Beta(2) adrenergic receptors mediate important electrophysiological effects in human ventricular myocardium.

OBJECTIVE: To define the effects of beta(2) adrenergic receptor stimulation on ventricular repolarisation in vivo. DESIGN: Prospective study. SETTING: Tertiary referral centre. PATIENTS: 85 patients with coronary artery disease and 22 normal controls. INTERVENTIONS: Intravenous and intracoronary salbutamol (a beta(2) adrenergic receptor selective agonist; 10-30 microg/min and 1-10 microg/min), and intravenous isoprenaline (a mixed beta(1)/beta(2) adrenergic receptor agonist; 1-5 microg/min), infused during fixed atrial pacing. MAIN OUTCOME MEASURES: QT intervals, QT dispersion, monophasic action potential duration. RESULTS: In patients with coronary artery disease, salbutamol decreased QT(onset) and QT(peak) but increased QT(end) duration; QT(onset)-QT(peak) and QT(peak)-QT(end) intervals increased, resulting in T wave prolongation (mean (SEM): 201 (2) ms to 233 (2) ms; p < 0.01). There was a large increase in dispersion of QT(onset), QT(peak), and QT(end) which was more pronounced in patients with coronary artery disease-for example, QT(end) dispersion: 50 (2) ms baseline v 98 (4) ms salbutamol (controls), and 70 (1) ms baseline v 108 (3) ms salbutamol (coronary artery disease); p < 0.001. Similar responses were obtained with isoprenaline. Monophasic action potential duration at 90% repolarisation shortened during intracoronary infusion of salbutamol, from 278 (4.1) ms to 257 (3.8) ms (p < 0.05). CONCLUSIONS: beta(2) adrenergic receptors mediate important electrophysiological effects in human ventricular myocardium. The increase in dispersion of repolarisation provides a mechanism whereby catecholamines acting through this receptor subtype may trigger ventricular arrhythmias.

Action Potentials↗
PubMed2001

Microsatellite mutation of type II transforming growth factor-beta receptor is rare in atherosclerotic plaques.

A somatic mutation within a microsatellite polyA tract in the coding region of the type II transforming growth factor (TGF)-beta receptor gene was reported to occur in human atherosclerotic and restenotic lesions. This mutation occurs frequently in colorectal cancer with the replication error repair phenotype and results in loss of sensitivity to the growth inhibitory effects of TGF-beta in cells from the tumors. The mutation was proposed to account for the clonal expansion of vascular smooth muscle cells observed in atherosclerotic plaques, through loss of the growth inhibitory effect of TGF-beta. The frequency of the mutation and the extent of clonal expansion of the mutated cells have major implications for the mechanism of atherogenesis and therapeutic strategies. We analyzed a set of 22 coronary arterial and 9 aortic samples containing early to advanced atherosclerotic lesions for the mutation in the type II TGF-beta receptor polyA tract. Only 1 coronary arterial sample from an advanced lesion showed detectable amounts of the mutation, present at a low level (8% of the DNA sample). The data imply that the mutation occurs only at low frequency and is not a major mechanistic contributor to the development of atherosclerosis.

Adult↗
PubMed2000

Amphetamine withdrawal alters bistable states and cellular coupling in rat prefrontal cortex and nucleus accumbens neurons recorded in vivo.

Repeated amphetamine administration is known to produce changes in corticoaccumbens function that persist beyond termination of drug administration. We have found previously that long-term alteration in dopamine systems leads to changes in gap junction communication, expressed as dye coupling, between striatal neurons. In this study, the cellular bases of amphetamine-induced changes were examined using in vivo intracellular recordings and dye injection in ventral prefrontal-accumbens system neurons of control and amphetamine-treated rats. Rats that had been withdrawn from repeated amphetamine displayed a significant increase in the incidence of dye coupling in the prefrontal cortex and nucleus accumbens, which persisted for up to 28 d after withdrawal. The increased coupling was limited to projection neurons in both prefrontal cortical and accumbens brain regions, as identified by their axonal trajectory or the absence of interneuron-selective immunocytochemical markers. These changes occurred with no substantial loss of tyrosine hydroxylase-immunoreactive terminals in these cortical and accumbens regions, ruling out dopamine degeneration as a precipitating factor. Previous studies showed that nitric oxide plays a role in the regulation of coupling; however, amphetamine-withdrawn rats had fewer numbers of neurons and processes that stained for nitric oxide synthase immunoreactivity. In amphetamine-treated rats, a higher proportion of cortical cells fired in bursts, and a larger proportion of accumbens and prefrontal cortical neurons exhibited bistable membrane oscillations. By increasing corticoaccumbens transmission, amphetamine withdrawal may lead to neuronal synchronization via gap junctions. Furthermore, this adaptation to amphetamine treatment persists long after the drug is withdrawn.

Action Potentials↗
PubMed2000

Estimation of systolic and diastolic free intracellular Ca2+ by titration of Ca2+ buffering in the ferret heart.

Spectroscopic Ca(2+)-indicators are thought to report values of free intracellular Ca(2+) concentration ([Ca(2+)](i)) that may differ from unperturbed values because they add to the buffering capacity of the tissue. To check this for the heart we have synthesized a new (19)F-labelled NMR Ca(2+) indicator, 1, 2-bis-[2-bis(carboxymethyl)amino-4,5-difluorophenoxy]ethane ('4, 5FBAPTA'), with a low affinity (K(d) 2950 nM). The new indicator and four previously described (19)F-NMR Ca(2+) indicators 1,2-bis-[2-(1 - carboxyethyl)(carboxymethyl)amino - 5 - fluorophenoxy]ethane ('DiMe-5FBAPTA'), 1, 2-bis-[2-(1-carboxyethyl)(carboxymethyl)amino-4-fluorophenoxy]ethane ('DiMe-4FBAPTA'), 1, 2-bis-[2-bis(carboxymethyl)amino-5-fluorophenoxy]ethane ('5FBAPTA') and 1, 2-bis-[2-bis(carboxymethyl)amino-5-fluoro-4-methylphenoxy]ethane ('MFBAPTA'), with dissociation constants for Ca(2+) ranging from 46 to 537 nM, have been used to measure [Ca(2+)](i), over the range from less than 100 nM to more than 3 microM, in Langendorff-perfused ferret hearts (30 degrees C, pH 7.4, paced at 1.0 Hz) by (19)F-NMR spectroscopy. Loading hearts with indicators resulted in buffering of the Ca(2+) transient. The measured end-diastolic and peak-systolic [Ca(2+)](i) were both positively correlated with indicator K(d). The positive correlations between indicator K(d) and the measured end-diastolic and peak-systolic [Ca(2+)](i) were used to estimate the unperturbed end-diastolic and peak-systolic [Ca(2+)](i) by extrapolation to K(d)=0 (diastolic) and to K(d)=infinity (systolic) respectively. The extrapolated values in the intact beating heart were 161 nM for end-diastolic [Ca(2+)](i) and 2650 nM for peak-systolic [Ca(2+)](i), which agree well with values determined from single cells and muscle strips.

Animals↗
PubMed2000

Ca2+ buffering in the heart: Ca2+ binding to and activation of cardiac myofibrils.

The measurement of cardiac Ca(2+) transients using spectroscopic Ca(2+) indicators is significantly affected by the buffering properties of the indicators. The aim of the present study was to construct a model of cardiac Ca(2+) buffering that satisfied the kinetic constraints imposed by the maximum attainable rates of cardiac contraction and relaxation on the Ca(2+) dissociation rate constants and which would account for the observed effects of (19)F-NMR indicators on the cardiac Ca(2+) transient in the Langendorff-perfused ferret heart. It is generally assumed that the Ca(2+) dependency of myofibril activation in cardiac myocytes is mediated by a single Ca(2+)-binding site on troponin C. A model based on 1:1 Ca(2+) binding to the myofilaments, however, was unable to reproduce our experimental data, but a model in which we assumed ATP-dependent co-operative Ca(2+) binding to the myofilaments was able to reproduce these data. This model was used to calculate the concentration and dissociation constant of the ATP-independent myofilament Ca(2+) binding, giving 58 and 2.0 microM respectively. In addition to reproducing our experimental data on the concentration of free Ca(2+) ions in the cytoplasm ([Ca(2+)](i)), the resulting Ca(2+) and ATP affinities given by fitting of the model also provided good predictions of the Ca(2+) dependence of the myofibrillar ATPase activity measured under in vitro conditions. Solutions to the model also indicate that the Ca(2+) mobilized during each beat remains unchanged in the presence of the additional buffering load from Ca(2+) indicators. The new model was used to estimate the extent of perturbation of the Ca(2+) transient caused by different concentrations of indicators. As little as 10 microM of a Ca(2+) indicator with a dissociation constant of 200 nM will cause a 20% reduction in peak-systolic [Ca(2+)](i) and 30 microM will cause approx. 50% reduction in the peak-systolic [Ca(2+)](i) in a heart paced at 1.0 Hz.

Adenosine Triphosphate↗
PubMed2000

Gating of information flow within the limbic system and the pathophysiology of schizophrenia.

Although first thought of as a dopaminergic disorder, there is little direct evidence to support a primary pathology in the dopamine system as the etiological factor in schizophrenia. In contrast, evidence is amassing in support of a cortical disturbance in this disorder; one consequence of which is a disruption in the cortical regulation of subcortical dopamine systems. Our studies show that the hippocampus plays a major role in this interaction, in that, along with the dopamine system, it provides a gating influence over information flow from the prefrontal cortex at the level of the nucleus accumbens. Moreover, chemically-induced disruption of the development of the hippocampus and entorhinal cortex were found to lead to pathophysiological changes in these interactions in the limbic system of adult rats. Therefore, schizophrenia is proposed to be a developmentally-related disorder, in which disruption of the hippocampal influence over the limbic system during ontogeny results in a pathological alteration of corticoaccumbens interactions in the adult organism.

Animals↗
PubMed2000

Dopamine-mediated regulation of striatal neuronal and network interactions.

The dopaminergic system exerts dynamic modulation of glutamatergic afferent drive that is dependent on the temporal pattern of the dopaminergic input and the subtypes of striatal neurons affected. The differences in feedforward inhibition between striatal neurons comprising the direct and indirect output pathway confer distinct response-pattern differences in their respective targets,supporting brief bursts of activity in Type-I neurons but attenuating repetitive activity in Type-II cells. This temporal patterning is further modulated by NO-mediated signaling, and by tonic and phasic dopamine-mediated stimulation, which exerts preferential actions on indirect and direct output neurons, respectively. As a result,the striatal network is forced into state-dependent patterns of activity that differentially regulate muscle tone and voluntary motor activity via distinct output projections from the striatum.

Animals↗
PubMed2000

The tonic/phasic model of dopamine system regulation and its implications for understanding alcohol and psychostimulant craving.

All drugs of abuse have been shown to act either directly or indirectly by increasing dopamine neurotransmission within the limbic system. Thus, alcohol has been shown to increase dopamine transmission primarily by activating dopamine cell spike activity, whereas psychostimulants increase dopamine transmission by inhibiting the removal of dopamine from the synaptic space after its release. The spike-dependent release of dopamine that is modulated by drugs of abuse to lead to their rewarding actions has been termed the phasic dopamine response. In contrast, with repeated drug administration, dopamine will also accumulate in the extracellular space of the nucleus accumbens in concentrations too low to stimulate postsynaptic receptors, but of sufficient magnitude to activate dopamine release-inhibiting autoreceptors. In addition, the level of extracellular dopamine is proposed to be under the regulatory influence of cortico-accumbens afferents. This steady-state level of extrasynaptic dopamine has been termed the tonic dopamine response. In this paper it is proposed that several of the aspects of drug addiction, withdrawal and craving associated with the continued use of these drugs can be explained on the basis of their effects on tonic versus phasic dopamine system function. Thus, the increase in tonic dopamine levels that occurs with repeated drug administration would serve to oppose phasic dopamine release via stimulation of dopamine terminal autoreceptors, causing the subject to increase drug administration to restore the phasic response. Moreover, after withdrawal from the drugs, exposure to priming doses of drug or to drug-related stimuli are proposed to increase tonic dopamine levels, again triggering drug-seeking behavior in order to restore balance between the tonic and phasic dopamine systems. Therefore, one consequence of continued drug use is that these parameters of dopamine system function that normally serve to keep the system stable will enter into a new steady-state homeostasis, from which the system is particularly susceptible to destabilizing influences that may precipitate relapse.

Animals↗
PubMed2000

Striatal nitric oxide signaling regulates the neuronal activity of midbrain dopamine neurons in vivo.

A major component of the cortical regulation of the nigrostriatal dopamine (DA) system is known to occur via activation of striatal efferent systems projecting to the substantia nigra. The potential intermediary role of striatal nitric oxide synthase (NOS)-containing interneurons in modulating the efferent regulation of DA neuron activity was examined using single-unit recordings of DA neurons performed concurrently with striatal microdialysis in anesthetized rats. The response of DA neurons recorded in the substantia nigra to intrastriatal artificial cerebrospinal fluid (ACSF) or drug infusion was examined in terms of mean firing rate, percent of spikes fired in bursts, cells/track, and response to electrical stimulation of the orbital prefrontal cortex (oPFC) and striatum. Intrastriatal infusion of NOS substrate concurrently with intermittent periods of striatal and cortical stimulation increased the mean DA cell population firing rate as compared with ACSF controls. This effect was reproduced via intrastriatal infusion of a NO generator. Infusion of either a NOS inhibitor or NO chelator via reverse microdialysis did not affect basal firing rate but increased the percentage of DA neurons responding to striatal stimulation with an initial inhibition followed by a rebound excitation (IE response) from 40 to 74%. NO scavenger infusion also markedly decreased the stimulation intensity required to elicit an IE response to electrical stimulation of the striatum. In single neurons in which the effects of electrical stimulation were observed before and after drug delivery, NO antagonist infusion was observed to decrease the onset latency and extend the duration of the initial inhibitory phase induced by either oPFC or striatal stimulation. This is the first report showing that striatal NO tone regulates the basal activity and responsiveness of DA neurons to cortical and striatal inputs. These studies also indicate that striatal NO signaling may play an important role in the integration of information transmitted to basal ganglia output centers via corticostriatal and striatal efferent pathways.

Animals↗
PubMed1999

Modulation of basolateral amygdala neuronal firing and afferent drive by dopamine receptor activation in vivo.

The basolateral amygdala (BLA) is implicated in responding to affective stimuli. Dopamine (DA) is released in the BLA during numerous conditions; however, the neurophysiological effects of DA in the BLA have not been examined in depth. In this study, the effects of DA receptor manipulation on spontaneous and afferent-driven neuronal firing were examined using in vivo extracellular single-unit recordings in parallel with systemic and iontophoretic drug application, and stimulation of the substantia nigra/ventral tegmental area in the rat. The effects of DA receptor activation in the BLA were found to depend on the characteristics of the BLA neuron examined, causing an increase in the firing rate of putative interneurons and a decrease in the firing of identified projection neurons. Additionally, DA receptor activation attenuated short-latency spikes evoked by electrical stimulation of prefrontal cortical and mediodorsal thalamic inputs to the BLA while potentiating the responses evoked by electrical stimulation of sensory association cortex. DA receptor activation can thus attenuate BLA projection neuron firing via two mechanisms: (1) by a direct inhibition, and (2) by indirect actions mediated via activation of BLA interneurons. This is hypothesized to lead to a global filtration of weaker inputs. Moreover, DA potentiates sensory inputs and attenuates medial prefrontal cortex inputs to the BLA. Conditions in which DA is released in the BLA, such as during the presentation of an affective stimulus, will lead to a potentiation of the strongest sensory input and a dampening of cortical inhibition over the BLA, thus augmenting the response to affective sensory stimuli.

Afferent Pathways↗
PubMed1999

Brugada syndrome.

Explore the source record for details and available documents.

Death, Sudden, Cardiac↗
PubMed1999

The regulation of forebrain dopamine transmission: relevance to the pathophysiology and psychopathology of schizophrenia.

Since the discovery that the therapeutic efficacy of antipsychotic drugs was significantly correlated to their ability to block dopamine D2 receptors, abnormal dopamine transmission in the forebrain has been postulated to underlie psychosis in schizophrenia. In the past 15 years, an impressive amount of clinical and basic research aimed at the study of schizophrenia has indicated that prefrontal and temporal cortical abnormalities may be more important in the etiology of many of the symptoms of schizophrenia, including psychosis. However, the cortical systems that appear to have structural and/or metabolic abnormalities in schizophrenia patients potently regulate forebrain dopamine transmission through a number of mechanisms. In turn, dopamine modulates excitatory transmission mediated by frontal and temporal cortical projections to the basal ganglia and other regions. The present review summarizes the multiple interactions between forebrain DA systems and frontal and temporal corticostriatal transmission. It then examines the role of these interactions in normal behaviors and the psychopathology of schizophrenia.

Basal Ganglia↗
PubMed1999

Modulation of cell firing in the nucleus accumbens.

Pennartz et al. have proposed that functions of the nucleus accumbens (NA) are subserved by the activity of ensembles of neurons rather than by an overall neuronal activation. Indeed, the NA is a site of convergence for a large number of inputs from limbic structures that may modulate the flow of prefrontal cortical information and contribute to defining such ensembles, as exemplified in the ability of hippocampal input to gate cortical throughput in the nucleus accumbens. NA neurons exhibit a bistable membrane potential, characterized by a very negative resting membrane potential (down state), periodically interrupted by plateau depolarizations (up state), during which the cells may fire in response to cortical inputs. A dynamic ensemble can be the result of a distributed set of neurons in their up state, determined by the moment-to-moment changes in the spatial distribution of hippocampal inputs responsible for transitions to the up state. Ensembles may change as an adaptation to the contextual information provided by the hippocampal input. Furthermore, for dynamic ensembles to be functionally relevant, the model calls for near synchronous transitions to the up state in a group of neurons. This can be accomplished by the cell-to-cell transfer of information via gap junctions, a mechanism that can allow for a transfer of slow electrical signals, including "up" events between coupled cells. Furthermore, gap junction permeability is tightly modulated by a number of factors, including levels of dopamine and nitric oxide, and cortical inputs, allowing for fine-tuning of this synchronization of up events. The continuous selection of such dynamic ensembles in the NA may be disputed in schizophrenia, resulting in an inappropriate level of activity of thalamocortical systems.

Afferent Pathways↗