QT dispersion and triple-vessel coronary disease.
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Adult↗
Biomedical subjects
A A Grace
Publications and source records attributed to A A Grace.
Interconnected parallel circuits between rat nucleus accumbens and thalamus revealed by retrograde transynaptic transport of pseudorabies virus.
One of the primary outputs of the nucleus accumbens is directed to the mediodorsal thalamic nucleus (MD) via its projections to the ventral pallidum (VP), with the core and shell regions of the accumbens projecting to the lateral and medial aspects of the VP, respectively. In this study, the multisynaptic organization of nucleus accumbens projections was assessed using intracerebral injections of an attenuated strain of pseudorabies virus, a neurotropic alpha herpesvirus that replicates in synaptically linked neurons. Injection of pseudorabies virus into different regions of the MD or reticular thalamic nucleus (RTN) produced retrograde transynaptic infections that revealed multisynaptic interactions between these areas and the basal forebrain. Immunohistochemical localization of viral antigen at short postinoculation intervals confirmed that the medial MD (m-MD) receives direct projections from the medial VP, rostral RTN, and other regions previously shown to project to this region of the thalamus. At longer survival intervals, injections confined to the m-MD resulted in transynaptic infection of neurons in the accumbens shell but not in the core. Injections that also included the central segment of the MD produced retrograde infection of neurons in the lateral VP and the polymorph (pallidal) region of the olfactory tubercle (OT) and transynaptic infection of a small number of neurons in the rostral accumbens core. Injections in the lateral MD resulted in retrograde infection in the globus pallidus (GP) and in transynaptic infection in the caudate-putamen. Viral injections into the rostroventral pole of the RTN infected neurons in the medial and lateral VP and at longer postinoculation intervals, led to transynaptic infection of scattered neurons in the shell and core. Injection of virus into the intermediate RTN resulted in infection of medial VP neurons and second-order infection of neurons in the accumbens shell. Injections in the caudal RTN or the lateral MD resulted in direct retrograde labeling of cells within the GP and transynaptic infection of neurons in the caudate-putamen. These results indicate that the main output of VP neurons receiving inputs from the shell of the accumbens is heavily directed to the m-MD, whereas a small number of core neurons appear to influence the central MD via the lateral VP. Further segregation in the flow of information to the MD is apparent in the organization of VP and GP projections to subdivisions of the RTN that give rise to MD afferents. Collectively, these data provide a morphological basis for the control of the thalamocortical system by ventral striatal regions, in which parallel connections to the RTN may exert control over activity states of cortical regions.
Animals↗
Dopamine-cell depolarization block as a model for the therapeutic actions of antipsychotic drugs.
Antipsychotic drugs used in the treatment of schizophrenia have in common the property of being dopamine-receptor antagonists. However, the rapid timecourse of receptor blockade produced upon drug administration does not correlate with the emergence of clinical actions, which typically require weeks of treatment to become manifest. Studies in rats have shown that repeated antipsychotic drug treatment results in a delayed inactivation of dopamine-neuron firing in the midbrain due to depolarization block. Furthermore, the therapeutic efficacy of antipsychotic drugs in humans correlates with their ability to induce depolarization block of mesolimbic dopamine neurons, whereas their potential to produce extrapyramidal side effects correlates with their propensity for inducing depolarization block in the nigrostriatal dopamine system. Therefore, dopamine-cell depolarization block is an effective model for evaluating antipsychotic drug efficacy, and provides a potential mechanism to account for their therapeutic impact on a dysregulated dopamine system.
Animals↗
Cortical afferents modulate striatal gap junction permeability via nitric oxide.
Nitric oxide is a ubiquitous cellular messenger that plays a role in a variety of biological mechanisms. Within the central nervous system, it is formed in glia and neuronal cells and can diffuse away from its site of origin to modulate membrane conductances, neurotransmitter release, behavior, or to control the blood flow within its region of action. Nitric oxide has been shown to modulate gap junction conductance in the retina and cortex, an action it shares with a number of neurotransmitters. In this study, we found that the activation of cortical afferents increased dye coupling between rat neostriatal neurons recorded in vitro. This effect was mimicked by a nitric oxide donor and prevented by a nitric oxide synthase inhibitor, suggesting that activation of corticostriatal fibers may open putative gap junctions in the striatum via release of nitric oxide. This is the first report showing that synaptic modulation of gap junctions can be mediated by nitric oxide, and may provide a mechanism to explain cortical modulation of subcortical pattern formation within this highly integrative structure.
Animals↗
Toward molecular strategies for heart disease--past, present, future.
The past two decades of cardiovascular biology and medicine have been based largely upon the consideration of the heart and vasculature as an integrated physiological system, a view that has resulted in major therapeutic advances. With the advent of developments of gene transfer, mouse and human genetics, genetic engineering of intact animals, and molecular and cellular technology, cardiovascular medicine is now on the threshold of a molecular therapeutic era. Major steps have been taken toward unraveling the molecular determinants of complex, integrative, and polygenic cardiovascular disease states, including atherogenesis, hypertension, cardiac hypertrophy and failure, congenital heart disease, and coronary restenosis following balloon angioplasty. Our improved understanding of the fundamental basis of these important cardiovascular disease processes has established a scientific foundation for diagnostic, prognostic, and therapeutic advances in the mainstream of cardiovascular medicine.
Animals↗
Effects of haloperidol on the activity and membrane physiology of substantia nigra dopamine neurons recorded in vitro.
A variety of experimental evidence suggests that one function of dendritically released dopamine is the feedback modulation of dopamine neuron firing rate via stimulation of the somatodendritic autoreceptors located on these cells. Under these conditions, blockade of these receptors should result in an alteration in the firing rate of dopamine neurons. In order to test this prediction, we have examined whether haloperidol alters the electrophysiological activity of dopamine neurons recorded from nigral slices maintained in vitro. This preparation permits examination of the effects of haloperidol when the substantia nigra is isolated from long-loop afferent cell populations, and also facilitates the performance of intracellular recordings to allow the assessment of alterations in membrane properties that underlie any changes in firing rate. Addition of haloperidol to the media bathing nigral slices caused increases in the spontaneous firing rate of some dopamine neurons. It also caused depolarization of the membrane and increases in input resistance in a subset of dopamine neurons. However, this drug had no consistent effects on the delayed repolarization or the anomalous rectification that are characteristic of activity in these cells. Morphological assessment of dopamine neurons stained in the coronal sections used in these studies confirmed that the dendrites of dopamine neurons were largely intact in these slices. These results demonstrate that blockade of the somatodendritic autoreceptors located on dopamine neurons does cause alterations in the electrophysiological activity of these cells, substantiating the role of nigral dopamine release in the modulation of dopamine neuron activity.
Animals↗
Dopaminergic reduction of excitability in nucleus accumbens neurons recorded in vitro.
Dopamine (DA) receptor activation has been shown to affect the striatal complex in a multidimensional manner. However, the question of whether its net effect on postsynaptic targets in the nucleus accumbens and striatum is excitatory or inhibitory in nature has been a topic of controversy for some time. This study focuses on the effects of DA agonists on indices of postsynaptic cell membrane excitability in nucleus accumbens neurons, such as the amount of intracellular current injection required to elicit spike firing and the membrane potential at which action potentials are evoked. Administration of the nonspecific D1/D2 DA agonist apomorphine induced a membrane depolarization that was not mimicked by the D1 agonist SKF 38393, by the D2 agonist quinpirole, or by the combined administration of both drugs. On the other hand, subsets of neurons responded to apomorphine or combined D1/D2 agonist administration with a response that reversed near -90 mV. Following the administration of apomorphine or the combined administration of the D1 and D2 agonists, nucleus accumbens neurons required significantly higher amplitudes of depolarizing current injection to elicit spike firing. These results suggest that coactivation of D1 and D2 receptors on accumbens neurons causes a reduction in their membrane excitability.
Animals↗
Angiotensin II stimulates sodium-dependent proton extrusion in perfused ferret heart.
The Na+/H+ antiport and Na(+)-HCO3- coinflux carrier contribute to recovery from intracellular acidosis in cardiac tissue. The effects of angiotensin II (10(-12)-10(-6) M) on H+ fluxes after intracellular acid loading and during reperfusion after myocardial ischemia have been investigated in the isovolumic, Langendorff-perfused ferret heart. Intracellular pH (pHi) was estimated using 31P nuclear magnetic resonance (NMR) spectroscopy from the chemical shift of intracellular deoxyglucose-6-phosphate or inorganic phosphate. Angiotensin II produced concentration-dependent stimulation (maximum at 10(-6) M: 67%) of 5-(N-ethyl-N-isopropyl)amiloride (EIPA)-sensitive Na(+)-dependent of H+ efflux consistent with stimulation of the Na+/H+ antiport. Half-maximal stimulation of H+ efflux occurred at approximately 10(-9) M, which is close to the dissociation constant of the cardiac angiotensin AT1 receptor. Stimulation via this receptor was confirmed with the nonpeptide AT1 receptor blocker, GR-117289. Angiotensin II had less pronounced effects on HCO3(-)-dependent pHi recovery after acid loading with no effect on pHi recovery after intracellular alkalosis. During reperfusion, angiotensin II significantly increased H+ extrusion but impaired contractile recovery. The results support the hypothesis that angiotensin II facilitates H+ extrusion in the heart. This may help maintain physiological homeostasis, but the hypothesized obligated Na+ influx could exacerbate cellular dysfunction during reperfusion.
Alkalosis↗
Carbonic anhydrase and cardiac pH regulation.
Membrane-bound carbonic anhydrase (CA) has recently been identified in mammalian cardiac tissue. In this study, we have investigated the histochemical location and functional role of CA in the ferret heart. Heart sections stained by a modified Hansson's technique showed CA to be located on capillary endothelial membranes as well as on sarcolemmal membranes. In the Langendorff-perfused heart, washout of CO2 brought about by switching perfusion between 25 mM HCO3(-)-5% CO2-buffered solution and nominally HCO3(-)-CO2-free solution caused a transient rise in intracellular pH (pHi) measured by the chemical shift of 2-deoxy-D-glucose 6-phosphate with 31P nuclear magnetic resonance spectroscopy. The initial rate of change of pHi, measured over the first 60-75 s of CO2 efflux, was significantly reduced from 0.41 +/- 0.03 pH units/min (n = 9) in control hearts to 0.28 +/- 0.02 pH units/min (n = 5) in the presence of the membrane-permeable CA inhibitor 6-ethoxzolamide (P < 0.05 compared with control) and to 0.22 +/- 0.04 pH units/min (n = 5) in the presence of the membrane-impermeable CA inhibitor CL-11,366 (P < 0.01 compared with control). After reperfusion of the ischemic myocardium, both CA inhibitors caused a significant slowing of initial rate of change in pH (and initial rate of recovery of contractile function) compared with control hearts. These results suggest that CA, by facilitating the hydration-dehydration of CO2-H2CO3, alters the relative concentrations of CO2 inside and outside the cells, thus enhancing the rate of CO2 transfer from the intracellular to extracellular compartments, which contributes significantly to pHi recovery after reperfusion of the ischemic myocardium.
Animals↗
Physiological properties of rat ventral pallidal neurons recorded intracellularly in vivo.
1. The physiology of ventral pallidal (VP) cells was investigated using in vivo intracellular recording and staining techniques in adult rats. Based on electrophysiological criteria, three different types of cells were found: type A cells, which fired phasic spikes that did not exhibit a substantial afterhyperpolarization (AHP), type B cells, which exhibited a slow ramplike depolarization that preceded the short-duration action potential; the spike was followed by a prominent AHP, and type C cells, which were the only cells that fired spikes in couplets or bursts, with the spikes in a burst exhibiting a progressive increase in duration and a decrease in amplitude. These cells also exhibited a rebound low threshold spikelike event. Furthermore, 18% of the VP cells recorded exhibited a slow subthreshold oscillation of the membrane potential (< 1 Hz). 2. The response of VP cells to stimulation of fibers arising from the prefrontal cortex, nucleus accumbens, and mediodorsal thalamic nucleus (MD) was examined. In contrast to our initial predictions, all cells responded to nucleus accumbens stimulation with excitation. Type A and B cells responded to nucleus accumbens stimulation with excitation and to MD stimulation with antidromic-like responses, orthodromic excitation, or evoked inhibitory postsynaptic potentials. Only type A cells responded to prefrontal cortical stimulation. Type C cells only responded to stimulation of the nucleus accumbens, which resulted in evoked excitatory postsynaptic potentials. 3. The cells in the VP therefore can be segregated into three physiologically defined groups according to action potential discharge patterns and their response to afferent fiber stimulation.
Action Potentials↗
Congenital long QT syndromes. Toward molecular dissection of arrhythmia substrates.
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Arrhythmias, Cardiac↗
The significance of paced electrogram fractionation in hypertrophic cardiomyopathy. A prospective study.
BACKGROUND: Increased duration of paced right ventricular (RV) electrograms in hypertrophic cardiomyopathy has been shown in 37 patients to correlate with the risk of ventricular fibrillation (VF). The changes in electrogram duration with pacing stimulus prematurity discriminated patients into three groups: VF survivors, an intermediate group with either non-sustained ventricular tachycardia (NSVT) on ambulatory monitoring or a family history of sudden death (FHSD), and those with none of these risk factors (noRF) for sudden death (SD). The consistency of these original groups has been tested prospectively in a further 64 patients. METHODS AND RESULTS: Of 64 patients with hypertrophic cardiomyopathy, 3 had documented VF, 1 had witnessed SD and is assumed to have had VF, 25 had NSVT, 21 had FHSD, and 14 had noRF. Nineteen patients had syncope. They were studied by pacing one RV site with a decremental sequence and recording high-pass filtered electrograms from three other RV sites. The delay of each fractionated potential in the electrogram was determined relative to a pacing stimulus of increasing prematurity. These measurements were repeated by pacing each ventricular site in turn. The electrograms were characterized by two parameters: the extrastimulus coupling interval (S1S2) at which delay increased by more than 0.75 ms/20 ms decrease in S1S2 interval and the change in electrogram duration between an S1S2 of 350 ms and ventricular effective refractory period. The 4 VF patients had a mean increase in electrogram duration of 16.1 ms and an increase in delay at a mean S1S2 of 368 ms. Three VF patients were within the original VF group, while only 6 of 60 non-VF patients were within this group, discriminating between VF patients and the remainder (P < .007). The 14 noRF patients had a mean change in electrogram duration of 4.5 ms and an increase in delay at a mean S1S2 of 301 ms. Eleven patients were within the original noRF group, and only 8 of the remaining 50 patients also were within the noRF group, discriminating between the noRF patients and the remainder (P < .0005). Most of the NSVT and FHSD patients were between the original VF and noRF groups, with 5 of 25 NSVT and 1 of 31 FHSD patients in the original VF group. There was no relation between syncope and electrophysiological characteristics. Programmed electrical stimulation (PES) was performed in the first 15 patients of this study. Of the total 52 patients from the original and current studies, PES identified 2 out of 6 VF patients, and there was no correlation between VF inducibility and intraventricular conduction delay. CONCLUSIONS: These data are consistent with the original VF and noRF groups. Most patients with FHSD or NSVT were between these groups. Pooled data from the original and current groups (n = 101) allow definition of a new VF group, which includes all patients with VF (n = 9), 8 of 30 patients with VT, and 3 of 31 patients with FHSD. This new group may be used as a criterion for implantable cardioverter-defibrillator implantation in a prospective trial of the technique for the prediction of SD.
Adult↗
Understanding cardiovascular development.
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Animals↗
Different effects of subchronic clozapine and haloperidol on dye-coupling between neurons in the rat striatal complex.
Atypical antipsychotic drugs, such as clozapine, are distinguished from classical antipsychotics (e.g. haloperidol) by their lower liability for producing motor side-effects. Although initial studies suggested that the clinical efficacy of antipsychotic drugs is related to their affinity for the D2 dopamine receptor, the delayed onset of both the therapeutic effects and the extrapyramidal symptoms associated with these drugs implicates a more complex mechanism of action. In this study, we found that continuous (but not acute) treatment of rats with either drug caused an increase in dye coupling between neurons in the limbic component of the rat striatal complex (i.e. the shell region of the nucleus accumbens) after withdrawal of the drugs. Furthermore, continuous treatment with haloperidol, but not clozapine, also increased dye coupling in the motor-related part of the striatal complex (i.e. the dorsal striatum). Thus, both therapeutically effective drugs show a delayed effect on dye coupling between neurons in the accumbens shell, whereas only the drug associated with motor side effects altered coupling between cells in the dorsal striatum. Antipsychotic drugs may therefore alleviate the profound disturbances in cognitive function of schizophrenics by producing sustained alterations in the way signals from the cortex are integrated within these brain regions.
Animals↗
The tonic/phasic model of dopamine system regulation: its relevance for understanding how stimulant abuse can alter basal ganglia function.
The changes in dopamine system regulation occurring during stimulant administration are examined in relation to a new model of dopamine system function. This model is based on the presence of a tonic low level of extracellular dopamine that is released by the presynaptic action of corticostriatal afferents. In contrast, spike-dependent dopamine release results in a phasic, high concentration of dopamine in the synaptic cleft that is rapidly inactivated by reuptake. Tonic dopamine has the ability to down-modulate spike-dependent phasic dopamine release via stimulation of the very sensitive dopamine autoreceptors present on dopamine terminals. Stimulants are known to elicit locomotion and stimulate reward sites by releasing dopamine from terminals in the nucleus accumbens, which is followed by a rebound depression. It is proposed that the initial activating action of stimulants is caused by increasing the release of dopamine into the synaptic cleft to activate the phasic dopamine response. However, by interfering with dopamine uptake, stimulants also allow dopamine to escape the synaptic cleft, thereby depressing subsequent spike-dependent phasic dopamine release by increasing the tonic stimulation of the autoreceptor. In contrast, repeated stimulant administration is proposed to cause long-term sensitization by pharmacological disruption of a cascade of homeostatic compensatory processes. Upon drug withdrawal, the fast compensatory systems that were blocked by stimulants rapidly restore homeostasis to the system at a new steady-state level of interaction. As a consequence, the slowly changing but potentially more destabilizing compensatory responses are prevented from returning to their baseline conditions. This results in a permanent change in the responsivity of the system. Homeostatic systems are geared to compensate for unidimensional alterations in a system, and are capable of restoring function even after massive brain lesions or the continuous presence of stimulant drugs. However, the system did not evolve to deal effectively with repetitive introduction and withdrawal of drugs that disrupt dopamine system regulation. As a consequence, repeated insults to a biological system by application and withdrawal of drugs that interfere with its homeostatic regulation may be capable of inducing non-reversible changes in its response to exogenous and endogenous stimuli.
Amphetamines↗
The serum concentration of active transforming growth factor-beta is severely depressed in advanced atherosclerosis.
Recent evidence has led us to propose that transforming growth factor-beta (TGF-beta) is a key inhibitor of atherosclerosis. We show here that a population of patients with advanced atherosclerosis all have less active TGF-beta in their sera than patients with normal coronary arteries, with a fivefold difference in average concentration between the two groups. This correlation with atherosclerosis is much stronger than for other known major risk factors and it may therefore have important diagnostic and prognostic significance. Aspirin medication correlates with an increase in active TGF-beta concentration, indicating that therapeutic interventions for TGF-beta are possible.
Aged↗
Repeated treatment with haloperidol and clozapine exerts differential effects on dye coupling between neurons in subregions of striatum and nucleus accumbens.
The delayed onset of action of antipsychotic drugs (APDs) during the treatment of schizophrenia has been hypothesized to temporally correlate with the induction of depolarization block in rat mesencephalic dopamine (DA) cell groups. Nevertheless, it is unknown whether these drugs also exert a delayed action on the dopaminoceptive postsynaptic target cells in the striatal complex. Using in vivo intracellular recording and dye labeling techniques, the effects of APDs on dye coupling were examined in subregions of the striatal complex defined by double staining for calbindin immunoreactivity. Rats treated repeatedly with APDs were found to exhibit a 66-71% higher incidence of coupling that occurred in a drug- and a region-specific manner, that is, both drug treatments increased dye coupling in the limbic-associated accumbens shell region whereas only haloperidol increased dye coupling in the motor-related striatal matrix and accumbens core regions. In addition, cells located in regions in which dye coupling was altered also showed significantly higher input resistance. These changes were not observed in response to DA receptor blockade by acute drug administration or when haloperidol was administered for a period sufficient to induce DA receptor supersensitivity but not DA cell depolarization block (i.e., 2 weeks). Therefore, alteration in dye coupling appears to be correlated temporally with the induction of DA cell depolarization block. The finding that both APDs exert a common action on neurons in the accumbens shell region is consistent with its identification as the site of therapeutic drug actions, whereas the capacity of haloperidol to also affect cells in the motor-related matrix and core regions correlates with its high propensity to induce extrapyramidal side effects.
Animals↗
Activation of dopamine cell firing by repeated L-DOPA administration to dopamine-depleted rats: its potential role in mediating the therapeutic response to L-DOPA treatment.
The administration of L-dihydroxyphenylalanine (L-DOPA) to patients with Parkinson's disease is known to produce acute effects that include the reduction of rigidity as well as delayed therapeutic actions involving the resumption of complex motor behavior. In order to examine the potential role of dopamine (DA) cell activity in mediating these responses, the effects of acute and repeated L-DOPA administration on the electrophysiological activity of the residual dopamine (DA) neurons were examined in rats that had received partial 6-hydroxydopamine (6-OHDA)-induced DA lesions. DA cell activity was assessed along three dimensions: (1) the relative proportion of DA neurons exhibiting spontaneous spike firing, (2) their basal firing rate, and (3) their firing pattern. Following 6-OHDA-induced DA depletion, rats were treated for 1 month with saline or L-DOPA. In addition, rats from each group received either an acute injection of L-DOPA or saline on the day of recording. In rats receiving repeated saline treatment, the DA neurons recorded following acute L-DOPA administration were firing at significantly slower basal firing rates and exhibited less burst firing when compared to saline-pretreated rats given acute saline. In contrast, DA cells recorded from rats that had received repeated L-DOPA administration for 4 weeks followed by an acute saline injection did not exhibit any significant differences from DA cells of intact control rats with respect to basal firing rate or firing pattern; however, there was a substantial increase in the proportion of DA neurons exhibiting spontaneous spike firing after correcting for 6-OHDA-induced cell loss. In addition, in rats receiving repeated L-DOPA treatment, the DA cells recorded following acute administration of L-DOPA showed significantly less of a reduction in firing rate when compared to the cells recorded following acute L-DOPA in the saline treatment group. These results show that: (1) acute L-DOPA administration appears to exert its actions by DA autoreceptor stimulation, whereas (2) repeated L-DOPA administration increases the proportion of spontaneously active DA neurons in partially lesioned rats. As a result, repeated L-DOPA administration would be expected to cause an increase in spike-dependent DA release as a consequence of the greater proportion of DA cells showing spontaneous activity. This may be the major factor underlying the delayed therapeutic benefits of L-DOPA therapy in the treatment of Parkinson's disease.
Animals↗