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Biomedical subjects

A A Grace

Publications and source records attributed to A A Grace.

At least 73 records · Page 4Linked to original sources
PubMed1998

Ventricular pacemaker upgrade: experience, complications and recommendations.

OBJECTIVE: To assess outcomes of pacemaker upgrade from single chamber ventricular to dual chamber. DESIGN: Retrospective analysis of patients undergoing the procedure. SETTING: Specialist cardiothoracic unit. PATIENTS: 44 patients (15 female, 29 male), mean (SD) age at upgrade 68.2 (12.9) years. INTERVENTIONS: Upgrade of single chamber ventricular to dual chamber pacemaker. MAIN OUTCOME MEASURES: Procedure duration and complications. RESULTS: Principal indications for upgrade were pacemaker syndrome (17), "opportunistic"--that is, at elective generator replacement (8), heart failure (7), non-specific breathlessness/fatigue (7), and neurally mediated syncope (3). Mean (SD) upgrade procedure duration (82.9 (32.6) minutes) significantly exceeded mean VVI implantation duration (42.9 (13.3) minutes) and mean DDD implantation duration (56.6 (22.7) minutes) (both p < 0.01). Complications included pneumothorax (1), ventricular arrhythmia requiring cardioversion (2), protracted procedure (10), atrial lead repositioning within six weeks (8), haematoma evacuation (1), superficial infection (1), and admission to hospital with chest pain (1); 20 patients (45%) suffered one or more complications including four of the eight who underwent opportunistic upgrade. CONCLUSIONS: Pacemaker upgrade takes longer and has a higher complication rate than either single or dual chamber pacemaker implantation. This suggests that the procedure should be performed by an experienced operator, and should be undertaken only if a firm indication exists. Patients with atrial activity should not be offered single chamber ventricular systems in the belief that the unit can be upgraded later if necessary at minimal risk.

Aged↗
PubMed1998

Sotalol associated polymorphic ventricular tachycardia and coronary spasm.

Sotalol may induce torsade de pointes through cardiac action potential prolongation, but a proarrhythmic effect secondary to its beta blocking action has not been reported. A 54 year old man presented with symptoms of angina and presyncope, subsequently demonstrated to be associated with coronary spasm. Treatment with sotalol exacerbated his symptoms and resulted in recurrent polymorphic ventricular tachycardia with a pattern indistinguishable from that caused by a class III action. Following sotalol with-drawal polymorphic ventricular tachycardia resolved completely. Polymorphic ventricular tachycardia in patients treated with sotalol may therefore not always be the result of delayed repolarisation, but may be caused by beta adrenoceptor blockade.

Adrenergic beta-Antagonists↗
PubMed1998

Changes in ventricular repolarization during acidosis and low-flow ischemia.

Myocardial ischemia, primarily a metabolic insult, is also defined by altered cardiac mechanical and electrical activity. We have investigated the metabolic contributions to the electrophysiological changes during low-flow ischemia (7.5% of the control flow) using 31P NMR spectroscopy to monitor metabolic parameters, suction electrodes to study epicardial monophasic action potentials, and 86Rb as a tracer for K+-equivalent efflux during low-flow ischemia in the Langendorff-perfused ferret heart. Shortening of the action potential duration at 90% repolarization (APD90) was most marked between 1 and 5 min after induction of ischemia, at which time it shortened from 261 +/- 4 to 213 +/- 8 ms. The period of marked APD90 shortening was accompanied by a fivefold increase in the rate of 86Rb efflux, both of which were inhibited by the ATP-sensitive K+ (KATP)-channel blockers glibenclamide and 5-hydroxydecanoate (5-HD), as well as by a significant fall in intracellular pH (pHi) from 7.14 +/- 0.02 to 6.83 +/- 0.03 but no change in intracellular ATP concentration ([ATP]i). We therefore investigated whether a fall in pHi could be the metabolic change responsible for modulating cardiac KATP channel activity in the intact heart during ischemia. Both metabolic (30 mM lactate added to extracellular solution) and respiratory (PCO2 increased to 15%) acidosis caused an initial lengthening of APD90 to 112 +/- 1.5 and 113 +/- 0.9%, respectively, followed by shortening during continued acidosis to 106 +/- 1.2 and 106 +/- 1.4%, respectively. The shortening of APD90 during continued acidosis was inhibited by glibenclamide, consistent with acidosis causing activation of KATP channels at normal [ATP]i. The similar responses to metabolic (induced by adding either l- or d-lactate) and respiratory acidosis suggest that lactate has no independent metabolic effect on action potential repolarization.

Acidosis↗
PubMed1998

Transforming growth factor-beta dynamically regulates vascular smooth muscle differentiation in vivo.

Variations in the levels of smooth muscle-specific isoforms of contractile proteins have been reported to occur in many different vascular diseases. However, although much work has been done in vitro to investigate the regulation of smooth muscle cell differentiation, the molecular mechanisms which regulate the differentiation of vascular smooth muscle tissue in vivo are unknown. Using quantitative immunofluorescence, we show that in rat arteries levels of smooth muscle differentiation markers correlate with the levels of the cytokine TGF-beta. In young mice with one allele of the TGF-beta1 gene deleted, the levels of both TGF-beta1 and smooth muscle differentiation markers are reduced compared to wild-type controls. This regulation of smooth muscle differentiation by TGF-beta during post-natal development also occurs dynamically in the adult animal. Following various pharmacological or surgical interventions, including treatment of mice with tamoxifen and balloon injury of rat carotid arteries, there is a strong correlation between the changes in the levels of TGF-beta and changes in the levels of smooth muscle differentiation markers (r=0. 9, P<0.0001 for n=26 experiments). We conclude that TGF-beta dynamically regulates smooth muscle differentiation in rodent arteries in vivo.

Animals↗
PubMed1997

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↗
PubMed1997

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↗
PubMed1997

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↗
PubMed1997

Chronic cold stress alters the basal and evoked electrophysiological activity of rat locus coeruleus neurons.

In vivo extracellular single-unit recording techniques revealed that chronic cold stress significantly alters both the basal and the evoked electrophysiological activity of noradrenergic neurons in the locus coeruleus of the anaesthetized rat. Following 17-21 days of chronic cold exposure (5 degrees C), the single-unit activity of histologically-identified locus coeruleus neurons in chloral hydrate-anaesthetized rats was recorded and analysed in terms of their basal firing rate and pattern of spike activity, as well as their response to footshock stimulation. There was no significant difference in the incidence of spontaneously active cells/electrode track between cold-stressed rats and control rats. However, the basal spike activity of locus coeruleus cells recorded from cold-stressed rats differed significantly from that of control rats along two dimensions: i) they displayed significantly higher basal firing rates (mean = 1.88 Hz vs 1.20 Hz, respectively); and ii) they frequently exhibited spontaneous burst-firing activity that was not observed in control rats (observed in 15/17 cold-stressed rats vs 1/26 control rats). The evoked spike activity of locus coeruleus cells in cold-stressed rats also differed significantly from that of control rats along two dimensions: i) they were more likely to respond to footshock stimulation (mean = 90.3% vs 74.4%, respectively); and ii) these responses were more likely to consist of multispike bursts of action potentials (mean = 8 bursts/50 stimulations vs 1 burst/50 stimulations, respectively). These results indicate that alterations in the electrophysiological activity of noradrenergic locus coeruleus neurons may contribute to the phenomenon of stress-induced sensitization of norepinephrine release that is thought to underlie some of the neuropathological changes that accompany long-term stress.

Animals↗
PubMed1997

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↗
PubMed1996

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↗
PubMed1996

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↗
PubMed1996

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↗
PubMed1996

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↗
PubMed1996

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↗