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Biomedical subjects

A M Dart

Publications and source records attributed to A M Dart.

At least 19 recordsLinked to original sources
PubMed1995

Suppression of ventricular arrhythmias during ischemia-reperfusion by agents inhibiting Ins(1,4,5)P3 release.

BACKGROUND: Reperfusion following myocardial ischemia causes a rapid and transient release of inositol (1,4,5)triphosphate [Ins(1,4,5)P3]. The aim of this study was to test whether this increased Ins(1,4,5)P3 release was important for the development of ventricular arrhythmias and whether agents that inhibit this signal transduction pathway, such as aminoglycoside antibiotics, suppress arrhythmias. METHODS AND RESULTS: In perfused rat hearts, ventricular tachycardia (VT), ventricular fibrillation (VF), and accumulation of Ins(1,4,5)P3 were measured during early reperfusion. A number of different compounds, including neomycin, gentamicin, streptomycin, spermine, reserpine, and prazosin, were effective in inhibiting the reperfusion-induced Ins(1,4,5)P3 release and the onset of VT and VF in parallel. A strong correlation existed between Ins(1,4,5)P3 content, measured at 2 minutes of reperfusion, and the incidence of reperfusion VT and VF. In addition, intravenous gentamicin suppressed the onset of arrhythmias under ischemic and reperfusion conditions in vivo. CONCLUSIONS: Our results are consistent with the view that Ins(1,4,5)P3 release plays a pivotal role in mediating arrhythmias during early reperfusion. Agents inhibiting Ins(1,4,5)P3 release are antiarrhythmic and may have potential use clinically.

Alkaloids↗
PubMed1995

Sympatholytic action of intravenous amiodarone in the rat heart.

BACKGROUND: Amiodarone is a commonly used antiarrhythmic agent with complex pharmacological effects. Although ventricular arrhythmias can be suppressed soon after intravenous amiodarone, the mechanisms responsible for this action are unclear. We studied the effects of acute treatment with amiodarone on the metabolism and release of norepinephrine (NE) in intact rats and in perfused rat hearts. METHODS AND RESULTS: Experiments were performed in anesthetized rats and in perfused, innervated hearts with amiodarone administered intravascularly. NE release was induced by electrical stimulation of the sympathetic ganglion. Concentrations of NE and its intraneuronal metabolite dihydroxyphenylglycol (DHPG) in hearts, plasma, and coronary venous effluent were measured by high-performance liquid chromatography. Acute administration of amiodarone induced dose-dependent increases in DHPG concentrations in plasma (5 mg/kg, +48%; 15 mg/kg, +84%; and 50 mg/kg, +467%) and in coronary venous effluent (1 mumol/L, +37%; 3 mumol/L, +510%; and 10 mumol/L, +1100%) together with an unchanged basal overflow of NE. In perfused hearts, NE release evoked by nerve stimulation was inhibited by infusion of amiodarone (1 mumol/L, -16%; 3 mumol/L, -24%; and 10 mumol/L, -64%) or by intravenous amiodarone (50 mg/kg) given 1 hour before heart perfusion (-70%), and the extent of this suppression correlated well with levels of DHPG overflow present immediately before nerve stimulation. When given in vitro and in vivo, amiodarone also significantly reduced NE and increased DHPG content in the heart, leading to a raised DHPG/NE ratio. All these effects of amiodarone were similar to those found with reserpine but less potent. In contrast, oral amiodarone produced none of these effects. CONCLUSIONS: Acute administration of amiodarone in perfused hearts or intact rats induces partial NE depletion in the heart by interfering with vesicular NE storage and enhancing intraneuronal NE metabolism, effects associated with an impaired NE release during sympathetic activation. Oral dosing with amiodarone has no such effect. Further study is required to test whether this novel sympatholytic effect of amiodarone contributes to its antiarrhythmic action after intravenous administration.

Administration, Oral↗
PubMed1995

Effects of dietary fat supplementation on inositol phosphate release and metabolism in rat left atria.

Eight weeks dietary supplementation with oils enriched in saturated fats, n-6 polyunsaturated fats and n-3 polyunsaturated fats resulted in a reduced inositol phosphate response in isolated rat left atria. Reductions in both basal activity and norepinephrine-stimulated activity were observed. Diets supplemented with n-3 polyunsaturated fats produced a greater decrease in the norepinephrine-stimulated release than the other dietary groups. In addition, supplementation with n-6 polyunsaturated fats resulted in higher levels of the Ca(2+)-releasing compound inositol(1,4,5)trisphosphate while addition of n-3 fats eliminated accumulation of inositol(1, 4)bisphosphate in response to norepinephrine. The reduction in inositol phosphate accumulation observed in all fat-supplemented groups demonstrates the need for caution in choosing relevant control groups in such dietary studies. The specific effects of n-6 and n-3 polyunsaturated fats on individual inositol phosphate isomers demonstrates subtle effects on inositol phosphate metabolism, the significance of which requires further investigation.

Animals↗
PubMed1995

How do fish oils affect vascular function?

1. This is a review on the mechanisms by which fish oils affect vascular function and how such changes contribute to their documented cardioprotective effects. 2. Evidence that fish oils depress vascular responses to contractile agents will be examined. It is concluded that this effect of fish oils is mediated predominantly by alterations in prostanoid profile. 3. Effects of fish oils on arterial relaxation are discussed with particular emphasis on endothelium dependent relaxation. It is suggested that the functional impairment of endothelium dependent relaxation documented in a number of cardiovascular disease states can be reversed by dietary fish oils. 4. In addition, possible effects of fish oils on growth factors, inositol trisphosphate and lipid metabolism, the sympathetic nervous system, rheological and membrane properties and inducible nitric oxide are reviewed.

Acetylcholine↗
PubMed1995

Arterial compliance may influence baroreflex function in athletes and hypertensives.

The present study investigated arterial compliance as a possible influence on mean arterial pressure-heart rate (MAP-HR) reflex function in athletes and hypertensives. Aortic stiffness and systemic arterial compliance (SAC) were estimated in 25 elite male athletes and 25 age-matched sedentary controls. Blood pressure did not vary between groups, but SAC was higher in the athletic compared with the sedentary group (0.46 +/- 0.04 vs. 0.37 +/- 0.02 arbitrary compliance units; P = 0.03). In five hypertensives and six age-matched normals and in a subgroup of seven athletes and seven age-matched controls the sigmoidal MAP-HR reflex was assessed using phenylephrine and nitroprusside. In athletes compared with sedentary subjects MAP-HR reflex sensitivity was the same; however, the maximum tachycardia in response to blood pressure reduction was lower in the athletic group (87.1.1 +/- 3.7 vs. 97.1 +/- 2.9 beats/min; P = 0.05). Athletes had a higher blood pressure corresponding to 95% of the HR range (64.2 +/- 3.2 vs. 54.0 +/- 2.1 mmHg; P = 0.02), but there was no difference in the blood pressure corresponding to 5% of the HR range. The blood pressure excursion necessary to traverse the baroreceptor transducer range (MAPd) was therefore less in athletes compared with normals. The beta-index of aortic stiffness correlated closely with MAPd (R = 0.70; P < 0.01). In hypertensives reflex sensitivity was reduced, the minimum HR was elevated, and the MAPd was 56% greater compared with normals.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Inositol phosphate release and metabolism during myocardial ischemia and reperfusion in rat heart.

A detailed study of the effects of global myocardial ischemia and reperfusion on inositol phosphate release and metabolism has been undertaken by using isolated perfused rat hearts. Ischemia for longer than 5 minutes caused a cessation of inositol phosphate production, with inositol phosphates initially present accumulating as isomers of inositol monophosphate. This inhibition was independent of norepinephrine. In contrast, 2-minute reperfusion following 20-minute ischemia produced a rapid and transient release of inositol phosphates that was dependent on the release of norepinephrine and mediated by alpha 1-adrenergic receptors. By a number of criteria, this reperfusion response was different from the norepinephrine response in normoxic tissue. First, total release of inositol phosphates was greater (466 +/- 37 compared with 345 +/- 29 cpm/mg protein, P < .05). Second, inositol 1,4,5-trisphosphate was released with postischemic reperfusion (103 +/- 18 to 207 +/- 11 pmol/mg protein), whereas release was not detected in normoxic myocardium. In agreement with this, neomycin (0.5 and 5 mmol/L) inhibited inositol phosphate release only under reperfusion conditions. Third, the reperfusion response, unlike the response in nonischemic tissue, required extracellular Ca2+. Longer periods of reperfusion resulted in a return to a pattern of inositol phosphate release that was not different from that seen in normoxic tissue. The rapid and transient release of inositol 1,4,5-trisphosphate at 2-minute postischemic reperfusion provides an explanation for the enhanced role of alpha 1-adrenergic receptors under these conditions and suggests an important role for this compound in initiating reperfusion-induced pathological events.

Animals↗
PubMed1995

Cardiovascular protection by oestrogen is partly mediated through modulation of autonomic nervous function.

Experimental studies have provided evidence that the autonomic nervous activity is modulated by oestrogen. Such modulation at central and peripheral levels tends to suppress sympathetic but elevate parasympathetic tone to the cardiovascular system. Thus, available data support the view that cardiovascular protection by oestrogen may, at least in part, be mediated by its influence on autonomic nervous function.

Adult↗
PubMed1994

HBPRCA Astra Award. Therapeutic restoration of endothelial function in hypercholesterolaemic subjects: effect of fish oils.

1. Endothelial dysfunction, evidenced as an impaired response to acetylcholine, is well documented in hypercholesterolaemic subjects. We examined the ability of dietary supplementation with fish oils to restore endothelial function in forearm resistance vessels in these patients and compared this with restoration by lipid-lowering therapy. 2. Responses of forearm blood flow to acetylcholine (4.6, 9.25, 18.5 and 37 micrograms/min) and sodium nitroprusside (200, 400, 800 and 1600 ng/min) were obtained using forearm venous occlusion plethysmography in nine hypercholesterolaemic and seven age-matched control subjects. The dose-response curve to acetylcholine was significantly blunted in hypercholesterolaemic subjects when compared with controls (P < 0.001). Responses to sodium nitroprusside were not different between the two groups (P = 0.37). 3. Lipid-lowering therapy decreased total plasma cholesterol levels by 33% and significantly augmented the responses to acetylcholine (P = 0.001) but not to sodium nitroprusside in the hypercholesterolaemic subjects. 4. Dietary supplementation with fish oils had no effect on either total or low density lipoprotein-cholesterol but significantly augmented the responses to acetylcholine (P = 0.011) in hypercholesterolaemic subjects. Responses to sodium nitroprusside were not altered (P = 0.94). 5. This study shows that endothelium-dependent relaxation is impaired in subjects with high cholesterol levels and that this impairment can be reversed by lowering low density lipoproteins (LDL) cholesterol levels. In addition, we demonstrate that restoration of endothelial function can occur without changes in LDL levels, by dietary supplementation with fish oils.

Acetylcholine↗
PubMed1994

Reperfusion following myocardial ischaemia enhances inositol phosphate release in the isolated perfused rat heart.

1. Global myocardial ischaemia (MI) for periods greater than 5 min caused an inhibition of phosphatidylinositol specific phospholipase C (PtdIns-PLC) activity. 2. Two min reperfusion following a 20 min MI period, a time point associated with reperfusion-induced arrhythmias, resulted in an activation of PtdIns-PLC activity, dependent on endogenous noradrenaline and mediated via alpha 1-adrenoceptors. 3. This 2 min reperfusion response, in contrast to healthy myocardium, resulted in: (i) enhanced PtdIns-PLC activity; (ii) increased sensitivity to endogenous noradrenaline; (iii) rapid increases in inositol(1,4,5)trisphosphate (Ins(1,4,5)P3); and (iv) PLC hydrolysis primarily of PtdIns(4,5)P2, such that the majority of InsP isomers derive from Ins(1,4,5)P3. 4. Together, these data suggest a functional role for Ins(1,4,5)P3 under post-ischaemic reperfusion conditions, and provide a possible link between alpha 1-adrenoceptor stimulation of the PtdIns turnover pathway and reperfusion injury.

Animals↗
PubMed1994

Sex differences in the parasympathetic nerve control of rat heart.

1. As it has been shown that oestrogen enhances the cholinergic muscarinic activity in the central nervous system, we studied sex differences in the response to parasympathetic nervous stimulation in the rat heart using in vivo and in vitro preparations. 2. In in situ perfused, innervated hearts, stimulation of bilateral vagus nerves (15 Hz with 1 mumol/L physostigmine) inhibited sympathetic nerve stimulation (5 Hz) induced noradrenaline release to a greater extent in female than in male rats (54 +/- 5 vs 72 +/- 5% of control). Similarly, vagus nerve stimulation at 1-20 Hz reduced heart rate (HR) more in females than males, and this sex difference became more marked in the presence of physostigmine. The chronotropic effect of vagal stimulation was attenuated after ovariectomy but potentiated after castration when compared with sham-operated controls. In contrast, the muscarinic agonist methacholine reduced neural NA release and HR equally well in both sexes. 3. In anaesthetized rats, reduction in HR and mean arterial pressure by vagus nerve stimulation (1-20 Hz) was more pronounced in females than in males after inhibition of acetylcholinesterase with physostigmine. 4. The results indicate that activation of parasympathetic nerve leads to greater presynaptic and postsynaptic effects in female than in male rat hearts, presumably due to a higher level of acetylcholine release following nerve activation.

Anesthesia↗
PubMed1994

Low cholesterol and impaired cardiac function following heart transplantation.

1. During follow-up of 59 cardiac transplant recipients over 2 or more years, a small group of subjects was observed who displayed an unpredictable, relatively marked, reduction in plasma cholesterol. 2. A significant proportion of these subjects were subsequently observed as having experienced a marked decline in left ventricular function at the time of routine radionuclide ventriculography. 3. While the mechanism for this fall in cholesterol is unclear, the observation of such an unexpected reduction in total cholesterol, late after heart transplantation should be considered significant and prompt further investigation including an assessment of allograft function.

Cholesterol↗
PubMed1994

Interactions between the effects of exercise and weight loss on risk factors, cardiovascular haemodynamics and left ventricular structure in overweight subjects.

OBJECTIVE: To assess the individual and combined effects of exercise and weight loss on the cardiovascular risk factors and cardiac left ventricular structure and function in overweight individuals. METHODS: A randomized, parallel-group, crossover study design was adopted. The following treatments were employed: exercise three times a week at 70% maximum work capacity for 30 min; dietary modification to achieve weight loss involving 4200 kj/day dietary restriction; and a combination of both exercise and dietary modification weight-loss programmes. Each subject was randomly assigned to one group only and was studied after a 12-week treatment and 12-week control period, performed in a random order. Thirty subjects entered the trial, 23 completing both treatment and control phases. RESULTS: Body weight remained unchanged with exercise alone and fell significantly both with weight loss and with the combination. The corresponding effects on blood pressure were also significant. Exercising groups also showed a significant increase in maximal oxygen consumption and a reduction in heart rate. Serum cholesterol and triglycerides fell significantly only after the combination, whereas high-density lipoprotein-cholesterol increased with exercise, decreased with weight loss and did not change with the combination. Interventricular septum and posterior wall thickness measurements remained unchanged after 12 weeks' treatment in all groups. No significant changes occurred in left ventricular internal diastolic diameter, wall thickness:radius ratio or the heart rate corrected ratio of peak early diastolic filling velocity:peak late diastolic filling velocity. Left ventricular mass and mass indexed to body surface area were not changed in any group. CONCLUSIONS: The results indicate that the effects of exercise and weight reduction on blood pressure are additive, although a positive interaction may exist with respect to lipids. Despite lowering blood pressure, exercise and weight loss had no effect on cardiac left ventricular structure or function in these overweight individuals.

Adult↗
PubMed1993

Sympathetic activation and increased extracellular potassium: synergistic effects on cardiac potassium uptake and arrhythmias.

During acute myocardial ischemia, a combination of increased extracellular K+ concentration and sympathetic nerve activation exists. Using a perfused innervated rat heart model, we studied the influence of increased extracellular K+ concentrations on neural norepinephrine (NE) release, adrenergic stimulation-induced K+ uptake by the heart, and the occurrence of ventricular arrhythmias. Hearts were globally perfused with control (4 mM) or increased concentrations of K+ (7-16 mM). Sympathetic nerve stimulation-induced NE release was analyzed by radioenzymatic assay. Cardiac K+ uptake was assessed by the reduction in K+ concentration in the coronary venous effluent induced by nerve stimulation. Neural NE release was not influenced by increasing K+ from 4 mM to 7, 10, and 13 mM, but was suppressed by 16 mM K+ (-40 +/- 10%). Nerve stimulation induced cardiac uptake of K+, which was blocked by the beta-adrenoceptor antagonist timolol. This stimulated K+ uptake was substantially enhanced by increasing extracellular K+ and was also dependent on the intensity of sympathetic stimulation at 10 mM K+. Sympathetic nerve stimulation, together with a high K+ of 10 mM, was potent in initiating ventricular tachyarrhythmias, and quantitative NE release was well correlated with the frequency of ventricular arrhythmias. Our results demonstrate the synergistic effects of increased extracellular K+ and sympathetic activation, which may be involved in the genesis of ventricular arrhythmias.

Animals↗
PubMed1992

Exercise training reduces the sympathetic component of the blood pressure-heart rate baroreflex in man.

1. Exercise training reduces resting sympathetic activity, but the effects on sympathetic activation or withdrawal during baroreflex responses to blood pressure perturbations are controversial. The purpose of this study was to investigate the effects of training on both the vagal and sympathetic reflex heart rate responses to blood pressure changes. 2. Using 10 healthy males in a randomized cross-over design, we examined the effects of three 30 min cycling sessions at 70% of maximal capacity for 4 weeks on the steady-state reflex heart rate responses to perturbations in mean arterial pressure induced with injections of nitroprusside and phenylephrine. The method provides a sigmoidal relationship between changes in heart rate and blood pressure. The upper plateau (maximum tachycardia in response to blood pressure reduction) and lower plateau (maximum bradycardia in response to blood pressure elevation) are mainly mediated by the cardiac sympathetics and vagus, respectively. The slope of the relationship is a measure of reflex gain. 3. Training, which increased maximal oxygen consumption by 13 +/- 2% (mean +/- standard error of the difference), reduced supine and standing blood pressures by 3 +/- 1/3 +/- 1 mmHg (P less than 0.05) and 4 +/- 1/2 +/- 2 mmHg (P less than 0.05 for systolic), respectively, whereas resting heart rate was lowered by 6 +/- 1 beats/min (P less than 0.05). Reflex sensitivity in the presence of functioning vagus and sympathetics was not altered with training, but the vagal component of sensitivity, as assessed after sympathetic blockade with propranolol, was significantly reduced.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Effects of 4 weeks endurance training on cardiac left ventricular structure and function.

1. The effect of 4 weeks of moderate exercise training on cardiac left ventricular structure and function was examined by repeated echocardiographic/Doppler examination in 10 previously sedentary volunteers participating in a single blind, sedentary phase controlled, cross-over study. 2. Left ventricular internal diastolic diameter increased after 4 weeks of training from 4.98 to 5.11 cm with a further increase to 5.24 cm after 2 weeks of detraining (s.e.d. 0.05 cm, P < 0.01). These increases were still significant after adjustment for heart rate which fell from a pretraining average of 67.0-59.9 beats/min after 4 weeks of training. 3. There were no significant changes in systolic diameter or function and left ventricular wall thicknesses were unchanged during training, but were thinned after 2 weeks subsequent detraining. 4. The ratio of early to late transmitral filling velocity (E/A ratio) was significantly increased by training. Although E/A ratio was shown to be heart rate sensitive, training effects were still evident after adjustment for heart rate. 5. These changes in left ventricular volumes and function may contribute to the cardiovascular reflex changes previously shown to be produced by identical training programmes.

Adult↗
PubMed1991

Aortic distensibility in patients with isolated hypercholesterolaemia, coronary artery disease, or cardiac transplant.

The stiffness of the thoracic aorta can be assessed non-invasively. If aortic stiffness can be shown to be related to coronary heart disease, perhaps it can be used to identify which patients with hypercholesterolaemia are most likely to have atheromatous changes and thus to be selected for intensive cholesterol-lowering treatment. Hence the distensibility of the transverse aortic arch was measured by echocardiography of the aortic arch in four groups of patients--symptom-free patients with normal serum cholesterol; symptom-free patients with raised serum cholesterol; patients with coronary heart disease (all with raised serum cholesterol), and post-heart-transplant patients. In all groups distensibility fell with age. The regression slope was steeper (p less than 0.05) for patients with known coronary disease than for either of the disease-free groups, and among cardiac transplant recipients there was also a segregation of distensibility values between those with and without atheroma in their native hearts. The results indicate that aortic distensibility might be an indicator of coronary heart disease and that it might be useful in identifying which symptom-free subjects with modest hypercholesterolaemia should be treated aggressively.

Aging↗