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Biomedical subjects

S G Ball

Publications and source records attributed to S G Ball.

At least 91 records · Page 5Linked to original sources
PubMed1996

Who should be treated with angiotensin-converting enzyme inhibitors after myocardial infarction?

Angiotensin-converting enzyme (ACE) inhibitors are now established drugs in the treatment of hypertension and heart failure. However, their use in patients after a myocardial infarction has occurred remains controversial. The major clinical question regarding ACE inhibitors is whether they should be given to all patients immediately after thrombolysis or whether their use should be restricted to a particular subgroup. This question has now been addressed in several large-scale trials of mortality after myocardial infarction, and no important new information seems likely to emerge on the issue. Clinicians must therefore decide what their practice will be on the basis of data that are currently available. The authors of the recently published Gruppo italiano per lo Studio delta Sopravvlvenza nell' infarcto Miocardico (GISSI-3) and Fourth International Study of Infarct Survival (ISIS-4) mega-trials advocate a policy of widespread and early use of ACE inhibitors in all patients after myocardial infarction occurs. However, the small mortality benefit observed from use of ACE inhibitors in these studies lacks certainly and may prove difficult to reproduce in the general population of patients who have had an infarct outside the setting of a trial. Although patients were essentially not selected apart from the exclusion of those with marked hypotension, the low 6-month and 1-year mortality figures indicate "selection" compared with the typical population of patients who have had a myocardial infarction. Furthermore, a significant long-term mortality benefit was not observed with the short-term (4- to 6-week) use of ACE inhibitors in these trials. In contrast, in the Survival and Ventricular Enlargement (SAVE), Acute Infarction Ramipril Efficacy (AIRE), and Trandopril Cardiac Evaluation (TRACE) trials, where evidence of impairment of ventricular function was used to select patients, both a marked and certain benefit regarding mortality was apparent from long-term prescription of these drugs. Importantly, the marked benefit observed in these selected patients may have been "diluted out" in the larger scale trials of unselected patients where the majority may have gained little and some may have been harmed by treatment or its withdrawal. In most of the large mortality trials the rationale for use of ACE inhibitors after myocardial infarction was stated to be their likely beneficial effect on "remodeling" of the heart after "Infarct expansion." Because adverse remodeling occurs in only a proportion of patients after a heart attack, the benefits of ACE inhibitor therapy might be predicted to be largely limited to this group, which would favor a selective policy. However, strong claims have been made that ACE inhibitors have other important actions, including prevention of myocardial infarction. If this is confirmed in a number of ongoing large-scale trials. then an even ore widespread use of these agents can be expected.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1996

What have the ACE-inhibitor trials in postmyocardial patients with left ventricular dysfunction taught us?

A series of elegant experimental studies and careful clinical observation over a decade or more have led to the concept of 'infarct expansion' and 'remodelling' of the heart, culminating in a number of major mortality studies indicating the effectiveness of angiotensin-converting enzyme (ACE) inhibitors in patients after myocardial infarction (MI). But has this concept been too narrow in predicting which patients might benefit from treatment with ACE inhibitors? Measurable infarct-expansion with progressive dilatation probably occurs in less than 20% of patients, whereas increase in volume and hypertrophy of the heart as responses to compromised function are likely wherever significant myocardial damage has occurred. Irrespective of infarct expansion, cumulative extensive damage can lead to an inevitable downward spiral with gross ventricular dilatation and death in heart failure. But in the majority of patients after MI a 'new equilibrium' is established in which initial dilatation and subsequently hypertrophy restore adequate function. Is it possible to distinguish patients in whom the cost and inconvenience of long-term therapy with an ACE inhibitor justify the likely benefit from treatment after an MI? The SAVE, AIRE and recent TRACE studies allow a rational approach for the clinician, indicating the effectiveness of these drugs in patients with evidence of impaired ventricular function. However, the prospect that ACE inhibitors prescribed long term might also prevent myocardial reinfarction could justify wider use. Post-MI patients are an easily identifiable high-risk group for a cost-effective programme of secondary prevention. Reinfarction in an already damaged ventricle carries a particularly poor prognosis and its prevention by ACE inhibitors could make a major contribution to the undoubted benefit from these agents. The recently completed TRACE study with its long-term follow-up may help resolve this issue, which is also being investigated in a number of long-term prospective studies in populations at high risk of cardiovascular disease.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1996

Bilateral spontaneous dissecting aneurysm of the internal carotid arteries: report of two cases.

Spontaneous dissection (dissecting aneurysm) of the internal carotid artery is a common cause of ischemic stroke in young patients. Very infrequently, dissecting aneurysm of the internal carotid artery occurs bilaterally. This paper presents two such cases and discusses in detail variations in the time of occurrence, the angiographic characteristics and possible predisposing factors.

Aortic Dissection↗
PubMed1995

The effect of the angiotensin II (AT1A) receptor stably transfected into human neuroblastoma SH-SY5Y cells on noradrenaline release and changes in intracellular calcium.

A stable cell line expressing the angiotensin II (AII) receptor has been obtained by transfecting the human neuroblastoma SH-SY5Y with the plasmid pCEP4 containing the entire coding region of the rat angiotensin AII receptor AT1A. Angiotensin II (AII; 1-100 nM) evokes the release of [3H]noradrenaline ([3H]NA) in this cell line. Pretreatment with 100 nM 12-O-tetradecanoylphorbol-13-acetate (TPA) enhances the AII-evoked release of [3H]NA approximately two-fold. Removal of extracellular Ca2+ ([Ca2+]o) decreases 100 nM AII-evoked release of [3H]NA by over 50% both in the presence and absence of TPA. AII increases intracellular Ca2+ ([Ca2+]i) in this cell line which is consistent with the AT1A receptor being coupled to phospholipase C. Pretreatment with 100 nM TPA for 8 min attenuated the effect of AII on [Ca2+]i. The effects of AT1A receptor stimulation are therefore regulated differently in this cell line by activation of protein kinase C (PKC). Thus a useful cell line has been obtained from the human neuroblastoma SH-SY5Y in which to study at the molecular level the mechanism(s) by which AII regulates NA release.

Angiotensin II↗
PubMed1995

Functional domains of the C-terminus of the rat angiotensin AT1A receptor.

Previous work has shown that truncating the carboxyl terminus (C-terminus) of the rat angiotensin AT1A receptor to 309 amino acids abolished G-protein coupling and receptor internalization. This suggests that domains responsible for these functions lie beyond amino acid 309 of the C-terminus. The objective of this study was to determine the effect on angiotensin AT1A receptor function and regulation of deleting 41 amino acids from the C-terminus, which include the putative protein kinase C phosphorylation sites. Using site directed mutagenesis, the codon for Tyr319 was converted to a stop codon and the resulting truncated receptor permanently expressed in cultured human kidney cells. The properties of the truncated receptor were compared to those of the full length receptor. Expression of the truncated receptor was confirmed by sodium dodecyl sulphate polyacrylamide gel electrophoresis analysis of photolabelled membrane preparations. Angiotensin II activation of both full length and truncated receptors resulted in mobilization of inositol phosphates. However, whereas this was associated with rapid internalization of the full length receptor, the truncated receptor failed to internalize. Furthermore, pretreatment of cells with phorbol 12-myristate 13-acetate, a direct activator of protein kinase C, markedly attenuated the full length, but no the truncated receptor's ability to mobilise inositol phosphates. Thus, we conclude that the domain between amino acids 309 & 318 is important for G-protein coupling; that amino acids beyond 318 regulate internalization and one or more of the putative protein kinase C phosphorylation sites, present in the C-terminus of the angiotensin At1A receptor, actively regulate the receptor.

Angiotensin II↗
PubMed1995

The effect of barium on [3H]noradrenalin release from the human neuroblastoma SH-SY5Y.

Replacement of Ca2+ with Ba2+ in HEPES-buffered saline stimulated [3H]noradrenalin release in the human neuroblastoma clone SH-SY5Y by up to 20% of the cell content in the absence of other secretory stimuli. The Ba(2+)-evoked release was inhibited by 85% by 3 microM tetrodotoxin and 95% by 5 microM nifedipine. Ba2+ also increased the potency of K(+)-evoked release of [3H]noradrenalin, as maximal release was observed with 60 mM K+ compared with the 100 mM K+ necessary to achieve maximal release in the presence of Ca2+. In contrast, replacing Ca2+ with Ba2+ had little effect on carbachol- and bradykinin-evoked release of [3H]noradrenalin. No evidence was obtained from studies on changes in [Ca2+]i (in response to 100 microM carbachol) using fura-2 that Ba2+ could enter intracellular stores in SH-SY5Y cells. Whole-cell patch-clamp studies showed that Ba2+ depolarizes SH-SY5Y cells as well as enhancing inward Ca2+ channel currents and shifting their voltage dependence to more negative values. These results are discussed in terms of the hypothesis that Ba2+ blocks K+ channels, leading to depolarization followed by opening of voltage-sensitive Na+ channels. This in turn opens voltage-sensitive L-type Ca2+ channels, which are coupled to the release of [3H]noradrenalin in SH-SY5Y cells.

Barium↗
PubMed1995

Glucocorticoids regulate the expression of angiotensin AT1 receptors, in the human hepatoma cell line, PLC-PRF-5.

The effects of different steroids on the expression of angiotensin AT1 receptors by the human hepatoma cell line, PLC-PRF-5 was studied. Dexamethasone and aldosterone decreased the specific binding of [3H]angiotensin II to intact PLC-PRF-5 cells by 57 +/- 4% and 54 +/- 2%, respectively, compared to control, untreated cells. EC50 values for dexamethasone, cortisol and aldosterone were 1.8 +/- 0.6, 40 +/- 6, and 310 +/- 20 nM, respectively, suggesting that these effects were mediated via a glucocorticoid receptor. Scatchard analysis revealed that dexamethasone decreased the number of angiotensin AT1 receptors expressed (50 +/- 4% relative to control) with no change in receptor affinity. Treating cells with dexamethasone in the presence of either an angiotensin converting enzyme inhibitor or an angiotensin II receptor antagonist did not prevent the reduction in angiotensin AT1 receptor expression, ruling out a mechanism involving a dexamethasone induced increase in endogenous angiotensin II production. A ribonuclease protection assay established that the steady state level of angiotensin AT1 receptor mRNA in dexamethasone treated cells was reduced to 34.7 +/- 8.4% of untreated cells. The decrease in the number of angiotensin AT1 receptors expressed on the cell surface after treatment with dexamethasone therefore seems likely to reflect the decreased steady state level of the mRNA coding for this receptor.

Angiotensin II↗
PubMed1995

Angiotensin-converting enzyme inhibitors after myocardial infarction: indications and timing.

A number of major studies have examined the impact of angiotensin-converting enzyme inhibitors on mortality in patients with ischemic heart disease. However, in these studies, selection of patients, choice of agent and timing of treatment after myocardial infarction have differed. In the Second Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS II), all patients, unless hypotensive, were treated immediately after thrombolysis with placebo or intravenous enalaprilat followed by oral therapy. In contrast, in the Survival and Ventricular Enlargement (SAVE) study, patients were selected with a reduced radionuclide ejection fraction and without overt ongoing ischemia. Despite these different approaches, both studies were based on the rationale that angiotensin-converting enzyme inhibition would beneficially affect infarct expansion and subsequent remodeling. The SAVE study reported a significant reduction in mortality rate (19% risk reduction, 95% confidence interval [CI] 3% to 32%) over an average follow-up period of 42 months, but with no observable impact on mortality rate until almost 1 year into treatment. The CONSENSUS II trial closed prematurely, with no benefit (a 10% increase in risk, 95% CI 7% reduction to 29% increase) apparent from enalapril after 6 months of follow-up. The recently reported but unpublished findings of Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI-3) and the Fourth International Study of Infarct Survival (ISIS-4) indicate a small benefit from early (within 24 h) short-term (4 to 6 weeks) treatment of all patients, unless hypotensive, after a myocardial infarction.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1995

Depression and generalized anxiety symptoms in panic disorder. Implications for comorbidity.

Questionnaires and clinician rating scales have been used to assess anxious and depressive symptoms among patients with panic disorder, but these methods do not usually evaluate symptoms in the same terms as the standardized criteria of diagnostic interviews. The present study provides data on the prevalence of symptoms of major depressive disorder and generalized anxiety disorder in 64 patients with panic disorder. Symptoms were assessed using DSM-III-R definitional criteria that consider not only the presence and severity of symptoms, but also their duration and pervasiveness. Depressive symptoms that most frequently met definitional criteria for diagnostic significance were fatigue, insomnia, and concentration difficulties. Over 50% of the sample endorsed feelings of tension, irritability, and restlessness. Disturbances in appetite, feelings of worthlessness, and suicidal ideation were found in less than 10% of the nondepressed panic patients. The implications of these findings for conceptualizing the comorbidity among anxiety and depressive disorders are discussed.

Adult↗
PubMed1995

Clinical background to the use of ACE inhibitor therapy after myocardial infarction.

The rationale for using angiotensin converting enzyme (ACE) inhibitor therapy after acute myocardial infarction has been largely founded on observations made in experimental situations, and in humans before the routine introduction of reperfusion therapies. An important area of ongoing debate therefore continues to be the role of ACE inhibition as an early adjunct to attempts to achieve and maintain patency of infarct-related coronary arteries. Data from clinical trials indicate a substantial survival benefit in patients with impaired ventricular function, but provide little support for the routine treatment of the remaining majority of patients. An important issue in determining whether these agents should be used in a more general and long-term secondary prevention role, is their potential ability to prevent subsequent reinfarction. However, such a strategy is unlikely to be enhanced by either immediate initiation of treatment or withdrawal after just 1 month of therapy.

Angiotensin II↗
PubMed1994

Bradykinin-evoked release of [3H]noradrenaline from the human neuroblastoma SH-SY5Y.

Bradykinin (BK) evoked [3H]noradrenaline ([3H]NA) release from the human neuroblastoma SH-SY5Y and this was enhanced by pre-treatment with 12-O-tetradecanoylphorbol 13-acetate (TPA) for 8 min. This effect of BK was inhibited by 500 microM [D-Phe7]BK and 100 microM [Thi5,8,D-Phe7]BK but not by 500 microM [Des-Arg9,Leu8]BK. The BK (B1)-agonist [Des-Arg9]BK did not evoke [3H]NA release. This suggested that SH-SY5Y expressed BK (B2)-receptors coupled to the release of [3H]NA. BK acting at B2-receptors, also elevated intracellular calcium and depolarized SH-SY5Y cells. Although pre-treatment of SH-SY5Y cells with TPA enhanced BK-evoked [3H]NA release, the elevation of intracellular calcium [Ca2+]; was decreased by about 50%. BK-evoked release of [3H]NA in cells not pre-treated with phorbol ester was only 23% dependent on extracellular calcium. In comparison, following phorbol ester treatment approximately 40% of [3H]NA release was dependent on extracellular calcium. Nifedipine (5 microM), CoCl2 (1 mM) and NiCl2 (1 mM) inhibited NA release in SH-SY5Y cells pre-treated with TPA by 16.0, 47 and 44%, respectively. The results of this study showed that BK, acting at B2-receptors, activated [3H]NA release in SH-SY5Y. Part of this effect appeared to be due to activation of L-type calcium channels but the majority of BK-evoked [3H]NA release in SH-SY5Y cells appeared to depend on [Ca2+]i.

Bradykinin↗
PubMed1994

A role for protein kinase C subtypes alpha and epsilon in phorbol-ester-enhanced K(+)- and carbachol-evoked noradrenaline release from the human neuroblastoma SH-SY5Y.

Protein kinase C (PKC) consists of a family of closely related subtypes which differ in their localization and activation properties. Our previous studies have suggested a role for PKC in the regulation of noradrenaline (NA) release from the human neuroblastoma SH-SY5Y. Here we have used two approaches to characterize the PKC subtypes present in SH-SY5Y cells. Firstly, the PCR was used to show that SH-SY5Y cells contain mRNA encoding PKC subtypes alpha, beta, gamma, delta, epsilon and zeta. Secondly, immunoblotting showed that SH-SY5Y cells express PKC subtypes alpha, epsilon and zeta at the protein level. Prolonged (48 h) exposure of cells to the phorbol ester phorbol 12-myristate 13-acetate (PMA; 100 nM) resulted in a marked decrease in the amounts of PKC-alpha and PKC-epsilon, with no change in levels of PKC-zeta. Prolonged PMA treatment had no significant effect on K(+)-evoked NA release from SH-SY5Y cells, whereas carbachol-evoked release was increased 2.2-fold. However, prolonged exposure to PMA completely inhibited the ability of acute (12 min) PMA treatment to enhance both K(+)- and carbachol-evoked NA release. The specific PKC inhibitor RO 31-7459 (10 microM) was found to inhibit K(+)- and carbachol-evoked release by 27% and 68% respectively. RO 31-7549 also completely inhibited the ability of acute PMA treatment to enhance release. These data suggest that PKC-alpha and/or PKC-epsilon play an essential role in the regulation of PMA-enhanced K(+)- and carbachol-evoked NA release in SH-SY5Y cells.

Base Sequence↗
PubMed1994

Predicting prospective episodes of depression in patients with panic disorder: a longitudinal study.

This study used a naturalistic, longitudinal study to examine predictors of the emergence of major depression among 90 nondepressed patients with panic disorder who were followed for a 2-year period. Twenty-four percent of the sample experienced a major depressive episode during the study period. Adequacy and type of medication treatment were not associated with decreased risk. Past history of major depression was associated with a greater risk for a prospective episode. The degree of assertiveness, presence of comorbid generalized anxiety disorder, and severity of agoraphobia were each significant predictors of the occurrence of depression when considered alone and when the influence of past history of depression was statistically controlled. The implications of these findings for the clinical management of patients with panic disorder are discussed.

Adolescent↗
PubMed1994

Effects of ischaemic conditions on uptake of glutamate, aspartate, and noradrenaline by cell lines derived from the human nervous system.

The effect of hypoglycaemic, hypoxic, and ischaemic conditions on high-affinity neurotransmitter transport was studied in the human astrocytoma clone D384 and the human neuroblastoma clone SH-SY5Y. Both cell lines expressed a sodium-dependent glutamate/aspartate transporter. Km values for D-[3H]aspartate uptake were 6.1 +/- 0.9 microM for D384 cells and 5.3 +/- 0.3 microM for SH-SY5Y cells (mean +/- SEM of three experiments). In addition, SH-SY5Y, but not D384, expressed a sodium-dependent noradrenaline transporter with Km = 0.6 +/- 0.1 microM (mean +/- SEM of three experiments). Up to 3 h of hypoglycaemic conditions had no effect on neurotransmitter uptake or on ATP levels of each cell line. In sharp contrast, during hypoxic conditions, the uptake of D-[3H]-aspartate and [3H]noradrenaline declined by 43-56% within 5 min. These reduced rates of neurotransmitter uptake were maintained over 30 min of hypoxic conditions. Five minutes of ischaemic conditions caused similar reductions in neurotransmitter uptake rates. A correlation between reductions in rates of neurotransmitter uptake and in ATP levels was observed for each cell line. Results are discussed in relation to other brain preparations, which are used as models of the nervous system to study the effects of ischaemic conditions on neurotransmitter and energy metabolism.

Aspartic Acid↗