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Biomedical subjects

S G Ball

Publications and source records attributed to S G Ball.

At least 109 records · Page 6Linked to original sources
PubMed1994

Inhibition of ACE/kininase-II, acute myocardial infarction, and survival.

Three major trials, in patients with chronic heart failure, have shown that treatment with an ACE inhibitor reduces mortality. However, at the time of writing this review there continue to be strong grounds for uncertainty as to the role of these drugs after acute myocardial infarction in man. This uncertainty is exemplified by the findings of two recently published mortality trials, the CONSENSUS II and the SAVE investigations. Despite virtually identical premises, though widely differing therapeutic approaches, the observations reported in these two papers contrast markedly. In this review we have sought to analyse the possible reasons why the findings of the two trials differ. In our attempt to understand this important issue we have necessarily turned to smaller clinical studies, and also to investigations performed in animals. Furthermore, we review the investigational strategies which have been employed by other, currently unreported, large scale survival studies, as these will certainly hold many of the answers to the questions which the SAVE and CONSENSUS II trials have raised.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1994

ACE inhibition, atherosclerosis and myocardial infarction--the AIRE Study in practice. Acute Infarction Ramipril Efficacy Study.

Unlike most cell-types in the body, cardiomyocytes do not replicate in adult life. Consequently myocardial infarction produces irreparable damage to the heart which in turn increases the likelihood of premature death. Recent trials indicate that immediate aspirin and thrombolytic therapy beneficially modify the natural history of myocardial infarction, reducing both short- and long-term mortality rates. However, the occurrence of early heart failure in as many as one third of patients continues to carry with it a particularly poor prognosis. Recent trials with ACE inhibitors indicate that delayed initiation (beyond 24 h) and long-term maintenance treatment of patients selected on the basis of either heart failure (AIRE Study) or an ejection fraction of less than 40% (SAVE Study) result in large reductions in all-cause mortality. Although the exact mechanism of this benefit remains uncertain the reduction of further myocyte death due to reinfarction or gradual toxic attrition has been suggested. The currently unreported ISIS-4 and GISSI-3 should provide additional information as to whether the clinical indications for ACE-inhibitor therapy should be extended to other patient groups.

Coronary Artery Disease↗
PubMed1994

Comparative pharmacology of recombinant rat AT1A, AT1B and human AT1 receptors expressed by transfected COS-M6 cells.

1. Currently available antagonists and agonists cannot distinguish between angiotensin AT1 receptor subtypes. 2. We synthesized a series of compounds selected on the basis of having the most diverse structural features with respect to losartan (DuP753), the prototype non-peptide AT1 receptor antagonist. Using a radioligand-receptor binding assay and membranes prepared from COS-M6 cells transfected with individual AT1 receptor subtypes, we determined whether any of these compounds could distinguish between the receptor subtypes. 3. The diversity of the structural features of this series of compounds was reflected by the wide range of affinities (pIC50 values) displayed towards competing with [125I]-Sar1Ile8 angiotensin II for binding to the AT1 receptors. 4. Direct comparisons of the pIC50 values of individual compounds for rat AT1A, AT1B and human AT1 receptors revealed only minor differences. 5. It is concluded that compounds based structurally on losartan are unlikely to distinguish between these receptors.

Angiotensin I↗
PubMed1994

Cognitive-behavioral treatment of choking phobia: 3 case studies.

The present study describes 3 case examples of patients with choking phobia who were given a brief, cognitive-behavioral treatment that combined the interventions of psychoeducation, cognitive restructuring, interoceptive and in vivo exposure. This program was designed to address fears of anxiety and choking sensations as well as fears of swallowing. The patients were treated for 11-13 sessions. All 3 patients responded to the program as measured by their progression on their food hierarchy and by weight gain. Issues in the treatment of these patients are discussed.

Adult↗
PubMed1994

ACE-inhibitor therapy after myocardial infarction--a new treatment strategy.

Potential benefit or harm of drug therapy in patients with chronic congestive heart failure and those later presenting to hospital after an acute myocardial infarction (AMI) have been studied in a number of large-scale survival studies during the last few decades. Currently available data are reviewed in order to consider both methodology and also the clinical relevance of findings with emphasis on trials with ACE-inhibitors like CONSENSUS-II, the ISIS-4, GISSI-3 and Chinese mega-trials, TRACE, SAVE and AIRE. Results of SAVE and AIRE show a clear survival benefit for the patients. Furthermore, the benefit of both trials was in addition to any other benefit which resulted from aspirin, thrombolytic and beta-blocker therapies. In absolute terms, treatment of 1,000 patients with ramipril (AIRE) for 1 year would be expected to result in the prevention/delay of 40 premature deaths. The beneficial effects of ramipril were clearly apparent by 30 days though additional benefit beyond this point was also present. Furthermore, prespecified subgroup analysis revealed significant benefit for patients at risk like women and the elderly. A selective approach is argued for the treatment of patients with ACE-inhibitors after myocardial infarction.

Aged↗
PubMed1993

Phenoxybenzamine mediated inhibition of the vascular dopamine D1 receptor.

Cultures of rat mesenteric artery vascular smooth muscle cells express both vascular dopamine D1 receptors and beta 2-adrenoceptors but not alpha 1- or alpha 2-adrenoceptors, permitting direct investigation of the dopamine D1 receptor antagonist activity of phenoxybenzamine. After incubating cells with phenoxybenzamine (10(-5) M) for 20 min, an 80% inhibition of dopamine-induced (10(-4) M) cAMP formation was observed. Isoprenaline-induced (10(-5) M) cAMP formation remained unaffected by phenoxybenzamine. Inhibition of the dopamine response following 20 min incubation with phenoxybenzamine, was concentration-related and could not be reversed by repeated washing. Mean IC50 (95% confidence limits) = 4.68 x 10(-6) M (3.86-5.01). Exposure of cells to the selective dopamine D1 receptor partial agonist (+)-SKF 38393 (10(-6) M) prior to phenoxybenzamine incubation, resulted in protection of dopamine-induced cAMP formation. Exposure of cells to the stereo-enantiomer (-)-SKF 38393 (10(-6) M) did not produce any protective effect. The concentration-effect curve for (+)-SKF 38393 mediated protection had a mean EC50 value of 0.11 x 10(-6) M (0.10-0.11), which is comparable with the Ka apparent value (0.06 x 10(-6) M) for this compound when acting as an agonist to induce cAMP formation via the vascular dopamine D1 receptor. Previous studies of the vascular dopamine D1 receptor are likely to have been influenced by the frequent use of phenoxybenzamine, which we have shown to act as a potent antagonist at this site.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1993

Left ventricular hypertrophy and myocardial ischaemia in hypertension: the THAMES Study.

A multicentre epidemiological study to detect the prevalence of myocardial ischaemia in hypertensive left ventricular hypertrophy (LVH) was performed in 188 asymptomatic male hypertensives (131 treated). The mean age was 55 (range 40-82) years with blood pressure (BP) > or = 160/100 mmHg or a systolic BP > or = 180 mmHg. The participants were screened with echocardiography, and left ventricular hypertrophy (LVH), defined as LV mass index (LVMI) > or = 130 g.m-2, was found in 127 (68%), of whom 95 were on antihypertensive treatment. Patients with LVH underwent a maximal bicycle ergometer exercise test and significant ST depression, indicating possible stress-induced ischaemia, was found in 29 men (23%). These subjects were subjected to exercise thallium-201 scintigraphy, which was normal in 14 but showed reversible perfusion defects in 15. Thus, a high prevalence of LVH (70%) was detected in male hypertensives selected only on age and BP. In addition, although chest pain on exertion excluded patients from entry, a substantial portion had signs of ischaemia (23% on exercise ECG alone, and in 52% confirmed by thallium scan). The prevalence of these risk factors should be considered when evaluating hypertensive patients.

Adult↗
PubMed1993

Effect of inhibitors of eicosanoid metabolism on release of [3H]noradrenaline from the human neuroblastoma, SH-SY5Y.

Nordihydroguaiaretic acid (NDGA; a lipoxygenase inhibitor), LY-270766 (an inhibitor of 5-lipoxygenase), and the diacylglycerol lipase inhibitor RG 80267 completely eliminated potassium-evoked release of [3H]-noradrenaline ([3H]NA) from the human neuroblastoma clone SH-SY5Y with IC50 values of 10, 15, and 30 microM, respectively. In contrast, these inhibitors only partially inhibited carbachol-evoked release and had little effect on the calcium ionophore A23187-evoked release of NA in this cell line. Arachidonic acid partially inhibited potassium- and A23187-evoked release but did not reverse the inhibition of potassium-evoked release observed in the presence of RG 80267. These studies suggest that arachidonic acid (or its lipoxygenase products) are not important intermediates in the regulation of exocytosis in SH-SY5Y. This conclusion is strengthened by our studies in which SH-SY5Y cells were grown in medium supplemented with bovine serum albumin-linoleic acid (50 microM). Under these conditions there was a selective increase in content of membrane polyunsaturated fatty acids of the omega 6 series, including arachidonic acid; however, these changes did not effect potassium-, veratridine-, carbachol-, or calcium ionophore-evoked release of [3H]NA.

Arachidonic Acid↗
PubMed1993

Nicotinic receptor-mediated release of noradrenaline in the human neuroblastoma SH-SY5Y.

Dimethylphenylpiperazinium iodide (a nicotinic agonist) evokes noradrenaline release from human neuroblastoma SH-SY5Y cells that have been pretreated with 12-O-tetradecanoylphorbol 13-acetate for 8 min. This effect of dimethylphenylpiperazinium iodide was inhibited by 1 microM mecamylamine but not by 1 microM atropine, which suggests that SH-SY5Y cells express nicotinic receptors coupled to the release of noradrenaline. Dimethylphenylpiperazinium iodide-evoked release was enhanced by 5 microM Bay K 8644 (an L-type calcium agonist) and inhibited by 1 microM nifedipine. Dimethylphenylpiperazinium iodide depolarised SH-SY5Y cells and enhanced the level of intracellular calcium in cells loaded with fura 2. The effects of dimethylphenylpiperazinium iodide on noradrenaline release, depolarisation, and intracellular calcium levels were all inhibited by 1 microM desmethylimipramine. The results of this study show that nicotinic receptors in SH-SY5Y cells stimulate noradrenaline release by activation of L-type calcium channels.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1993

Pharmacological characterization of the dopamine receptor coupled to cyclic AMP formation expressed by rat mesenteric artery vascular smooth muscle cells in culture.

1. Mesenteric artery vascular smooth muscle cells derived from male Wistar rats and grown in culture were prelabelled with [3H]-adenine and exposed to a range of dopamine receptor agonists and antagonists. Resultant [3H]-cyclic AMP formation was determined and concentration-effect curves constructed, in the presence of propranolol (10-6) M) and the phosphodiesterase inhibitor IBMX (5 x 10(-4) M). 2. Ka apparent values for D1/DA1 dopamine receptor agonists SKF 38393, fenoldopam, 6,7-ADTN, and dopamine were 0.06, 0.59, 4.06 and 5.77 x 10(-6) M respectively. Although fenoldopam and SKF 38393 were more potent than dopamine, they were partial agonists with efficacies, relative to dopamine of approximately 48% and 24% respectively. 6,7-ADTN, in contrast, behaved as a full agonist. 3. Dopamine-stimulated cyclic AMP formation was inhibited in a concentration-dependent manner by the D1/DA1 dopamine receptor selective antagonists, SCH 23390 and cis-flupenthixol (Ki values 0.53 and 36.1 x 10(-1) M respectively). In contrast, the D2/DA2 dopamine receptor selective antagonists, domperidone and (-)-sulpiride, were less potent (Ki values 2.06 and 5.82 x 10(-6) M respectively). Furthermore, the stereoisomers of SCH 23390 and cis-flupenthixol, SCH 23388 and trans-flupenthixol, were at least two orders of magnitude less potent (Ki values 0.14 and 13.2 x 10(-6) M respectively) indicating the stereoselective nature of this receptor. 4. Our results indicate that rat mesenteric artery vascular smooth muscle cells in culture express a dopamine receptor coupled to cyclic AMP formation, which has the pharmacological profile, characteristic of the D1 dopamine receptor subfamily.

Animals↗
PubMed1993

Evaluation of ketanserin in the prevention of restenosis after percutaneous transluminal coronary angioplasty. A multicenter randomized double-blind placebo-controlled trial.

BACKGROUND: Ketanserin is a serotonin S2-receptor antagonist that inhibits the platelet activation and vasoconstriction induced by serotonin and also inhibits the mitogenic effect of serotonin on vascular smooth muscle cells. METHODS AND RESULTS: We conducted a randomized, double blind, placebo-controlled trial to assess the effect of ketanserin in restenosis prevention after percutaneous transluminal coronary angioplasty (PTCA). Patients received either ketanserin (loading dose, 40 mg 1 hour before PTCA; maintenance dose, 40 mg bid for 6 months) or matched placebo. In addition, all patients received aspirin for 6 months. Coronary angiograms before PTCA, after PTCA, and at 6 months were quantitatively analyzed. Six hundred fifty-eight patients were entered into the intention-to-treat analysis. The primary clinical end point of the study was the occurrence between PTCA and 6 months of any one of the following: cardiac death, myocardial infarction, the need for repeat angioplasty, or bypass surgery. It also included the need for revascularization actuated by findings at 6-month follow-up angiography. The primary clinical end point was reached by 92 (28%) patients in the ketanserin group and 104 (32%) in the placebo group (RR, 0.89; 95% CI, 0.70, 1.13; P = .38). Quantitative angiography after PTCA and at follow-up was available in 592 patients (ketanserin, 287; control, 305). The mean difference in minimal lumen diameter between post-PTCA and follow-up angiogram (primary angiographic end point) was 0.27 +/- 0.49 mm in the ketanserin group and 0.24 +/- 0.52 mm in the control group (difference, 0.03 mm; 95% CI, -0.05, 0.11; P = .50). CONCLUSIONS: Ketanserin at the dose administered in this trial failed to reduce the loss in minimal lumen diameter during follow-up after PTCA and did not significantly improve the clinical outcome.

Adult↗
PubMed1993

Early or late ACE inhibition after myocardial infarction.

There is justifiable enthusiasm for the use of angiotensin-converting enzyme (ACE) inhibitors in patients with heart failure. However, early after an acute myocardial infarction, the benefits (or harm) from use of these agents in individual patients may depend on the critical balance between the ischemic problem (the extent of coronary artery narrowing and risk of vessel occlusion) against the need to preserve remaining ventricular function. Patients who are hemodynamically stable without ongoing chest pain but with significantly impaired ventricular function seem likely to gain most from treatment with ACE inhibitors. Extrapolation to the acute infarct situation from the recently published trials in chronic stable heart failure may mislead, and the findings of a number of large ongoing mortality trials in patients with recent myocardial infarction are awaited.

Angiotensin-Converting Enzyme Inhibitors↗