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Articles
Mohammed MANSARAY, John W. HYND, Isobel VERGROESEN, Philip R. BELCHER, Angela J. DRAKE-HOLLAND, Mark I. M. NOBLE
Journal:
Clinical Science
Clin Sci (Lond) (2001) 100 (4): 405–410.
Published: 06 March 2001
Abstract
We investigated the effect of thrombosis in one coronary artery upon the vascular resistance of another coronary artery. In previous investigations, using an animal model of unstable angina, we have observed increased resistance downstream from thrombus within a left circumflex coronary artery (LCx) stenosis and vasoconstriction of collateral vessels from the left anterior descending artery (LAD) supplying the distal LCx vascular bed. In the present paper, we induced thrombosis within a stenosis of the LCx of 16 beagle dogs, and observed the changes in blood flow to the myocardium supplied by the LAD using the radioactive microsphere technique. This blood flow decreased with thrombosis ( P = 0.005) in these animals, whereas it did not do so in three time-control experiments. The pressures across the coronary vascular bed, i.e. arterial pressure to coronary venous pressure (coronary sinus catheter), did not change. Thus the vascular resistance of the LAD bed increased significantly from 147±ll.5 mmHg/ml/sec/g of tissue to 172±13.4 mmHg/ml/sec/g of tissue ( P = 0.02). As the LAD territory is not perfused with blood from the artery containing thrombus, we conclude that the effect observed is caused either by release of vasoconstrictors from the thrombus into the general circulation, or by activation of a neural reflex vasoconstriction. The study suggests that unstable angina involving thrombosis in one coronary artery is a global coronary vascular disease.
Articles
Journal:
Clinical Science
Clin Sci (Lond) (1999) 97 (3): 323–329.
Published: 21 July 1999
Abstract
The exocytosis of intracellular vesicles is an important function of the plasma membrane, which is responsible for hormone secretion, cell surface expression of antigens, ion transporters and receptors, and intracellular and intercellular signalling. Human aging is associated with many physiological and cellular changes, many of which are due to alterations in plasma membrane functioning. Alterations in vesicle externalization with age could account for many of these changes. We investigated whether alterations in vesicle exocytosis occur with increasing age by flow-cytometric determination of CD11b and CD69 expression on the surface of human polymorphonuclear leucocytes (PMN) stimulated with phorbol myristate acetate (PMA), a tumour promoter which binds to and activates protein kinase C (PKC) directly, or with formyl-Met-Leu-Phe (fMLP), which activates PKC indirectly via interactions with a cell surface receptor and G-protein, and subsequent inositol phosphate hydrolysis. Following stimulation with PMA, a decrease in the proportion of PMN expressing CD69 at high levels was observed in elderly compared with young subjects (young, 55.3%; elderly, 43.9%; P = 0.01). No aging-related differences in the proportion of PMN expressing CD11b (young, 73.7%; elderly, 68.4%; P = 0.15), or in the number of molecules of CD69 or CD11b expressed per cell, were observed. Stimulation with fMLP or low PMA concentrations resulted in full CD11b expression but minimal CD69 expression in both young and elderly subjects. Cells which expressed CD69 had no CD11b expression, while those cells expressing CD11b had minimal CD69 expression. Thus the PMA-induced expression of CD11b and CD69 in human PMN represents two separate processes, only one of which is affected in aging. CD11b expression appears to require a lesser degree of PKC stimulation compared with that required for CD69 expression. The age-associated reduction in PMA-stimulated CD69 expression may occur either at or distal to PKC activation. Such a decrease may contribute to the age-associated impairments in PMN function that contribute, in turn, to immunosenescence.
Articles
Journal:
Clinical Science
Clin Sci (Lond) (1999) 96 (6): 589–595.
Published: 07 May 1999
Abstract
We re-examined, in the context of modern practice, plasma insulin and stress hormone concentrations in patients admitted to hospital with acute coronary syndromes. Venous blood sampling was carried out prior to anti-thrombotic therapy in 148 patients with myocardial infarction (MI); 76 patients with unstable angina (UA) pectoris were also studied, together with 27 patients with non-cardiac chest pain (NCP). There were significant progressive increases in the concentrations of catecholamines, cortisol, glucose and insulin from NCP to UA to MI patients. Hyperglycaemia (glucose > 8 mmol/l) was present in over 50% of MI patients. The plasma cortisol and insulin levels were both significantly positively correlated with the glucose concentration on admission. Only the cortisol concentration was correlated with peak cardiac enzyme levels. The glucose and insulin concentrations on admission in 141 MI and UA patients were related to insulin resistance, as judged from subsequent insulin and glucose concentrations measured while fasting and during a glucose tolerance test. The product of admission insulin×glucose (divided by 25; the admission insulin-resistance index, or AIRI) was significantly correlated with indices of insulin resistance, and was significantly higher (approximately double) in the MI group (7.81±0.76) and the UA group (6.88±1.19) than in the control NCP group (3.59±0.06; Kuskul–Wallis: P = 0.0001), implying that the insulin levels in the first two groups were approximately twice as high as is appropriate for the glucose levels. The ethnic origin of 20% of the patients was the Indian subcontinent; admission insulin and glucose levels in this subgroup were higher than in the non-Asians across all the groups with chest pain. Cortisol was the only stress hormone that was raised in proportion to the size of the infarct, and is a likely partial cause of the elevation in blood glucose. The high insulin levels were related to the prevalence of insulin resistance, and this was particularly important in the Asian subgroup presenting with MI and UA. Thus it appears feasible to identify acute coronary syndrome patients who are insulin-resistant at a time (on admission) when alternative early therapeutic strategies can be instituted.
Articles
Journal:
Clinical Science
Clin Sci (Lond) (1997) 93 (3): 213–218.
Published: 01 September 1997
Abstract
1. Pacing-induced heart failure was studied in eight dogs. Heart failure was induced by right ventricular pacing at 250–260 beats/min for 6 weeks. Evidence of heart failure was determined clinically and by measurement of left ventricular (LV) dimensions by transoesophageal echocardiography. 2. Haemodynamic measurements of LV pressure, maximum rate of rise of LV pressure (LVdP/d t max ), cardiac output, mean arterial pressure, heart rate, pulmonary artery and pulmonary wedge pressures were made during infusion of solvent (control) and the calcium sensitizer EMD 57033 (0.6 mg min −1 kg −1 ). 3. The degree of heart failure varied from mild to severe in different individuals, but in each case EMD 57033 exerted a positive inotropic effect on LV haemodynamics and dimension. 4. The positive inotropic effect of the calcium sensitizer was manifest by increased peak LVdP/d t with a subsequent increase in cardiac output at the same mean arterial pressure. 5. This study clearly demonstrates that there is the potential for improvement of contractility of the failing myocardium of the intact mammal by an agent with a mechanism of action which does not involve an increase in intracellular calcium.
Articles
Journal:
Clinical Science
Clin Sci (Lond) (1996) 91 (1): 87–92.
Published: 01 July 1996
Abstract
1. In view of the importance of 5-hydroxytryptamine in coronary thrombosis, we wanted to know whether a potentially protective decrease in platelet 5-hydroxytryptamine could be achieved by treatment with an inhibitor of 5-hydroxytryptamine uptake, fluoxetine. 2. We studied 15 patients treated for psychiatric indications with fluoxetine, and compared the findings with those obtained with blood from 18 patients treated with amitriptyline and 13 controls previously treated for affective disorders. 3. Platelet-rich plasma 5-hydroxytryptamine levels were significantly decreased in the fluoxetine group ( P > 0.005) but not in the amitriptyline group compared with the control group. 4. Collagen-induced aggregation in whole blood anti-coagulated with hirudin was measured by sequential single platelet counting. The contribution of 5-hydroxytryptamine was assessed from the effect of adding the 5-hydroxytryptamine specific antagonist ICI 170809. This contribution was significantly decreased in the fluoxetine group but not in the amitriptyline group compared with the control group. 5. It is concluded that platelet 5-hydroxytryptamine is indeed decreased by fluoxetine, and we would predict a protective effect of fluoxetine against coronary thrombosis.
Articles
Journal:
Clinical Science
Clin Sci (Lond) (1996) 90 (5): 363–368.
Published: 01 May 1996
Abstract
1. Recurrent occlusion after thrombolysis may be caused by thrombin receptor-mediated platelet thrombosis occurring in a residual stenosis. To test the relative importance of the platelet thrombin receptor under conditions of high shear and endothelial damage (the Folts model of intracoronary thrombosis) we used the specific thrombin inhibitor recombinant hirudin. 2. A critical coronary artery stenosis overlying an area of crushed endothelium was used in a repeated measures study of eight open-chest anaesthetized dogs. In the control period, recurrent thrombosis occurred at an average rate (± SD) of 4.4 ± 1.4 ml/min 2 . Infusion of recombinant hirudin at 1.6 mg h −1 kg −1 abolished recurrent thrombosis in three dogs, but the thrombosis rate averaged 4.7 ± 2.9 ml/min 2 in the remaining five animals. 3. Haematological measurements demonstrated the activity of recombinant hirudin: thrombin time rose from 13 ± 3 s to>165 s universally ( P <0.01), partial thromboplastin time rose from 14 ± 2 s to 29 ± 10 s ( P <0.01). Bleeding time rose from 2.3 ± 0.8 min to 4.7 ± 1.8 min ( P <0.05). 4. It is concluded that specific thrombin inhibition, despite affecting coagulation, is relatively ineffective in preventing intracoronary thrombosis under conditions of high shear.
Articles
Valentine C. Menys, Philip R. Belcher, Mark I. M. Noble, George E. Drossos, Ravi Pillai, Steve Westaby
Journal:
Clinical Science
Clin Sci (Lond) (1995) 88 (3): 269–275.
Published: 01 March 1995
Abstract
1. We tested the effect of intravenous adrenaline at 0.55–1.10 nmol min −1 kg −1 (for 3–8 min, at 7–10 min post bypass; n = 7) on both microaggregation in hirudinized whole blood, using platelet counting, and macroaggregation in platelet-rich plasma, using optical aggregometry. Control ( n = 12) blood samples were taken before and at 10 and 20 min after bypass. 2. Post-bypass plasma adrenaline levels (nmol/l) increased slightly in controls (1.0 versus 0.7 at 10 min, medians; P = 0.05) and markedly with adrenaline infusion (36 versus 0.5 before infusion, P = 0.02). Microaggregation (percentage decrease in single platelets) in stirred blood, reflecting largely ADP-dependent ‘spontaneous’ aggregation, was not influenced by adrenaline infusion. In contrast, collagen (0.2 μg/ml)-induced microaggregation in blood was enhanced by adrenaline (92% versus 41%, P = 0.02), with no change in controls (60% versus 53%, P = 0.61). 3. In controls, collagen (0.6 μg/ml)-induced macroaggregation in platelet-rich plasma (extent of increase in light transmission, cm) was impaired at 10 min post bypass (5.3 versus 12.1 before bypass, P = 0.01), but was enhanced by adrenaline (7.0 versus 3.6 before infusion, P = 0.02). Platelet counts (×10 9 /1) were decreased postbypass (155 versus 220, P = 0.02) and were not influenced by adrenaline infusion (167, P = 0.93). 4. In conclusion, following bypass and at normocalcaemia, adrenaline enhances collagen-induced aggregation in both plasma and whole blood ex vivo , independently of any change in platelet counts, but has no effect on stirring-induced ‘spontaneous’ aggregation in blood.
Articles
Journal:
Clinical Science
Clin Sci (Lond) (1994) 87 (5): 547–551.
Published: 01 November 1994
Abstract
1. An increase in length in isolated animal muscles causes an immediate increase in contractile force, which is followed by a slower further progressive increase: the slow component. However, the pressure-volume concept, used in characterizing left ventricular function, is dependent on a constant relationship between pressure and volume. 2. We therefore examined the possible occurrence of the slow inotropic component of the response to cardiac muscle stretch in man at cardiac catheterization. 3. Human subjects undergoing left heart catheterization for clinical indications were studied. The development of the slow component was studied by measurement of rate of rise in left ventricular developed pressure and the time course after an increase in end-diastolic volume. 4. No evidence for any slow component was elicited. 5. It is concluded that the slow component of force (or pressure) increase after an increase in cardiac muscle length (or volume) does not have a role in the human heart in situ.
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Articles
K P Walsh, T D M Williams, S R Morris, A J Drake-Holland, M I M Noble, E Pitts, S L Lightman, R Sutton
Journal:
Clinical Science
Clin Sci (Lond) (1988) 74 (s18): 61P–62P.
Published: 01 January 1988
Articles
K P Walsh, T D M Williams, M I M Noble, A J Drake-Holland, C Spiteri, E Pitts, S L Lightman, R Sutton
Journal:
Clinical Science
Clin Sci (Lond) (1988) 74 (s18): 62P.
Published: 01 January 1988
Articles
Articles
Journal:
Clinical Science
Clin Sci (Lond) (1985) 69 (6): 737–743.
Published: 01 December 1985
Abstract
1. The mechanism by which noradrenaline stimulates ouabain-sensitive rubidium uptake in guinea-pig myocardial tissue has been studied. 2. The stimulatory action of low concentrations of noradrenaline was reversed by high doses of propranolol (10 −5 mol/l) in atrial tissue, but was not reversed by α- or β-, or combined α- and β-adrenoceptor antagonists in ventricular tissue. 3. Rubidium uptake was also found to increase with increasing extracellular potassium concentration ([K] o ). The percentage values of stimulation by noradrenaline decreased with increasing [K] o . 4. Noradrenaline had no effect on the rate of ATP splitting by an isolated membrane preparation of Na,K-ATPase. 5. It is proposed that noradrenaline stimulates active cation transport by either (a) an effect secondary to increased passive efflux of K ions, or (b) an action at a novel adrenergic receptor, distinct from the ATPase enzyme itself.
Articles
Articles
Journal:
Clinical Science
Clin Sci (Lond) (1982) 62 (3): 311–319.
Published: 01 March 1982
Abstract
1. The potential value of right vagotomy for the relief of breathlessness has been explored in five patients with emphysema. Two patients had symptomatic improvement, two had minor symptomatic improvement, and one was unchanged. 2. Exercise ventilation was not noticeably depressed by unilateral right vagotomy in the two patients investigated fully, but the pattern of breathing was altered. After vagotomy, breathing was deeper, and the rise in the frequency of breathing with exercise was depressed. 3. After right vagotomy the response to rebreathing carbon dioxide also consisted of slower deeper breaths. 4. Right vagotomy sometimes appears to remove an influence preventing slow deep breathing and exacerbating dyspnoea. 5. Results of bilateral pulmonary denervation, attempted in one patient, were complicated by the need for left thoracotomy, which removed any possible beneficial effects.
Articles
Articles
Journal:
Clinical Science
Clin Sci (Lond) (1981) 60 (1): 17–23.
Published: 01 January 1981
Abstract
1. Nineteen patients (three normal subjects, and 16 patients with chronic airway disease) were investigated with radionuclide lung-imaging and pulmonary function tests. 2. There was a statistically significant correlation between the ratio of residual volume to total lung capacity and alveolar dead-space ventilation for nitrogen as a percentage of alveolar ventilation (an index of gas mixing inefficiency); r S = 0.54, P < 0.05. 3. There were statistically significant associations between an abnormal ventilation or perfusion radionuclide lung image and (a) the ratio of residual volume to total lung capacity and (b) the alveolar dead-space ventilation for nitrogen as a percentage of alveolar ventilation. 4. The radionuclide counts from the posterior images were normalized for lung size and injected dose; perfusion counts were then subtracted from ventilation counts at locations from the top to the bottom of the lungs. 5. There was a statistically significant association between low ventilation minus perfusion areas and arterial hypoxia. 6. There was a statistically significant association between high ventilation minus perfusion areas and an increased alveolar dead-space ventilation for carbon dioxide as a percentage of alveolar ventilation.
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Journal:
Clinical Science
Clin Sci Mol Med (1974) 46 (1): 49–59.
Published: 01 January 1974
Abstract
1. Maximum acceleration of blood has been measured in the aorta using a catheter tip velocity transducer in twelve patients undergoing diagnostic coronary angiography. Signals were obtained with the catheter tip transducer 5–6 cm above the aortic valve. From these signals, the values for peak velocity were measured, and acceleration was derived by continuous differentiation of the velocity signal. 2. The values obtained for maximum acceleration and peak velocity were inversely related to the severity of coronary artery disease as indicated by coronary angiography. 3. There was a close relationship between peak velocity, maximum acceleration and ejection fraction calculated from the left-ventricular angiogram. 4. Three patients with chest pain and no cardiac abnormality detectable by cardiac catheterization had maximum acceleration values above 1500 cm/s 2 and peak velocity above 60 cm/s. 5. Four patients with definite coronary artery disease had normal intracardiac pressures and cardiac indices, but decreased ejection fractions. The values for maximum acceleration were between 750 and 1100 cm/s 2 and for peak velocity between 32.0 and 58.0 cm/s. 6. Five patients had severe coronary disease with abnormal intracardiac pressures, cardiac indices and decreased ejection fraction. Values for maximum accelerations were below 850 cm/s 2 and for peak velocity, below 41.0 cm/s.
Articles
Journal:
Clinical Science
Clin Sci Mol Med (1973) 44 (6): 519–538.
Published: 01 June 1973
Abstract
1. The effect of breathing anaesthetic aerosols (lignocaine 20% and bupivacaine 5%) on respiratory reflexes was studied in rabbits. 2. The cough reflex was blocked in every experiment. 3. The inflation reflex was abolished in eleven out of twenty-six rabbits given lignocaine aerosol and in fourteen out of fifteen rabbits given bupivacaine aerosol. 4. The deflation reflex was blocked pari passu with the inflation reflex. 5. The ventilatory response to histamine was sometimes blocked; more commonly it was partially preserved. 6. The ventilatory response to phenyldiguanide was never impaired and often enhanced. 7. Bronchoconstriction produced by electrical stimulation of the peripheral cut ends of the cervical vagus nerves was unaffected. 8. Block of the above respiratory reflexes was associated with slower, deeper breathing. 9. Bupivacaine has produced more consistent and reliable results than lignocaine; the effects were reversible in both cases usually within 30 min. 10. Plasma concentrations of both anaesthetics were usually below the generally accepted toxic concentrations in man. 11. Control experiments using intravenous infusions of the anaesthetics proved that none of the effects could have been produced by systemic effects of the absorbed anaesthetic. 12. No pathological changes were found in the airways on both macroscopic and microscopic examination. 13. The experiments show that it is possible to block respiratory reflexes whose afferents arise from the airways, and to preserve a reflex arising at alveolar level.
Articles
Articles
Journal:
Clinical Science
Clin Sci (1971) 41 (3): 275–283.
Published: 01 September 1971
Abstract
1. Block of the phrenic nerves in three normal subjects, produced by injection of lignocaine in the neck, caused alleviation of the thoracic sensation during breath holding and prolonged breath-holding time. 2. Injection of lignocaine in the neck without nerve block had no effect on breath holding sensation or breath-holding time. 3. A patient with a spinal-cord transection at the third cervical segment with paralysed diaphragm and chest wall, had no sensation in the chest or abdomen during breath holding. 4. This patient maintained normal ventilation by using hypertrophied sternomastoid muscles. During breath holding he experienced no sensation in the neck despite the presence of sternomastoid contraction. 5. There is previous evidence that complete muscular paralysis abolishes breath-holding sensation but that paralysis of all muscles innervated from spinal segments below the eighth cervical has no effect.
Articles
Journal:
Clinical Science
Clin Sci (1971) 41 (3): 285–287.
Published: 01 September 1971
Abstract
1. Resistive loads were added to the airways of patients with tracheostomies; the patients were blindfolded and the loads introduced without their knowledge. 2. The ability to detect the loads was the same in a patient with C3 transection (chest wall and diaphragm disconnected from the brain) as in a control group of patients with no neurological lesion. 3. It is concluded that receptors in the chest wall and diaphragm are not involved in the genesis of the sensation by which added resistive loads are detected.
Articles
Journal:
Clinical Science
Clin Sci (1971) 40 (6): 451–461.
Published: 01 June 1971
Abstract
1. The effect of lung deflation was studied during treatment of patients for spontaneous pneumothorax: (a) in four patients acute lung deflation was produced by opening the chest drain to the atmosphere and the immediate effect on breathing was observed and (b) breath-holding time and the ventilatory response to CO 2 were determined on admission to hospital and after recovery in a further four patients. 2. Allowing one lung to deflate suddenly produced an immediate increase in respiratory rate and electrical activity in inspiratory muscles. 3. Maximum breath-holding times were always decreased by pneumothorax. 4. In the presence of pneumothorax, the ventilatory response to rebreathing CO 2 was increased at the break point, the respiratory rate was increased and the P co 2 at the breakpoint decreased in three out of four patients. 5. These results are consistent with the hypothesis that lung deflation has a reflex excitatory effect on breathing (Hering—Breuer deflation reflex). If this hypothesis is correct, it would appear that the threshold for the reflex is higher than for other mammalian species.
Articles