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Biomedical subjects

M I Noble

Publications and source records attributed to M I Noble.

At least 19 recordsLinked to original sources
PubMed1998

Metabolic alterations in the chronically denervated dog heart.

OBJECTIVE: Previous studies have shown that chronic cardiac denervation impairs myocardial glucose oxidation. To investigate this further we tested whether the tissue content of glucose transporters, activity of glycolytic enzymes or metabolic capacity of pyruvate dehydrogenase were altered. Moreover, we investigated whether the decline in glucose utilization was associated with an upregulation of proteins and enzymes involved in fatty acid handling. Chronic cardiac denervation results also in decreased left ventricular efficiency. We explored whether alterations in mitochondrial properties could be held responsible for this phenomenon. METHODS: Twelve adult dogs were included in the study. In 6 of them chronic cardiac denervation was accomplished by surgical ablation of the extrinsic nerve fibers. The other 6 dogs were sham-operated. Biopsies were obtained from the left ventricle after 4-5 weeks of denervation. The content or enzymatic activity of proteins involved in fatty acid and glucose handling was assessed. Features of glutamate oxidation were measured in freshly isolated mitochondria. RESULTS: The content or activity of a set of fatty acid handling proteins did not change during chronic cardiac denervation. In contrast GLUT1 content significantly increased in the chronically denervated left ventricle, while the active form of pyruvate dehydrogenase declined (p < 0.05). Glutamate oxidation characteristics in freshly isolated mitochondria were not affected by chronic denervation. CONCLUSION: The impairment of glucose oxidation in the chronically denervated myocardium is most likely caused by a decline of pyruvate dehydrogenase in its active form. It is unlikely that the decrease in work efficiency is caused by alterations in mitochondrial properties.

Animals↗
PubMed1998

Depletion of endogenous dopamine stores and shift in beta-adrenoceptor subtypes in cardiac tissue following five weeks of chronic denervation.

Surgical ablation of extrinsic cardiac nerve fibers results in a chronically denervated state of the left ventricle of the heart. The present study was performed to elucidate the effect of a period of 5 weeks of chronic denervation on cardiac catecholamine levels in general and dopamine in particular. Moreover, the possible effect on cardiac beta-adrenoceptor subtypes was investigated. Experiments were performed on adult dogs. In addition to adrenaline and noradrenaline the tissue levels of dopamine were found to be severely depressed. A significant shift from beta1- to beta2-adrenoceptor subtype was observed, while the total beta-adrenoceptor density remained unaffected. The present findings indicate that catecholamine synthesis in chronically denervated hearts is impaired upstream of dopamine and that a shift in beta-adrenoceptor subtype occurs already within a relatively short period of five weeks of denervation, and suggest that the lack of endogenous catecholamines influence the relative expression levels of the two subtypes of beta-adrenoceptors present in cardiac tissue.

Animals↗
PubMed1997

Early presentation of dilated cardiomyopathy as a part of seroconversion illness in human immunodeficiency virus infection.

It has been debated whether dilated cardiomyopathy seen in patients with acquired immune deficiency syndrome is caused by the virus itself or by the combination of other factors such as presence of opportunistic pathogens and/or severe immunosuppression. This paper describes the first reported case of a patient with human immunodeficiency virus (HIV) infection presenting with dilated cardiomyopathy during his acute seroconversion illness. Presence of cardiac involvement at a very early stage of HIV infection with no evidence of opportunistic infections, or immunosuppression with high CD4 count indicates that HIV may itself be a cardiac pathogen. This case also illustrates the importance of testing for HIV infection as part of the assessment of any patient presenting with myocarditis or dilated cardiomyopathy.

Adult↗
PubMed1997

Beneficial effect of the calcium-sensitizing drug EMD 57033 in a canine model of dilated heart failure.

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/dtmax), 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/dt 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.

Animals↗
PubMed1997

Increased urinary albumin and retinol-binding protein in type I diabetes. A study of identical twins.

OBJECTIVE: Indexes of early renal glomerular and tubular dysfunction have been demonstrated in type I diabetes, but it remains uncertain whether such changes are genetically determined or are secondary to the disease process. We therefore undertook to study whether early markers of renal dysfunction are a consequence of type I diabetes or inherited. RESEARCH DESIGN AND METHODS: We estimated both urinary albumin excretion (UAE) and urinary retinol-binding protein (RBP) in 51 identical twin pairs discordant for type I diabetes and in 51 matched control subjects. RESULTS: UAE and RBP were significantly higher in the diabetic twins than in their nondiabetic co-twins (P < 0.0001 and P < 0.0002, respectively). Seven diabetic twins had elevated UAE, but none of the nondiabetic co-twins did. In a subgroup of 44 twins with normal UAE (albumin excretion rate < 20 micrograms/min), diabetic twins had both a higher albumin excretion function (median [range]; 0.64 [0.18-2.74] mg/mmol creatinine) than their nondiabetic co-twins (0.48 [0.24-1.40], P < 0.01) and higher levels of RBP excretion (10.4 [4.0-167.0] micrograms/mmol creatinine) than their nondiabetic co-twins (7.5 [0.97-23.0], P < 0.05). Values between twins of a pair were significantly correlated for RBP (r = 0.36, P < 0.05) but not for UAE (r = 0.13). CONCLUSIONS: These results suggest that in type I diabetes, an index of renal tubular function (RBP), but not glomerular function (UAE), is influenced by shared genetic and nongenetic factors. Type I diabetes can affect renal tubular function even when glomerular function is normal. We conclude that neither the increased UAE nor urinary RBP found in type I diabetes is inherited independently of the diabetes process.

Adult↗
PubMed1996

Failure of thrombin inhibition to prevent intracoronary thrombosis in the dog.

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/min2. 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/min2 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.

Animals↗
PubMed1996

Platelet 5-hydroxytryptamine is decreased in a preliminary group of depressed patients receiving the 5-hydroxytryptamine re-uptake inhibiting drug fluoxetine.

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 anticoagulated 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.

Adult↗
PubMed1996

Natriuresis caused by blood volume expansion in dogs is not mediated by the renal nerves.

The influence of renal denervation on the renal response to rapid blood volume expansion was investigated by measurement of urine volume, sodium and osmolar excretion rates, sodium p-aminohippurate and free water clearances, and systemic haemodynamic and plasma hormone (atrial natriuretic peptide, arginine vasopressin and plasma renin activity (PRA)) changes in ten control and ten renal-denervated chloralose-anaesthetized mongrel dogs. Following renal denervation, blood volume expansion caused a similar increase in sodium excretion to that in the control group. Renal denervation resulted in systemic vasodilatation and decreased PRA. During fluid loading the right atrial pressure and pulmonary capillary wedge pressure were significantly higher in the control group. In the control group, volume expansion caused a large fall in PRA, whereas in the renal-denervated dogs, PRA remained suppressed. We conclude, from the fact that natriuresis is preserved after renal denervation, that this response is not mediated by a reflex with efferent limb in the renal nerves.

Animals↗
PubMed1996

Tachycardia-induced failure alters contractile properties of canine ventricular myocytes.

OBJECTIVE: Rapid cardiac pacing has been used as a model for experimentally-induced cardiomyopathy. However, its relevance to human heart failure is not clear at present because little is known about changes in size and function of ventricular myocytes. We have therefore studied the responses to graded increases in frequency and calcium in canine ventricular myocytes from failing hearts. The aim of our study was to evaluate the resemblance between canine pacing-induced and human end-stage heart failure. METHODS: Myocytes were isolated from the left ventricular wall of dogs that were in heart failure after 6 weeks of pacing at 250 beats/min. Cell shortening was measured by edge detection. RESULTS: Clinical signs of failure included dyspnea, ascites, and heart dilatation; the hemodynamic parameters were: LVdP/dtmax 1613 +/- 149 vs. 4713 +/- 304 mmHg/s in 6 control dogs; LVEDP 17.2 +/- 4.4 vs 5.6 +/- 1.1 mmHg; LV volume 60.5 +/- 6.2 vs. 30-35 ml. Myocytes from failing hearts were longer and thinner than those from controls (from factor: 0.40 +/- 0.01 vs. 0.47 +/- 0.01, P < 0.001, > 30 cells/heart). With 6 mM Ca2+ and at 0.5 Hz, contraction amplitude was significantly attenuated in myocytes from failing hearts: 6.6 +/- 0.9% cell shortening vs. 10.0 +/- 0.8% in controls (P < 0.05). This deficit was exacerbated at higher stimulation rates. Time-to-peak contraction and time-to-50% relaxation were not altered. There was no difference in sensitivity to thapsigargin. CONCLUSION: As with cells from human failing hearts, contraction amplitude showed rate-dependent depression in this animal model, whereas features like slowing of contraction and relaxation and reduced sensitivity to thapsigargin, were not reproduced.

Animals↗
PubMed1995

Limitation of infarct size by trimetazidine in the rabbit.

The influence of trimetazidine on infarct size was studied with a 45-minute period of coronary occlusion followed by 24 hours of blood reperfusion in the rabbit heart. The groups studied were 7 control rabbits and 7 rabbits pretreated with 3 mg/kg of trimetazidine. Twenty-four hours after coronary artery ligation for 45 minutes, infarct size was measured in myocardial slices using trinitrophenyl tetrazolium staining, and the area at risk was determined by injection of zinc/cadmium particles and delineated at the same time by imaging, under fluorescent light, the areas of tissue that fluoresced. The range of area at risk was similar in both of the groups. There was a significant reduction in the size of infarct that developed in the trimetazidine-treated group when compared with the control rabbits. It is concluded that pretreatment with trimetazidine in the blood-perfused rabbit heart is effective in reducing myocardial infarct size.

Animals↗
PubMed1995

Doppler determined aortic acceleration after dipyridamole in the prediction of coronary artery disease.

Change in the acceleration of aortic blood flow with stress testing is reported to reflect the presence of myocardial ischaemia. We studied its clinical usefulness when compared with dipyridamole thallium scintigraphy in 101 patients, of whom 64 had coronary angiography. Maximum aortic acceleration increased after dipyridamole (P < 0.0001), although no correlation existed between the aortic acceleration and evidence of thallium perfusion abnormalities. For the patients who had angiography, the increase in aortic acceleration was similar for those with no significant coronary stenoses, single vessel or multi-vessel disease. Compared with coronary angiography, Doppler measurement of maximum aortic acceleration had a sensitivity of 92% and a specificity of 37% for the detection of coronary artery disease. When patients with previous myocardial infarction or left ventricular dysfunction were excluded, there was still no relationship between the maximum aortic acceleration and the presence of coronary artery disease. We conclude that changes in the acceleration of aortic blood flow after dipyridamole stressing do not predict the presence or severity of coronary artery disease as measured from perfusion defects at thallium scintigraphy or by coronary angiography. We have observed a wide variability of aortic maximum acceleration in the evaluation of myocardial ischaemia, which we feel introduces serious limitations to its use in routine clinical practice.

Acceleration↗
PubMed1995

Impaired platelet aggregation after cardiopulmonary bypass in man: enhancement of collagen-induced aggregation in whole blood and plasma by adrenaline ex vivo.

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 microgram/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 microgram/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 (x 10(9)/l) were decreased postbypass (155 versus 220, P = 0.02) and were not influenced by adrenaline infusion (167, P = 0.93).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Post-rest potentiation and its decay after inotropic interventions in isolated rat heart muscle.

The effects of various inotropic interventions on post-rest potentiation and its decay were investigated in isolated cardiac muscle. The inotropic interventions studied were: reduced extracellular Na+ and elevated extracellular Ca2+ concentration; exposure to ouabain, monensin, isoprenaline, phenylephrine and cirazoline. Force of contraction (stimulation frequency 2 Hz) was measured isometrically in left atria and right ventricular strips of rat hearts. Maximum post-rest potentiation was reached after 10 sec. of rest and amounted to 245 +/- 26% of pre-rest control in ventricle and 192 +/- 15% in atria. Ca(2+)-recirculation fraction was calculated from the decay of post-rest potentiation after resumption of regular stimulation, it was 0.77 +/- 0.01 in 11 control ventricular strips. High concentrations of caffeine (3 mmol/l) completely abolished post-rest potentiation in both tissues. The development of post-rest potentiation was accelerated in the presence of most of the inotropic agents. However, with the exception of ouabain and only in atrial muscle, none of the inotropic interventions produced higher post-rest contraction amplitudes than during controls. In rat heart muscle, the inotropic interventions studied are not any more effective in augmenting force of contraction than prolonged stimulation intervals. This suggests that (1) the distribution of Ca2+ into the sarcoplasmic reticulum is at a maximum during post-rest potentiation; (2) modifications of signal transduction pathways cannot further increase post-rest potentiation; and therefore that (3) shifts in Ca2+ distribution act as a limiting factor.

Animals↗
PubMed1995

The pressure-flow relation in the canine coronary artery: combined effects of critical stenosis and intracoronary thrombosis.

OBJECTIVE: To characterise the effect of coronary intra-arterial thrombosis upon the downstream vascular bed. BACKGROUND: The vascular response downstream from a coronary intra-arterial thrombus has not previously been characterised. We postulated that downstream vasoconstriction might result from the presence of endothelial damage with consequent growth of platelet-rich thrombus. METHODS: We measured the pressure gradient and flow across, and the pressure/flow ratio distal to, a canine left circumflex artery stenosis with and without endothelial damage causing intracoronary thrombosis. We also observed the effects of transient complete conclusions. RESULTS: At occlusion, the pressure gradient was maximal; relief of occlusion caused a rapid increase flow and distal pressure with a rapid decrease in stenosis pressure gradient and resistance. Subsequently there was a period of stable stenosis resistance with pressure gradient and flow declining; distal pressure therefore increased at this time. Finally in the thrombus group only, stenosis resistance increased again towards re-occlusion. During occlusion, distal pressure averaged 49 +/- 18 mmHg in the presence of thrombus vs. 22 +/- 4 mmHg in its absence (P < 0.001). Following release of occlusion, the flow increased faster than distal pressure, so that the ratio (distal pressure/flow) fell rapidly. Subsequently, distal pressure continued to increase after flow had reached a peak and begun to decline, suggesting vasoconstriction. In the presence of thrombus, the distal pressure/flow ratio was higher than in the absence of thrombus, both at maximal vasodilation (P < 0.005) and at maximum vasoconstriction (P < 0.025). CONCLUSIONS: During cyclic flow variations the stenosis resistance changes are exactly as expected from thrombus growth and embolisation. The distal pressure/flow ratio showed a time-dependent increase which appeared greater when conditions favoured intracoronary thrombosis.

Animals↗
PubMed1994

Antagonism of the platelet 5HT2 receptor in the presence of thrombolysis.

Thrombolysis of coronary arterial thrombi is often accompanied by occlusion due to continued platelet thrombosis. We modified the Folts' model of intracoronary thrombosis (critical stenosis with endothelial damage) to produce up to 35-min occlusions of the circumflex coronary artery in seven open-chest anaesthetised dogs. Administration of recombinant plasminogen activator (rtPA 200 micrograms.kg-1 bolus plus 1 mg.kg-1.h-1 infusion), without heparin or aspirin, always produced effective thrombolysis. Fibrinogen decreased (P < 0.05), thrombin time increased (P < 0.025), bleeding time trebled (P < 0.025) and initial arterial patency was achieved. Addition of a selective 5HT2 antagonist, increased coronary blood flow (P < 0.01) and reduced rethrombosis rate (P < 0.025), but did not affect coagulation or bleeding. The time the vessel spent occluded was significantly decreased (P < 0.01) and correlated with the fibrinogen level (r = 0.97, P < 0.01), thereby implying the presence of fibrin within the thrombus. After rt-PA was withdrawn, bleeding time and fibrinogen level normalised within 30 and 60 min, respectively, but full coronary patency was maintained. Thus, when rt-PA alone had produced full thrombolysis, 5HT2 antagonism prevented intracoronary thrombosis without additional bleeding complications.

Animals↗