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Biomedical subjects

A J Drake-Holland

Publications and source records attributed to A J Drake-Holland.

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.

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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.

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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.

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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.

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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.

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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.

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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.

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PubMed1995

Modification of coronary artery disease using antithrombotic therapy.

I review some of the literature concerning antithrombotic therapy in coronary artery disease. The beneficial effects shown are compatible with the unitary hypothesis of thrombosis as a fundamental of cardiovascular risk. The therapeutic approach is limited by the haemorrhagic risk produced by most antithrombotic therapies. A search should therefore be made for antithrombotic therapies without this risk, of which serotonin antagonism appears to be the most promising at present.

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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.

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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.

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PubMed1994

Lack of importance in humans of the slow component of the response of force to an increase in cardiac muscle length.

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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PubMed1993

Effects of trimetazidine on in vivo coronary arterial platelet thrombosis.

We used Folts' model of critical coronary artery stenosis with endothelial damage, which measures platelet-rich thrombus accumulation from cyclic flow reductions (CFRs). This paper reports results applied to trimetazidine, a member of the piperazine group. Trimetazidine at a dose of 1 mg/kg completely abolished CFRs caused by accumulating thrombus in the circumflex coronary artery in 4 of 8 open-chest anesthetized beagles. More trimetazidine (up to 5 mg/kg) abolished CFRs in two more and attenuated them in the remaining two dogs. There were no systemic hemodynamic effects observed. Adrenaline was then infused to stimulate platelet activation. At a rate of 0.4 microgram/kg/min, CFRs were restored in one dog only. Adrenaline given at 1.6 micrograms/kg/min resulted in restoration or increase in the slope of CFRs in all animals. A further six nonoperated dogs were anesthetized and given trimetazidine 3 mg/kg. Routine coagulation studies were not altered. However, aspirin 5 mg/kg significantly increased bleeding time, whereas trimetazidine alone did not. These findings suggest that trimetazidine is effective in preventing intracoronary platelet aggregation in this model. Because of its demonstrated sparing of coagulation factors and its lack of effect on bleeding time, the cause is unlikely to be inhibition of the fibrinogen or thrombin receptors, or interference with arachidonic acid metabolism.

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PubMed1993

Do the cardiac nerves optimise efficiency?

The cardiac nerves were removed by surgical dissection in anaesthetised dogs. At least 3 weeks were then allowed to elapse to permit degeneration of post-ganglionic sympathetic nerve fibres and myocardial catecholamines. We then established that: 1) Myocardial oxygen consumption was increased for a given work output, indicating metabolic inefficiency; 2) glucose oxidation was inhibited; 3) uncoupled oxygen consumption of isolated myocardial tissue was increased, and 4) sodium-potassium ATPase activity was enhanced. These results are compatible with the hypothesis that the cardiac nerves optimise efficiency. There is some evidence from cardiac transplantation studies in man that a similar effect of innervation on efficiency is present. However, examination of this concept as a postulated result of evolutionary pressure led us to reject such a hypothesis (at least in man) because such a mechanism should be irrelevant to the factors determining survival at the time of human evolution. However, the hypothesis may be tenable for the situation at some earlier evolutionary era. This could be determined, in theory, by a comparative study between species of the effect of cardiac innervation upon efficiency.

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PubMed1992

Dispersion of coronary artery thrombi by antagonism of platelet serotonin receptor in the dog.

OBJECTIVE: Blockade of platelet 5HT2 receptors prevents coronary artery thrombi. This study explores the dispersal of established thrombus by such 5HT2 antagonism. METHODS: Seven open chest anaesthetised beagles were used in a repeated measures study of the action of MDL 11,939 to remove the participation of platelet 5HT2 receptors in the natural history of intracoronary thrombosis with cyclic blood flow reduction. Endothelial damage and critical diameter constrictors were applied to the circumflex coronary artery, and systemic blood pressure and circumflex blood flow were measured continuously. RESULTS: Cyclic flow reductions, which were established by build up and embolisation of platelet thrombi, were completely abolished by the 5HT2 antagonist MDL 11,939. The dose given in the first two experiments was 0.5 mg.kg-1, reduced to 0.2 mg.kg-1 for the third. Subsequent animals received 0.1 mg.kg-1. Mean blood pressure rose slightly. Adrenaline infusion at 0.4 micrograms.kg-1.min-1 failed to restore cyclic flow reductions in any animal and caused a small flow increase without affecting mean blood pressure. The pattern of blood flow restitution after administration of MDL 11,939 was of great interest. In all the animals flow spontaneously increased in a stepwise fashion (a double step in five dogs). The step up was markedly different from the increase in flow seen during adrenaline infusion. CONCLUSIONS: (1) These results are further evidence of the importance of serotonin as a mediator of platelet thrombus in stenosed coronary arteries. (2) The apparent dissipation of thrombi by MDL 11,939 may be of importance.

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PubMed1992

Effect of adrenaline on cardiac force-interval relationship.

OBJECTIVE: The aim was to test the hypothesis that adrenaline affects the force-interval processes. METHODS: The force-interval processes were studied in eight guinea pig papillary muscles (isometric force) and five anaesthetised dogs with atrioventricular block (maximum rate of rise of left ventricular pressure, LVdP/dtmax). The contractility indices were measured during pacing sequences in which a steady state was interrupted after a variable interval by a premature beat followed by an immediate return to the steady state. RESULTS: The relationship between contractility of the premature beat and the preceding interstimulus interval displays an approximately monoexponential initial rising phase, ie, mechanical restitution. With increasing adrenaline dosage in the isolated preparation there was always a significant increase in the force, and in its rate of rise with interval in some cases. Adrenaline had a variable accelerating effect on the time course of this mechanical restitution in isolated papillary muscles, but no effect in the dog preparation. In the isolated preparation adrenaline also slowed the decay in potentiation of the two beats immediately following the premature contraction. A slope of the relationship between the contractility of the second potentiated beat and that of the first was thus increased. This difference was not apparent in the intact preparation. CONCLUSIONS: The speeding up of mechanical restitution by adrenaline may be interpreted as reflecting the time course of reavailability of contractile activator. The slope of the relationship of contractility to that of the previous beat during the decay of postextrasystolic potentiation may be interpreted as the recirculation fraction of contractile activator; this is increased by adrenaline. However, in addition, adrenaline exerts an inotropic effect by another mechanism.

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PubMed1990

Do studies of mechanical restitution tell us anything about the mechanism of Ca2+ release in myocardial cells?

We present information from the literature which is discordant with the idea that the trigger Ca2+ for Ca2(+)-induced Ca2+ release from the myocardial sarcoplasmic reticulum (SR) is carried by the inward current. In addition, evidence is emerging to show that recovery of contractility with increasing interval after an excitation-contraction-relaxation cycle (mechanical restitution) begins with repolarization of the sarcolemma, not mechanical relaxation (SR Ca2+ uptake). These two phenomena, if confirmed, would be compatible with a sarcolemmal source of trigger Ca2+.

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