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Biomedical subjects

A L Clark

Publications and source records attributed to A L Clark.

At least 91 records · Page 5Linked to original sources
PubMed1997

Neurosteroids modulate nicotinic receptor function in mouse striatal and thalamic synaptosomes.

Progesterone and its A-ring reduced metabolites are allosteric activators of GABA(A) receptors. The studies reported here examined the effects of these steroids on brain nicotinic receptors using an 86Rb+ efflux assay that likely measures the function of alpha4beta2-type nicotinic receptors and [3H]dopamine release, which may be modulated by an alpha3-containing nicotinic receptor. Both of the A-ring reduced metabolites of progesterone were noncompetitive inhibitors of both assays, whereas progesterone inhibited only the 86Rb+ efflux assay. The 86Rb+ efflux assay was slightly more sensitive than was the dopamine release assay to steroid inhibition. Inhibition developed slowly for both assays (t1/2 = 0.4 min) and was reversed even more slowly (t1/2 = 10-15 min). Steroid addition did not alter either the rate of association of [3H]nicotine binding to brain membranes, nor was equilibrium binding changed. These findings argue that neurosteroids are allosteric inhibitors of brain nicotinic receptors.

5-alpha-Dihydroprogesterone↗
PubMed1997

Catecholamines contribute to exertional dyspnoea and to the ventilatory response to exercise in normal humans.

BACKGROUND: Exogenous catecholamine administration in humans stimulates ventilation. The present study was designed to investigate whether increased endogenous catecholamine release influences objective measures of ventilation and subjective measures of breathlessness in normal subjects. METHODS: Yohimbine, a pre-synaptic alpha 2 adrenoceptor antagonist, or placebo was administered to 10 normal male subjects in a double-blind cross-over fashion. Ventilation and metabolic gas exchange were measured during steady state exercise at 60% of previously determined maximal oxygen consumption. Venous lactate and noradrenaline were measured during exercise. Subjects' sensation of breathlessness and fatigue were recorded using visual analogue scales. RESULTS: Plasma noradrenaline was higher following yohimbine administration (at 6 min exercise; 4.58 +/- 0.56 nmol.l-1 vs 8.74 +/- 1.53; P < 0.05). Oxygen consumption was unchanged, but ventilation was greater throughout exercise following yohimbine. The sensation of exertion was greater following yohimbine, and at any given level of ventilation, the sensation of exertion was greater. CONCLUSIONS: Yohimbine administration causes increased noradrenaline release. This is associated with an increased ventilatory response and an increase in the sensation of exertion during steady state exercise. An increase in circulating noradrenaline might be a mechanism for both increased ventilation and pathological conditions of breathlessness such as chronic heart failure.

Adrenergic alpha-Antagonists↗
PubMed1997

The influence of muscle mass, strength, fatigability and blood flow on exercise capacity in cachectic and non-cachectic patients with chronic heart failure.

BACKGROUND: The influence of age, skeletal muscle function and peripheral blood flow on exercise capacity in chronic heart failure patients is controversial, possibly due to variations in skeletal muscle atrophy. METHODS AND RESULTS: To assess predictors of exercise capacity in patients with clinical cardiac cachexia, we studied 16 cachectic and 39 non-cachectic male chronic heart failure patients of similar age and ejection fraction. All cachectic patients were wasted (% ideal body weight: 81.2 +/- 1.9 vs 105.2 +/- 2.1, P < 0.0001, mean +/- SEM) and had documented weight loss (5-30 kg). Peak oxygen consumption (14.9 +/- 1.4 vs 16.3 +/- 0.6 ml.kg-1, min-1, resting and peak blood flow (plethysmography) and 20 min fatigability (% baseline strength) were all similar between the two groups. Quadriceps strength, muscle size (all P < 0.0001), strength per unit muscle (right: P < 0.05: left: P < 0.001) and 5 min fatigability (P < 0.05) were all lower in cachectic patients. In non-cachectic patients, age (R = 0.48) and quadriceps strength (R = 0.43, all P < 0.01) predicted peak oxygen consumption. Only in cachectic patients did peak blood flow predict peak oxygen consumption significantly (R = 0.72, P = 0.005), whereas age and strength did not. Similar findings were confirmed using other previously published definitions of cardiac cachexia. CONCLUSIONS: The predictors of exercise capacity change with the development of cardiac cachexia from age and strength to peak blood flow. This shift may be caused by additional endocrine or catabolic, abnormalities active in end stage heart failure.

Adult↗
PubMed1997

The increased ventilatory response to exercise in chronic heart failure: relation to pulmonary pathology.

OBJECTIVE: To assess the exercise limitation of patients with chronic heart failure (CHF) and its relation to possible pulmonary and ventilatory abnormalities. SETTING: A tertiary referral centre for cardiology. METHODS: The metabolic gas exchange responses to maximum incremental treadmill exercise were assessed in 55 patients with CHF (mean (SD) age 57.9 (13.0) years; 5 female, 50 male) and 24 controls (age 53.0 (11.1) years; 4 female, 20 male). Ventilatory response was calculated as the slope of the relation between ventilation and carbon dioxide production (VE/VCO2 slope). RESULTS: Oxygen consumption (VO2) was the same at each stage in each group. Ventilation (VE) was higher in patients at each stage. Patients had a lower peak VO2 and a steeper VE/VCO2 slope than controls. Dead space ventilation as a fraction of tidal volume (VD/VT) was higher in patients at peak exercise, but dead space per breath was greater in controls at peak exercise (0.74 (0.29) v 0.57 (0.17) litres/breath; P = 0.002). End tidal CO2 was lower in patients at all stages, and correlated with peak VO2 (r = 0.58, P < 0.001). Alveolar oxygen tension was higher in patients at each stage than in controls. CONCLUSIONS: Patients with CHF have an increased ventilatory response at all stages of exercise. Although this is accompanied by an increase in VD/VT, there is hyperventilation relative to blood gases. It is more likely that the excessive ventilation is not due to a primary pulmonary pathology, but rather, the increase in dead space is likely to be a response to increased ventilation.

Exercise Test↗
PubMed1997

Exercise capacity in chronic heart failure is related to the aetiology of heart disease.

OBJECTIVE: To assess whether the underlying aetiology of chronic heart failure is a predictor of exercise performance. SETTING: Tertiary referral centre for cardiology. PATIENTS AND OUTCOME MEASURES: Retrospective study of maximum exercise testing with metabolic gas exchange measurements in 212 patients with chronic heart failure who had undergone coronary angiography. Echocardiography and radionucleide ventriculography were used to determine indices of left ventricular function, and coronary arteriography was used to determine whether the cause of chronic heart failure was ischaemic heart disease (n = 122) or dilated cardiomyopathy (n = 90). RESULTS: The cardiomyopathy group was younger (mean (SD) age 58.45 (11.66) years v 61.49 (7.42); p = 0.02) but there was no difference between the groups in ejection fraction or fractional shortening. Peak oxygen consumption (VO2) was higher in the dilated group, while the slope relating carbon dioxide production and ventilation (VE/VCO2 slope) was the same in both groups. Both groups achieved similar respiratory exchange ratios at peak exercise, suggesting that there was near maximum exertion. There was a relation between peak VO2 and age (peak VO2 = 33.9-0.267*age; r = 0.36; p < 0.001). After correcting for age, the peak achieved VO2 was still greater in the cardiomyopathy group than in the ischaemic group (p < 0.002). CONCLUSIONS: Exercise performance for a given level of cardiac dysfunction appears to vary with the aetiology of heart failure. Thus the two diagnostic categories should be considered separately in relation to abnormalities of exercise physiology. The difference may in part account for the worse prognosis in ischaemic patients.

Cardiomyopathy, Dilated↗
PubMed1996

Exercise limitation in chronic heart failure: central role of the periphery.

The symptoms of chronic heart failure (CHF) are predominantly shortness of breath and fatigue during exercise and reduced exercise capacity. Disturbances of central hemodynamic function are no longer considered to be the major determinants of exercise capacity. The two symptoms of fatigue and breathlessness are often considered in isolation. A pulmonary abnormality is usually considered to be the cause of abnormal ventilation, and increased dead space ventilation has come to be accepted as a major cause of the increased ventilation relative to carbon dioxide production seen in CHF. Rather than decreased skeletal muscle perfusion, an intrinsic muscle abnormality is considered to be responsible for fatigue. Another abnormality seen in CHF is persistent sympathetic nervous system activation, which is difficult to explain on the basis of baroreflex activation. There is increasing evidence for the importance of skeletal muscle ergoreceptors or metaboreceptors in CHF. These receptors are sensitive to work performed, and activation results in increased ventilation and sympathetic activation. The ergoreflex appears to be greatly enhanced in CHF. We put forward the "muscle hypothesis" as an explanation for many of the pathophysiologic events in CHF. Impaired skeletal muscle function results in ergoreflex activation. In turn, this causes increased ventilation, thus linking the symptoms of breathlessness and fatigue. Furthermore, ergoreflex stimulation may be responsible for persistent sympathetic activation.

Chronic Disease↗
PubMed1996

Relation between chemosensitivity and the ventilatory response to exercise in chronic heart failure.

OBJECTIVES: This study sought to establish the chemosensitivity of patients with chronic heart failure. BACKGROUND: The ventilatory response to exercise is often increased in patients with chronic heart failure, as characterized by the steeper regression slope relating minute ventilation to carbon dioxide output. We hypothesized that the sensitivity of chemoreceptors may be reset and may in part mediate the exercise hyperpnea seen in this condition. METHODS: Hypoxic and peripheral hypercapnic chemosensitivity were studied in 38 patients with chronic heart failure (35 men, 3 women; mean [+/-SE] age 60.2 +/- 1.3 years; radionuclide left ventricular ejection fraction 25.7 +/- 2.3%) and 15 healthy control subjects (11 men, 4 women; mean age 54.9 +/- 3.0 years) using transient inhalations of pure nitrogen and single breaths of 13% carbon dioxide, respectively. The change in chemosensitivity during mild exercise (25 W) was assessed in the first 15 patients and all control subjects. Central hypercapnic chemosensitivity was also characterized in 25 patients and 10 control subjects by the rebreathing of 7% carbon dioxide in 93% oxygen. Cardiopulmonary exercise testing was performed in all subjects. RESULTS: Maximal oxygen consumption was 16.6 +/- 0.9 versus 29.7 +/- 2.2 mol/kg per min (p < 0.0001), and the ventilation-carbon dioxide output regression slope was 37.2 +/- 1.5 versus 26.5 +/- 1.4 (p < 0.0001) in patients and control subjects, respectively. Hypoxic and central hypercapnic chemosensitivity were enhanced in patients (0.707 +/- 0.076 vs. 0.293 +/- 0.056 liters/min per % arterial oxygen saturation [SaO2], p = 0.0001 and 3.15 +/- 0.41 vs. 2.02 +/- 0.25 liters/min per mm Hg, p = 0.025, respectively) and correlated significantly with the ventilatory response to exercise. Hypoxic chemosensitivity was augmented during exercise in patients and in control subjects but remained higher in the former (1.530 +/- 0.27 vs. 0.685 +/- 0.12 liters/min per %SaO2, p = 0.01). The peripheral hypercapnic chemosensitivity of patients at rest and during exercise was similar to that in control subjects, consistent with its lesser contribution to overall carbon dioxide chemosensitivity. CONCLUSIONS: Enhanced hypoxic and central hypercapnic chemosensitivity may play a role in mediating the increased ventilatory response to exercise in chronic heart failure.

Adult↗
PubMed1996

Contribution of muscle afferents to the hemodynamic, autonomic, and ventilatory responses to exercise in patients with chronic heart failure: effects of physical training.

BACKGROUND: A neural linkage between peripheral abnormalities and the exaggerated exercise responses in chronic heart failure (CHF) was postulated. We studied the ergoreceptors (afferents sensitive to skeletal muscle work) in CHF and whether training can affect their activity. METHODS AND RESULTS: In 12 stable CHF patients (ejection fraction [EF] = 26.4%) and 10 control subjects (EF = 55.3%), we compared the responses to dynamic handgrip and during a 3-minute period of posthandgrip regional circulatory occlusion (PH-RCO). The ergoreflex contribution was quantified as the percentage responses to exercise maintained by PH-RCO compared with recovery without PH-RCO. Patients showed ergoreflex overactivation compared with control subjects in terms of ventilation (86.5% versus 54.5%), diastolic pressure (97.8% versus 53.5%), and leg vascular resistance (108.1% versus 48.9%) (all P < .05). The contribution of the ergoreflex to vagal withdrawal (high frequency of RR variability) and sympathetic activation (low frequency of RR, pressure variability) was evident in both groups. Nine control subjects and nine CHF patients participated in 6 weeks of forearm training. Training reduced the ergoreflex contributions more in CHF than in control subjects: diastolic pressure (-33.2% versus -4.6%), ventilation (-57.6% versus -24.6%), and leg vascular resistance (-59.9% versus -8.0%) (all P < .05). CONCLUSIONS: (1) The ergoreflex role has a larger effect on the responses to exercise in CHF than in control subjects. (2) Training may reduce this exaggerated ergoreflex activity, thereby improving the responses to exercise.

Exercise Tolerance↗
PubMed1996

Blood flow in the lower limb after balloon angioplasty of the superficial femoral artery.

Using duplex ultrasonography lower-limb blood flow measurements were obtained in 20 patients with intermittent claudication. Assessments of flow were made in the common femoral artery, profunda femoris artery (PFA) and superficial femoral artery (SFA) before and after angioplasty for stenoses of short segments of the SFA. Blood flow was measured at rest and after exercise on a cycle ergometer. Collateral flow was calculated using an established mathematical model. Results were compared with the ankle:brachial systolic pressure index (ABPI) after exercise. Although there was no overall increase in resting limb blood flow, an increase in mean(s.d.) SFA flow from 148(79) to 312(94) ml min-1, with a concomitant decrease in PFA flow from 224(84) to 98(43) ml min-1 was noted 1 week after angioplasty (P < 0.05). At rest there was an increase in mean(s.d.) ABPI from 0.62(0.12) to 0.89(0.23) (P < 0.05). Collateral flow was estimated to have decreased from 186(34) to 18(8) ml min-1; the pattern of change in flow was similar after exercise. Angioplasty of the SFA remains controversial because of the risk of restenosis. The above methodology allows assessment of whether patients can re-establish collateral flow or whether limb blood flow will be significantly compromised if restenosis occurs.

Aged↗
PubMed1996

Factors which alter the relationship between ventilation and carbon dioxide production during exercise in normal subjects.

The slope of the linear relationship between ventilation (V(E)) and carbon dioxide production (VC0(2)) has been thought to indicate that VC0(2) is one of the major stimuli to V(E). A group of 15 normal subjects undertook different incremental treadmill exercise protocols to explore the relationship between V(E) and VCO(2). An incremental protocol using 1 instead of 3-min stages of exercise resulted in an increase in the V E to VCO(2) ratio [26.84 (SEM 1.23) vs 31.08 (SEM 1.36) (P <0.008) for the first stage, 25.24 (SEM 0.86) vs 27.83 (SEM 0.91) (P <0.005) for the second stage and 23.90 (SEM 0.86) vs 26.34 (SEM 0.81) (P = 0.001) for the third stage]. Voluntary hyperventilation to double the control level of V(E) during exercise resulted in an increase in the V(E) to VCO(2) slope [from 21.3 (SEM 0.71) for the control run to 35.1 (SEM 1.2) for the hyperventilation run (P <0.001)]. Prolonged hyperventilation (5 min) during exercise at stage 2 of the Bruce protocol resulted in a continued elevation of VCO(2) and the V(E)/VCO(2) slope. A steady state of V(E) and metabolic gas exchange can only be said to have been present after at least 3 min of exercise. Voluntary hyperventilation increased the slope of the relationship between V(E) and VCO(2). End-tidal carbon dioxide fell, but remained within the normal range. These results would suggest that a non-carbon dioxide factor may have been responsible for the increase we found in V(E) during exercise, and that factors other than increased dead space ventilation can cause an increased ventilation to VCO(2) slope, such as that seen in some pathophysiological conditions, such as chronic heart failure.

Adult↗
PubMed1996

Plasma hormone levels and haemodynamics in patients with chronic obstructive lung disease.

Chronic obstructive pulmonary disease (COPD) is associated with right heart failure and salt and water retention. The possible roles of haemodynamically active hormones in the early stages of COPD have not previously been described. Adrenaline, noradrenaline, renin activity, aldosterone, vasopressin, cortisol, growth hormone, prolactin and atrial natriuretic peptide (ANP) were measured during right heart catheterization in mixed venous blood and in a peripheral artery, in the supine and standing position, in two groups of patients with COPD: Group A with arterial oxygen tension (Pa,O2) < 8.0 kPa (60 mmHg) and Group B with Pa,O2 > 8.0 kPa (60 mmHg). A group of 15 control subjects was studied to obtain control hormonal measurements with a venous blood sample only. Haemodynamic and blood gas values and hormone levels were measured in the supine and standing positions to record changes in the various parameters in COPD patients, and the relationship between pulmonary haemodynamics and hormone levels. No differences were found in hormonal samples between peripheral artery and mixed venous blood. In comparison with the control group, both groups of COPD patients showed a significant reduction in cortisol (p < 0.0001) and in vasopressin (p < 0.005), and an increase in ANP (p < 0.05) and growth hormone (p < 0.05). A marked, but not significant, increase in renin activity, and aldosterone was also found. After standing the increment of adrenaline was significantly higher in COPD patients (p < 0.02). A significant inverse relationship was recorded between forced expiratory volume in one second (FEV1) and noradrenaline (p < 0.02). There is a complex hormonal response even in the early phase of chronic obstructive pulmonary disease. An increase of plasma levels of atrial natriuretic peptide appears to be the earliest neuroendocrine response in these patients.

Cardiac Catheterization↗
PubMed1995

Right ventricular diastolic function 15 to 35 years after repair of tetralogy of Fallot. Restrictive physiology predicts superior exercise performance.

BACKGROUND: We have shown previously that transient right ventricular restriction after tetralogy of Fallot repair prolongs postoperative course. This is a prospective study of right ventricular diastolic performance in late follow-up patients. METHODS AND RESULTS: We studied biventricular function, using Doppler echocardiographic examination. Pulmonary arterial, tricuspid, and mitral valves and superior vena cava Doppler spectrals were obtained in 41 patients (mean age, 28.8 years), 15 to 35 years (mean, 23.6) after complete repair of tetralogy of Fallot. Patients were considered to have evidence of right ventricular restriction if antegrade diastolic flow was detected in the main pulmonary artery, coinciding with atrial systole (A wave), throughout the respiratory cycle. Exercise function was measured by graded treadmill testing with respiratory mass spectrometry. Three patients were excluded because of pulmonary outflow obstruction (Doppler gradient > 40 mm Hg) or residual intracardiac shunts. Of the 38 patients, 37 were in sinus rhythm. Twenty (52.6%) had definite evidence of restriction with an A wave in the pulmonary artery, augmented during inspiration. In all 20 cases, there was superior vena caval flow reversal with atrial systole. Both inspiratory and expiratory transtricuspid E-wave deceleration time was significantly shorter in the restrictive group (P < .003 and P < .03, respectively). All patients had Doppler evidence of pulmonary regurgitation, but its duration was shorter in the restrictive group (P < .01) during inspiration. Cardiothoracic ratio was significantly lower in the restrictive group (P < .01), suggesting less severe pulmonary regurgitation. Both restrictive and nonrestrictive groups had reduced exercise MVO2 compared with healthy age- and sex-matched control subjects, but those with restrictive physiology had significantly better maximum oxygen uptake than the nonrestrictive group (P < .001). CONCLUSIONS: Isolated right ventricular restriction late after tetralogy of Fallot repair is common. Although it reflects abnormal hemodynamics, the A wave contributes to forward pulmonary arterial flow and shortens the duration of pulmonary regurgitation. Consequently, there is less cardiomegaly and improved exercise performance in those patients.

Adolescent↗
PubMed1995

Ventilation-perfusion matching in chronic heart failure.

BACKGROUND: The exercise limitation of patients with chronic heart failure is associated with an increased ventilatory response during exercise. This is thought to be due, at least in part, to excessive dead space ventilation. METHODS: To assess ventilation perfusion matching, 20 patients with chronic heart failure and eight controls with asymptomatic left ventricular dysfunction underwent symptom limited treadmill exercise with arterial blood sampling. Metabolic gas exchange was determined by expired gas analysis. Fractional dead space ventilation and the alveolar arterial oxygen difference were derived. RESULTS: There was a fall in fractional dead space ventilation (0.43 to 0.28; P < 0.001), more marked in the controls (peak dead space fraction 0.19 (controls), 0.32 (patients); P = 0.002). There was a rise in alveolar arterial difference in all patients (1.59 to 2.55 kPa; P = 0.006) with no difference between patients and controls. Arterial carbon dioxide tension fell during exercise (4.89 to 4.63 kPa; P < 0.001), with no difference between patients and controls. There was no significant change in arterial oxygen tension. CONCLUSIONS: The fall in arterial carbon dioxide was the same in both patients and controls. The modest increase in alveolar-arterial oxygen difference tension was the same in both groups, which, coupled with the stable arterial oxygen tension makes it unlikely that a primary change in ventilation-perfusion matching is the cause of increased ventilatory response to exercise in chronic heart failure.

Carbon Dioxide↗
PubMed1995

Intravenous immunoglobulin therapy for the antiphospholipid syndrome in pregnancy.

OBJECTIVE: Our purpose was to study the influence of intravenous immunoglobulin on pregnancy outcome. STUDY DESIGN: Pregnancy outcomes were evaluated in five patients with 17 unsuccessful previous pregnancies. Each patient received 400 mg/kg immunoglobulin for 5 days monthly beginning in the first or early second trimester. Four patients with previous thromboembolic events were treated with concomitant heparin prophylaxis. Four patients received 81 mg of aspirin daily. RESULTS: Short- and long-term decreases of anticardiolipin immunoglobulin G were noted in three patients. Four patients were delivered of healthy infants at term, one at 32 weeks' gestation with a diagnosis of fetal distress. Neither preeclampsia nor fetal intrauterine growth retardation were observed. The immunoglobulin therapy was not associated with major side effects. Significant placental histologic anomalies were not identified. CONCLUSIONS: The observations suggest that immunoglobulin therapy may improve pregnancy outcomes beyond that observed with heparin and aspirin. A prospective trial is encouraged.

Adult↗
PubMed1995

Chronotropic incompetence in chronic heart failure.

BACKGROUND: The exercise limitation of patients with chronic heart failure may be due in part to an inability to increase heart rate as normal, a limitation sometimes referred to as chronotropic incompetence. This may be due to down regulation of beta receptors. METHODS: Fifty-seven patients with chronic heart failure and 14 age-matched controls underwent symptom limited treadmill exercise tests with metabolic gas exchange measurements. Heart rate and blood pressure responses were also recorded. RESULTS: Peak oxygen consumption was reduced in the heart failure patients (19.6 (S.D. +/- 7.6) vs. 35.0 (+/- 9.9); P < 0.001). Heart rate at peak exercise (r = 0.47, P < 0.001), and change in heart rate from rest to peak exercise (r = 0.59; P < 0.001) and rate pressure product at peak exercise (r = 0.56, P < 0.001) all correlated with peak oxygen consumption. The percentage of predicted maximal heart rate at peak exercise correlated poorly with peak oxygen consumption (r = 0.29; P > 0.05). Peak systolic and diastolic blood pressures did not correlate with peak oxygen consumption. Sixteen patients had chronotropic incompetence. There was no significant difference between this group and those without chronotropic incompetence in the intensity of exercise performed, underlying diagnosis, drug therapy or prevalence of atrial fibrillation. There was a trend towards shorter exercise times in the incompetent group (430 (+/- 251) vs. 545 (+/- 216) s; P = 0.08) compared to the other patients. CONCLUSIONS: Chronotropic incompetence was seen in < 30% of patients with chronic heart failure. However, there are few differences between the group with chronotropic incompetence and the group without. Chronotropic incompetence is thus unlikely to be a major factor limiting exercise capacity in unselected patients with chronic heart failure and is likely to be the major factor limiting exercise in a much smaller proportion of patients.

Adolescent↗
PubMed1995

Relationship between arterial potassium and ventilation during exercise in patients with chronic heart failure.

The mechanisms underlying the increased ventilatory response to exercise seen in patients with chronic heart failure are not clearly understood. Arterial potassium has been suggested as an important ventilatory stimulant. The authors have investigated the arterial potassium response in patients with heart failure. Although arterial potassium rises during exercise, no evidence was found to suggest a greater potassium response in patients with heart failure compared to normal subjects. There was no direct correlation between the rise in ventilation and the rise in arterial potassium. It remains possible that there is an increased sensitivity to arterial potassium in patients with heart failure, but it would need to be three times greater than in normal subjects.

Aged↗