PubMed Health⌕ Search

Biomedical subjects

A Lockhart

Publications and source records attributed to A Lockhart.

At least 19 recordsLinked to original sources
PubMed1992

Improvement in exercise performance by inhalation of methoxamine in patients with impaired left ventricular function.

BACKGROUND: Bronchial hyperresponsiveness to cholinergic stimuli such as the inhalation of methacholine is common in patients with impaired left ventricular function. Such hyperresponsiveness is best explained by cholinergic vasodilation of blood vessels in the small airways, with extravasation of plasma due to high left ventricular filling pressure. Because this vasodilation may be prevented by the inhalation of the vasoconstrictor agent methoxamine, we studied the effect of methoxamine on exercise performance in patients with chronic left ventricular dysfunction. METHODS: We studied 19 patients with a mean left ventricular ejection fraction of 22 +/- 4 percent and moderate exertional dyspnea. In the first part of the study, we performed treadmill exercise tests in 10 patients (group 1) at a constant maximal workload to assess the effects of 10 mg of inhaled methoxamine on the duration of exercise (a measure of endurance). In the second part of the study, we used a graded exercise protocol in nine additional patients (group 2) to assess the effects of inhaled methoxamine on maximal exercise capacity and oxygen consumption. Both studies were carried out after the patients inhaled methoxamine or placebo given according to a randomized, double-blind, crossover design. RESULTS: In group 1, the mean (+/- SD) duration of exercise increased from 293 +/- 136 seconds after the inhalation of placebo to 612 +/- 257 seconds after the inhalation of methoxamine (P = 0.001). In group 2, exercise time (a measure of maximal exercise capacity) increased from 526 +/- 236 seconds after placebo administration to 578 +/- 255 seconds after methoxamine (P = 0.006), and peak oxygen consumption increased from 18.5 +/- 6.0 to 20.0 +/- 6.0 ml per minute per kilogram of body weight (P = 0.03). CONCLUSIONS: The inhalation of methoxamine enhanced exercise performance in patients with chronic left ventricular dysfunction. However, the improvement in the duration of exercise at a constant workload (endurance) was much more than the improvement in maximal exercise capacity assessed with a progressive workload. These data suggest that exercise-induced vasodilation of airway vessels may contribute to exertional dyspnea in such patients. Whether or not inhaled methoxamine can provide long-term benefit in patients with heart failure will require further study.

Administration, Inhalation↗
PubMed1992

Protein design on computers. Five new proteins: Shpilka, Grendel, Fingerclasp, Leather, and Aida.

What is the current state of the art in protein design? This question was approached in a recent two-week protein design workshop sponsored by EMBO and held at the EMBL in Heidelberg. The goals were to test available design tools and to explore new design strategies. Five novel proteins were designed: Shpilka, a sandwich of two four-stranded beta-sheets, a scaffold on which to explore variations in loop topology; Grendel, a four-helical membrane anchor, ready for fusion to water-soluble functional domains; Finger-clasp, a dimer of interdigitating beta-beta-alpha units, the simplest variant of the "handshake" structural class; Aida, an antibody binding surface intended to be specific for flavodoxin; Leather--a minimal NAD binding domain, extracted from a larger protein. Each design is available as a set of three-dimensional coordinates, the corresponding amino acid sequence and a set of analytical results. The designs are placed in the public domain for scrutiny, improvement, and possible experimental verification.

Algorithms↗
PubMed1992

Azelastine reduces allergen-induced nasal response: a clinical and rhinomanometric assessment.

The effect of azelastine 2 mg b.d. p.o. for 10 days on grass pollen-induced nasal responses in 16 patients with grass pollen allergic rhinitis has been assessed. The study was a double blind, randomized, placebo controlled, crossover trial, with a 10-14 day wash-out period. Patients were challenged with grass pollen before and after placebo and azelastine. The response was assessed by measurement of nasal resistance using active posterior rhinomanometry, by weighing nasal secretions, and by counting sneezes. The sensation of nasal obstruction was assessed with a visual analogue scale. After measurement of baseline total nasal resistance, doubling doses of allergen were sprayed into both nostrils at 15 min intervals until the nasal resistance was doubled. Cumulative doses of allergen that doubled prechallenge nasal resistance, numbers of sneezes and the amounts of nasal secretions were similar before azelastine as well as before and after placebo (cumulative dose, mean, (microgram): 2.3, 4.2 and 2.1 respectively, N.S.). After azelastine, the cumulative dose of allergen was increased (7.3 micrograms), and nasal secretions and the number of sneezes were decreased. The visual analogue scores were similar before and after azelastine as well as before and after the placebo. It is concluded that azelastine reduced the allergen-induced nasal responses.

Adult↗
PubMed1992

Relationship between spontaneous dyspnoea and lability of airway obstruction in asthma.

1. As marked lability of bronchial obstruction is a risk factor for asthma severity, it may influence dyspnoea, the most common subjective complaint in asthma. We therefore studied the relationship between spontaneous dyspnoea and the degree of bronchial lability, as assessed by the daily variability in peak expiratory flow rate and the bronchial responsiveness to either carbachol or salbutamol, in 33 stable symptomatic asthmatic patients. 2. Three times daily, for 10 consecutive days, the patients rated the intensity of their dyspnoea on a visual analogue scale and immediately afterwards recorded their peak expiratory flow rate. Within the next 5 days, we determined the bronchial response by measuring the forced expiratory volume in 1 s and the specific resistance of airways to either carbachol or salbutamol according to baseline airway obstruction. 3. We characterized dyspnoea for each patient by using two parameters: (1) the relationship with underlying airway obstruction, as assessed by the correlation coefficient r between dyspnoea scores and corresponding values of peak expiratory flow rate (r DSc-PEFR), and (2) the intensity, as assessed by the mean visual analogue scale dyspnoea score adjusted for comparable airway obstruction. Bronchial lability was characterized by (1) variability in mean daily peak expiratory flow rate and (2) bronchial responsiveness to either carbachol (as assessed by the threshold dose and the slope of the dose-response curve) or salbutamol (as assessed by the threshold dose and maximal response). We assessed the relationship between dyspnoea and bronchial lability by correlating each of their respective characteristics. 4. We found large inter-subject differences in both characteristics of dyspnoea.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1992

In vitro bronchial hyperresponsiveness after lung transplantation in the rat.

In this study, we examined the effect of unilateral lung transplantation on in vitro responses of bronchial smooth muscle to electrical field stimulation (EFS) and exogenous acetylcholine (ACh). In syngeneic Lewis rats, we compared the contractile responses of the left hilar transplanted bronchus with that of the nontransplanted right bronchus and the left and right bronchi from control and sham-operated animals. Atropine-sensitive bronchial contraction to EFS was greater on left transplanted than on right nontransplanted bronchi at all frequencies and voltages used. In control and sham-operated animals, contractile responses to EFS were identical on left and right sides and similar to the responses of the right nontransplanted bronchus of the lung transplant recipient. Concentration-response curves to exogenous ACh were similar on transplanted and all control bronchi. Intramural cholinergic nerve cell bodies reactive for acetylcholinesterase were present in the transplanted bronchus. We conclude that EFS-induced cholinergic contraction of rat bronchial smooth muscle is enhanced after lung transplantation. Enhancement is not a result of medication, inflammation, or rejection, absent from our syngeneic transplant, or of upregulation of muscarinic post-junctional receptors because the response to exogenous ACh was normal. Hence, an increased release of ACh from cholinergic nerve terminals may occur, due either to hyperexcitability of postganglionic parasympathetic nerves or to loss of inhibitory mechanism resulting from interruption of neural connections with the central nervous system.

Acetylcholine↗
PubMed1992

Bronchial provocation tests in small animals: a quantified and automated procedure.

Bronchial provocation tests using aerosols in laboratory animals are difficult to standardize and quantify, because the amount of drug actually reaching the airways is unknown. To improve the quantification of aerosolized inhaled stimuli, we designed an apparatus that allows, in anesthetized intubated ventilated animals, control of temperature and hygrometry of inspired air, computerized measurement of pulmonary resistance, and fully automated delivery of a known amount of aerosolized drug directly into the trachea. Calibration of the aerosol delivery involved direct measurement of liquid delivered at the tip of the tracheal cannula. Despite all our efforts at standardization and full automation of all steps, reproducibility of aerosol delivery was poor, with stroke-by-stroke differences of 26 or 42%, according to whether an air-jet or an ultrasonic nebulizer was used. Histamine dose-response curves performed in 15 guinea pigs with this device confirmed marked differences among animals and also disclosed large intraindividual changes in bronchial responsiveness.

Aerosols↗
PubMed1992

Effect of airway blood flow on airflow.

Resistance to gas flow of an airway is a function of both airway smooth muscle tone and thickness of the airway wall internal to the outer ring of airway smooth muscle. Schematically, the increase in airway resistance caused by shortening of airway smooth muscle may be potentiated by a concomitant increase in airway wall thickness caused by vasodilation of the bronchial vessels and/or microvascular leakage. Conversely, bronchial vasoconstriction may limit to some extent the increase in resistance to gas flow caused by airway smooth muscle shortening and/or congestion and edema of the airway wall. Many endogenous paracrine mediators, putatively involved in asthma and bronchial hyperresponsiveness, have both bronchomotor and vascular effects. The overall effects on resistance to airflow of endogenous or exogenous agents depend not only upon pre-existing airway smooth muscle tone and pre-existing condition of bronchial vessels but also upon two factors that facilitate microvascular leakage, namely, inflammation of the airway wall and outflow pressure of the bronchial circulation, which is close to left atrial pressure.

Airway Obstruction↗
PubMed1992

Carboxypeptidase M-like enzyme modulates the noncholinergic bronchoconstrictor response in guinea pig.

We studied the effects of aerosolized DL-2-mercaptomethyl-3-guanidino-ethylthiopropanoic acid (MGTA) (10(-4) M, 90 breaths), a specific inhibitor of carboxypeptidase B-type enzymes, on changes in total pulmonary resistance (RL) induced by aerosolized capsaicin (10(-7) to 10(-4) M; 10 breaths at each concentration) and vagus nerve stimulation (5 V, 5 ms, for 20 s at frequencies varying from 2 to 10 Hz) in anesthetized, atropinized, and ventilated guinea pigs. We also studied the effect of aerosolized MGTA on the bronchoconstrictor response to either aerosolized substance P, neurokinin A (10(-7) to 10(-4) M; 10 breaths at each concentration), and carbachol (10(-5) to 2 x 10(-4) M; 10 breaths at each concentration) or to i.v. administration of neurokinin A (10(-11) to 10(-8) mol/kg), bradykinin (10(-10) to 10(-7) mol/kg), and histamine (10(-8) to 10(-6) mol/kg). Although aerosolized MGTA caused no change in basal RL (P > 0.5), it did potentiate the noncholinergic bronchoconstrictor response to capsaicin (n = 5; P < 0.001) as well as to vagus nerve stimulation (n = 5; P = 0.001). In contrast, MGTA did not potentiate the bronchoconstrictor response to either aerosolized substance P, neurokinin A, and carbachol or to i.v. administration of neurokinin A, histamine, and bradykinin. Carboxypeptidase activity cleaving C-terminal arginine or lysine was found in the membrane preparations of trachea and lung from guinea pigs. The membrane-bound carboxypeptidase activity was maximal at pH 7.0 and was enhanced by the presence of CoCl2 (1 mM) in both the tracheal and lung tissue.(ABSTRACT TRUNCATED AT 250 WORDS)

3-Mercaptopropionic Acid↗
PubMed1992

Passive partitioning of respiratory volumes and time constants in ventilated patients.

If the thoracoabdominal partitioning of volumes in the mechanical respiratory apparatus was constant, one transducer of indirect spirometry should be sufficient to measure volume variations. To verify this hypothesis we used respiratory inductive plethysmography (RIP) in 16 paralysed patients, of whom eight had normal lungs and 8 had not, to measure: 1) the thoracoabdominal partitioning of volumes (400-1,200 ml) insufflated from either a syringe (Syr) or a ventilator (Vent); and 2) thoracic (Tho) and abdominal (Abd) time constants (T0.368) on spontaneous deflation to barometric pressure. In eleven additional subjects with normal lungs we measured only the time constants. 1) Correlation coefficients of the calibration lines were in all but one subject > 0.98. In all patients the error of volume was < +/- 10% when either one of two coils alone was used to assess volumes with no difference between the two coils; 2) Partitioning varied little with volumes (4 +/- 2%), but widely between subjects, with no group average significant difference between Syr and Vent; 3) T0.368 were identical for Tho and Abd except in one patient; 4) Partitioning and T0.368 were volume size independent. We conclude that, to measure volume variations and time constants in ventilated, paralysed patients, the use of either a thoracic or abdominal single coil RIP is justified. We also provide the normal range for time constant in 19 subjects (0.73 +/- 0.29 s).

Adult↗
PubMed1992

Modulation by theophylline and enprofylline of the excitatory non-cholinergic transmission in guinea-pig bronchi.

The mechanism of action of xanthines in asthma remains controversial. Since sensory innervation may play a role in the pathogenesis of asthma, we investigated whether xanthines were capable of reducing the contractile response of the bronchi to nerve stimulation. In guinea-pig bronchi in vitro, electrical field stimulation (EFS: 40 V, 16 Hz, 0.2 ms during 10 s) induces a rapid cholinergic contraction followed by a long-lasting contraction due to a local release of neuropeptides from C-fibre endings. We measured isometric neuronally-mediated contractions of bronchial smooth muscle and studied the effects of increasing concentrations of two xanthine derivatives, theophylline, an antagonist of adenosine receptors, and enprofylline, which has no effect on adenosine receptors. Both enprofylline (1-50 microM) and theophylline (10-100 microM) inhibited, in a concentration-dependent manner, the peptidergic contraction, an effect which was more marked with enprofylline than theophylline (EC50 = 9.6 +/- 0.7 microM and 62.0 +/- 4.7 microM, respectively). Conversely, the cholinergic response was unaffected. Contractions induced by exogenous substance P (0.03-3 microM) were also unaffected by theophylline and enprofylline at the above mentioned EC50s. Our results suggest that concentrations of theophylline, similar to those used therapeutically, reduce the release of sensory neuropeptides from C-fibre endings. This effect is unrelated to adenosine receptor blockade, since enprofylline had a similar inhibitory effect.

Airway Resistance↗
PubMed1992

Methods for clinical assessment of expectorants: a critical review.

The purpose of the paper is to discuss some aspects of the methods that are most appropriate for the clinical assessment of new expectorants. Expectorants are drugs devised to help in the removal of bronchial secretions. The evaluation of these drugs is aimed at demonstrating, in controlled trials, their efficacy, safety and, if possible, mechanism of action. Unfortunately, there is no universally accepted assessment technique available. Evaluation of symptoms with the use of self-reported measures is imprecise. Studies of quality of life can assist as a means of assessing the usefulness of this class of drug for patients. Lung function tests evaluate only the possible indirect effects of expectorants; the changes observed are often minor and they do not correlate with other methods of evaluation. Mucociliary clearance studies evaluate bronchial drainage by mucociliary transport and cough. They are a useful pharmacological approach but they cannot replace therapeutic trials. In vitro and ex vivo studies of bronchial secretion, while improving knowledge of the mechanisms of bronchial secretion, fail to predict the modifications of bronchial drainage produced in vivo by cough or mucociliary transport. To be considered efficient, expectorants should not only ease the removal of bronchial secretions, but also improve the patient's condition for the duration of treatment.

Animals↗
PubMed1991

Decreased bronchial response to methacholine in IDDM patients with autonomic neuropathy.

This study was designed to evaluate the involvement of airways innervation during diabetic autonomic neuropathy. Bronchial response to methacholine was assessed by inhalation of serially doubling doses in 22 insulin-dependent diabetes mellitus (IDDM) patients and 11 nondiabetic control subjects selected for their nonsmoking habits. Cardiovascular autonomic control was studied by four standardized tests, i.e., blood pressure and heart-rate variations during orthostatism, heart-rate variation during Valsalva maneuver, and deep breathing. Magnitude and time-course of response to methacholine were similar in nondiabetic subjects and IDDM patients without any abnormal result on cardiovascular tests. Conversely, bronchial response to methacholine was markedly reduced in IDDM patients with one or more abnormal results by cardiovascular assessment of autonomic control. In the IDDM patients, bronchial response to methacholine was significantly correlated to indexes of cardiovascular autonomic control. These results suggest that, during diabetic neuropathy, innervation of the airways likewise involves cardiac autonomic control and leads to impairment of defense reflexes of the airways.

Adult↗
PubMed1991

A single-compartment model cannot describe passive expiration in intubated, paralysed humans.

The time-course of thoracic volume changes (respiratory inductive plethysmograph) during relaxed expiration was studied in 11 intubated, paralysed, mechanically ventilated subjects. The semilog volume-time curves show that expiration is governed by two apparently separate mechanisms: one causes emptying of most of the expired volume (approximately 80%) with a time constant of 0.50 +/- 0.22 s for a baseline tidal volume of 0.44 +/- 0.12 l (mean +/- SD) and 0.37 +/- 0.14 s when the tidal volume is reduced (VTP); the other contributes a relatively small amount to the expired volume over a significantly longer time, the time constant amounting to 3.27 +/- 1.54 s for baseline VT and 2.95 +/- 1.65 s for VTp. The first mechanism probably reflects the standard elastic and flow resistive properties of the respiratory system, while the second, slower compartment, is probably an expression of the viscoelastic properties of the pulmonary and chest wall tissues.

Adult↗
PubMed1991

[Maximal ventilatory pressure through the mouth in adults: normal values and explanatory variables].

Mouth pressure measured during maximal inspiratory or expiratory efforts depends on the force exerted by ventilatory muscles. Normal values and anthropometric factors accounting for maximal inspiratory and expiratory pressures (MIP, MEP) are not fully agreed upon to date. We measured MIP and MEP in 253 normal subjects (135 females and 118 males, age 15-59 years) using a digital transducer (163 Sibelmed). All subjects had normal forced vital capacity (FVC) and one second forced expiratory volume (FEV1). Sex, age, height and weight were recorded for all subjects and were entered as independent variables in computation of linear multiple regressions with MEP or MIP the dependent variables. MEP and MIP were greater in males than in females (p less than 0.01) with MIP lower than MEP in both sexes (p less than 0.01). In both males and females, FVC and FEV1 depend on age and height (p less than 0.01). In the entire group, we found a correlation of MIP in females and MEP in males with age (p less than 0.01) and of both MIP and MEP in females with weight (p less than 0.01). However, in subjects aged 20-59 years, there was no significant dependence of MIP and MEP on age, and when the weight of subjects was normal (n = 170), MIP and MEP were independent of weight. We conclude that in adults aged 20-59 years and with normal weight, maximal ventilatory pressures depend solely on sex. In this subgroup mean (+/- SD) values of MEP and MIP were 111 +/- 25 cmH2O and 79 +/- 19 cmH2O respectively in females and 192 +/- 42 cmH2O and 117 +/- 25 cmH2O in males.

Adolescent↗
PubMed1991

[Cough and bronchial obstruction induced by citric acid in smokers, occasional smokers and non-smokers].

We have studied cough and bronchial constriction induced by inhaling citric acid in 15 smokers with baseline airflow obstruction, in 13 occasional smokers and 13 non smokers. The threshold for cough was significantly higher in occasional smokers in relation to smokers and non smokers. Citric acid produced the same degree of bronchial constriction at the same time in smokers and occasional smokers: the maximum fall in forced expired volume (FEV1-VEMS) was recorded five seconds after inhalation of the citric acid (dose threshold) and there was no significant difference between the two groups. In the non smokers, the maximum fall in VEMS was recorded twenty seconds after inhalation of the citric acid and was significantly less in relation to that of the smokers and occasional smokers. In the smokers the degree of smoking could influence the fall of VEMS (% predicted). Cough and bronchial constriction after the inhalation of citric acid are probably related to different physiological mechanisms and are linked to the history of smoking.

Adult↗