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Biomedical subjects

P Lekeux

Publications and source records attributed to P Lekeux.

At least 19 recordsLinked to original sources
PubMed2001

Impaired accumulation of granulocytes in the lung during ozone adaptation.

Respiratory alterations induced by an acute exposure to ozone (O(3)) paradoxically resolve during multiday exposure. This adaptation is characteristically accompanied by a gradual attenuation of lung neutrophilia. As maintenance of neutrophilia at the site of inflammation is due to cytokine-mediated delayed neutrophil apoptosis, which is associated with reduced levels of Bax, a proapoptotic protein, we sought to determine whether defects in these mechanisms could account for O(3) adaptation. Lung granulocytes obtained at different time points from calves exposed to 0.75 ppm O(3) for 12 h/d for 7 consecutive days neither showed enhancement of survival nor Bax deficiency, when compared to blood granulocytes. To further investigate the effects of an exogenous oxidative stress on neutrophil survival, human granulocytes were treated with hydrogen peroxide alone, or in combination with granulocyte/macrophage colony-stimulating factor, an antiapoptotic cytokine. Both treatments led to rapid apoptosis associated with downregulation of Bcl-x(L) and Bcl-2, two antiapoptotic proteins. This study shows that O(3) adaptation is associated with a failure in the mechanisms leading to accumulation of neutrophils at the site of inflammation, and suggests that this defect is due to direct proapoptotic effects of exogenous oxidative stress on granulocytes.

Adaptation, Physiological↗
PubMed2001

p65 Homodimer activity in distal airway cells determines lung dysfunction in equine heaves.

Nuclear factor-kappaB (NF-kappaB) activity, which is a key regulator of inflammatory gene expression, is increased in bronchial epithelial cells from horses suffering from heaves (a hypersensitivity-associated inflammatory condition of the lung). To determine whether this increased activity extends to distal airways and to other pulmonary cells, cells recovered by broncho-alveolar lavage (BAL) in healthy and heaves-affected horses were assessed for NF-kappaB activity. NF-kappaB activity was much higher in BAL cells from heaves-affected horses, especially during crisis (disease exacerbation), than in cells from healthy horses. Moreover, the level of NF-kappaB activity found in BAL cells was positively correlated to total lung resistance and to the proportion of neutrophils present in BAL fluid. Finally, prototypical p65-p50 NF-kappaB heterodimers were absent from BAL cells, which mostly contained p65 homodimers. These results (1) show that increased NF-kappaB activity is a general feature of heaves lung; (2) demonstrate the importance of p65 homodimers in neutrophilic inflammation; and (3) suggest that the use of specific NF-kappaB inhibitors could improve lung function in heaves-affected horses.

Animals↗
PubMed2001

Effects of 8-epi-PGF2alpha on isolated bronchial smooth muscle of healthy and heaves-affected horses.

8-Epi-PGF2alpha, a prostaglandin-like compound generated by oxidative stress, has been shown to be an in vitro bronchoconstrictor in airways from healthy laboratory animals and healthy humans, but it has never been studied in diseased airways. Here, the bronchoconstrictive capacity of 8-epi-PGF2alpha on isolated bronchial rings (BR) of healthy and heaves-affected horses was evaluated by comparing the maximal effect and the potency of 8-epi-PGF2alpha to those of (1) acetylcholine (ACh), (2) its stereoisomer PGF2alpha and (3) its synthetic receptor agonist, U46619. Furthermore, the potential capacity of 8-epi-PGF2alpha to enhance the cholinergic (ACh) responsiveness of bronchial smooth muscle was investigated. 8-Epi-PGF2alpha contracted BR with a rank order of efficacy of Ach > U44619 > PGF2alpha > 8-epi-PGF2alpha in both healthy and heaves-affected horses. The contractile maximal response elicited by 8-epi-PGF2alpha was significantly smaller than that elicited by the other drugs, but was significantly higher in BR from heaves-affected horses than in those sampled in healthy horses, whilst pD2 values were similar. A subthreshold concentration of 8-epi-PGF2alpha (10-7 M) did not induce in vitro cholinergic hyper-responsiveness in BR of either healthy or heaves-affected horses. In conclusion, it has been demonstrated that 8-epi-PGF2alpha is an in vitro bronchoconstrictor of minor importance in healthy horses, but whose efficacy is significantly increased in heaves-affected horses.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed2001

Enhanced survival of lung granulocytes in an animal model of asthma: evidence for a role of GM-CSF activated STAT5 signalling pathway.

BACKGROUND: As granulocyte/macrophage colony stimulating factor (GM-CSF) mediated delay of granulocyte apoptosis contributes to the accumulation of inflammatory cells at the site of inflammation in many diseases, we sought to determine whether asthma is also associated with a GM-CSF dependent increase in lung granulocyte survival. Moreover, because GM-CSF mediates its effects through activation of signal transducer and activator of transcription 5 (STAT5), we also investigated the potential role of STAT5 in allergic inflammation. METHODS: Blood granulocytes were recovered from six healthy and six heaves affected horses, a model of asthma. Lung granulocytes were obtained by bronchoalveolar lavage (BAL) from the same horses. Granulocytes were cultured in the presence or absence of anti-GM-CSF receptor antibodies for different times and apoptosis was determined using the Annexin-V/propidium iodide detection method. Nuclear protein extracts from cultured granulocytes were analysed for STAT5 binding activity by electrophoretic mobility shift assay. RESULTS: BAL fluid granulocytes from heaves affected horses demonstrated a significant delay in apoptosis compared with blood granulocytes from the same horses and blood and BAL fluid granulocytes from healthy horses. Conversely, the rate of apoptosis in blood granulocytes from healthy and heaves affected horses was comparable. The enhanced survival of BAL fluid granulocytes from affected horses was suppressed in the presence of antibodies directed against GM-CSF receptors. Increased levels of active STAT5 were found in BAL fluid granulocytes from heaves affected horses and were markedly reduced after treatment with anti-GM-CSF receptor antibodies. CONCLUSIONS: These data indicate that granulocyte survival is enhanced in the lung of heaves affected horses and suggest a role for a GM-CSF activated STAT5 pathway in delaying apoptosis of lung granulocytes in this model of asthma.

Animals↗
PubMed2001

Spirometric performance in Belgian Blue calves: II. Analysis of environmental factors and estimation of genetic parameters.

Genetic parameters and environmental effects for spirometric variables (SV) in calves were estimated using 734 Belgian Blue calves (15 to 297 d of age), sired by 20 AI bulls. For each calf, the following SV were measured: 1) the average ventilation (l/min) recorded during the 15 s of maximal ventilatory changes induced by lobeline administration (0.25 mg/kg, i.v.) (15-s MV(L)); 2) the vital capacity, and the maximal peak expiratory and inspiratory flows recorded after lobeline administration; and 3) the ventilatory reserve (15-s MV(L) - ventilation at rest). Analysis of environmental factors showed age of calf, herd, sex, and vaccination status had significant effects on SV. A sire model and a multiple-trait derivative-free REML procedure were used to estimate genetic parameters for SV, body weight, and muscling score. Heritabilities for SV ranged from 0.28 +/- 0.11 to 0.44 +/- 0.16. Genetic correlations among SV varied from 0.76 to 0.98 and environmental correlations from 0.69 to 0.80. Genetic correlations of SV with body weight (0.25 to 0.56) and with muscling score (0.21 to 0.76) were positive, as were environmental correlations of SV with body weight (0.44 to 0.70) and muscling score (0.09 to 0.25). These results suggest that selection may improve SV without impairing other traits of economic importance.

Animals↗
PubMed2001

Spirometric performance in Belgian Blue calves: I. Effects on economic losses due to the bovine respiratory disease complex.

The aim of this study was to determine whether high spirometric performances in calves are associated with low economic losses due to the bovine respiratory disease complex (BRDC). Five spirometric variables (SV) were measured in 909 double-muscled Belgian Blue calves from 15 to 60 d of age. Afterward, calves were monitored for 6 mo to determine whether they developed BRDC and to determine the costs due to BRDC (i.e., medicine costs and veterinarians' fees, plus estimated financial losses due to mortality in case of death). To analyze the effects of spirometric performances on BRDC cost, a fixed linear model was used for each SV. In addition to SV, each model included the effects of sex, dam's parity, vaccination status, muscular development score, herd-period, and BW. Only herd-period and the maximal ventilation and the vital capacity had significant effects on costs due to BRDC, indicating that these two SV are major physiological determinants of economic losses associated with BRDC. Accordingly, it is assumed that an amelioration of maximal ventilation and vital capacity could result in increased resistance to BRDC in calves.

Airway Resistance↗
PubMed2001

Endothelin in the equine hypoxic pulmonary vasoconstrictive response to acute hypoxia.

Elevated concentrations of endothelin (ET), a potent endothelium-derived vasoactive peptide, have been reported in a number of pathophysiological conditions associated with pulmonary hypertension, both in the horse and other species. We have previously shown, both in vitro and in vivo, that the pulmonary and systemic vascular response to exogenous ET is mediated predominantly via ET(A) receptors. Our hypothesis in the present study was that ET is involved in the equine hypoxic pulmonary vasoconstrictive response to acute hypoxia. In this study, we investigated the effects of a selective ET(A) receptor antagonist on hypoxic pulmonary hypertension in the mature horse. Horses were exposed to a 10 min period of hypoxia (F(I)O2 approximately 0.11) on 2 occasions, with and without pretreatment with the selective ET(A) receptor antagonist TBC11251 (10 mg/kg bwt i.v.). Hypoxia increased mean pulmonary artery pressure (PAP) from 18.3+/-0.9 (mean +/- s.e. normoxia) to 28.0+/-0.8 mmHg (hypoxia) in the session without ET(A) receptor antagonism. Carotid arterial pressure (CAP) also increased progressively throughout the period of hypoxic challenge and at the end was 153+/-5 mmHg (hypoxia) compared to during normoxia (140+/-5 mmHg). There was no significant overall effect of ET(A) receptor antagonism on the haemodynamic or ventilatory responses to acute hypoxia. However, between 5 and 10 min of hypoxia there was a trend for the mean PAP to diverge in the 2 treatments, which just failed to reach significance at 10 min of hypoxia (P = 0.053). In conclusion, this study describes the haemodynamic and ventilatory changes in response to a period of acute hypoxia in the adult horse. The results do not support a role for ET as a mediator of acute HPV in the horse, but suggest that it may be involved as a modulator or in the slower (>10 min) phase of HPV.

Animals↗
PubMed2001

Equine pulmonary and systemic haemodynamic responses to endothelin-1 and a selective ET(A) receptor antagonist.

Based on previous in vitro studies, we hypothesised that endothelin (ET) would induce vasoconstriction in the pulmonary circululation of the horse and that this action would be mediated via ET(A) receptors. Pulmonary and systemic haemodynamic responses to endothelin-1 (ET-1), a potent vasoactive endogenous peptide, were investigated in 6 conscious, nonsedated horses at rest. Bolus i.v. injections of exogenous ET-1 (0.1, 0.2 and 0.4 microg/kg bwt) caused significant increases in pulmonary (PAP) and carotid (CAP) artery pressures, with peak increases of 79% and 51% for mean PAP and CAP, respectively. The effect of ET-1 on PAP and CAP was rapid and transient for PAP (-10 min) but prolonged for CAP (up to 60 min). ET-1 significantly decreased cardiac output by up to 35% and significantly increased systemic vascular resistance (SVR) by up to 104%. Pulmonary vascular resistance (PVR) showed a trend (P>0.05) to increase with 0.2 and 0.4 microg/kg bwt ET-1. Infusion of a selective ET(A) receptor antagonist (TBC11251) completely inhibited the responses to a subsequent bolus of 0.2 microg/kg bwt ET-1. We conclude that exogenous ET-1 exerts a potent vasoconstrictive action on the pulmonary and systemic circulations of the horse. These effects appear to be mediated largely through ET(A) receptors in both circulations. Endothelin may play a role in hypertensive conditions in the horse.

Animals↗
PubMed2000

NF-kappaB activation in response to toxical and therapeutical agents: role in inflammation and cancer treatment.

The NF-kappaB transcription factor is ubiquitously expressed and controls the expression of a large number of genes. Experimental data clearly indicate that NF-kappaB is a major regulator of the inflammatory reaction by controlling the expression of pro-inflammatory molecules in response to cytokines, oxidative stress and infectious agents. We demonstrated that NF-kappaB activation by IL-1beta follows three distinct cell-specific pathways. Moreover, our studies indicated that in one model of inflammatory diseases, horse recurrent airway obstruction (RAO), the extent of NF-kappaB basal activity correlates with pulmonary dysfunction. Another role of NF-kappaB activity protects cancer cells against apoptosis and could participate in the resistance to cancer treatment. However, we did not observe any increased cytotoxicity after treatment with anticancer drugs or TNF-alpha of cells expressing a NF-kappaB inhibitor. Therefore, we can conclude that the inhibition of apoptosis by NF-kappaB is likely to be cell type and stimulus-dependent. Further studies are required to determine whether NF-kappaB could be a target for anticancer treatments.

Animals↗
PubMed2000

Mechanisms of persistent NF-kappa B activity in the bronchi of an animal model of asthma.

In most cells trans-activating NF-kappaB induces many inflammatory proteins as well as its own inhibitor, IkappaB-alpha, thus assuring a transient response upon stimulation. However, NF-kappaB-dependent inflammatory gene expression is persistent in asthmatic bronchi, even after allergen eviction. In the present report we used bronchial brushing samples (BBSs) from heaves-affected horses (a spontaneous model of asthma) to elucidate the mechanisms by which NF-kappaB activity is maintained in asthmatic airways. NF-kappaB activity was high in granulocytic and nongranulocytic BBS cells. However, NF-kappaB activity highly correlated to granulocyte percentage and was only abrogated after granulocytic death in cultured BBSs. Before granulocytic death, NF-kappaB activity was suppressed by simultaneous addition of neutralizing anti-IL-1beta and anti-TNF-alpha Abs to the medium of cultured BBSs. Surprisingly, IkappaB-beta, whose expression is not regulated by NF-kappaB, unlike IkappaB-alpha, was the most prominent NF-kappaB inhibitor found in BBSs. The amounts of IkappaB-beta were low in BBSs obtained from diseased horses, but drastically increased after addition of the neutralizing anti-IL-1beta and anti-TNF-alpha Abs. These results indicate that sustained NF-kappaB activation in asthmatic bronchi is driven by granulocytes and is mediated by IL-1beta and TNF-alpha. Moreover, an imbalance between high levels of IL-1beta- and TNF-alpha-mediated IkappaB-beta degradation and low levels of IkappaB-beta synthesis is likely to be the mechanism preventing NF-kappaB deactivation in asthmatic airways before granulocytic death.

Airway Obstruction↗
PubMed2000

Mechanics of the respiratory system in healthy newborn calves using impulse oscillometry.

Arterial blood gases, acid-base balance and respiratory function tests using impulse oscillometry (IOS) were performed on 40 clinically healthy newborn calves during the first 24 hours of life to evaluate their respiratory adaptation to extrauterine life. Gas exchange efficiency of the lung was significantly improved with time and was accompanied by the correction of the mixed acidosis observed at birth and by significant changes in respiratory mechanics. Major changes were detected within the first 6 hours. The significant decrease in resistance (R) and the increase in reactance (X) with time, demonstrate the improvement in respiratory mechanics of both upper and lower airways, and reflect the increase in lung volume, the improved lung tissue elasticity and/or distribution of the ventilation. Respiratory mechanical, arterial blood gases and acid-base balance data provided in this study describe a successful respiratory adaptation to extrauterine life in healthy newborn calves.

Acid-Base Equilibrium↗
PubMed2000

Comparison of the performance of linear resistance and ultrasonic pneumotachometers at rest and during lobeline-induced hyperpnoea.

The performance of a Fleisch No. 5 pneumotachometer (F), and two commercial ultrasonic pneumotachometers, the BRDL (B) and the Spiroson (S) systems were compared in respect to their use for determination of ventilatory parameters at rest and during lobeline-induced hyperpnoea. Five clinically healthy Thoroughbred horses were tested with the three pneumotachometers in random order. Respiratory airflow, respired gas concentrations, oesophageal pressures, pressures within the mask systems and arterial blood gases were determined before and during lobeline-induced hyperpnoea. Because measured peak expiratory airflow rates exceeded the stated linear range of the Fleisch pneumotachometer ( approximately +/- 25 l s(-1)) differential pressure-flow curves were determined in vitro over the range of flows recorded in vivo. Expired flows greater than the linear range were corrected according to the derived regression equation. No differences in any of the measured variables among the three systems were present at rest. At peak ventilation of lobeline-induced hyperpnoea mask pressures [Delta P(mask)(mean (SEM)): F: 9.6 (2.8) cm H(2)O, B: 0.8 (0.4) cm H(2)O, S: 1.4 (0.8) cm H(2)O] and end tidal carbon dioxide [ ET CO(2)(mean (SEM)): F: 2. 6 (0.1)%, B: 2.1 (0.2)%, S: 2.1 (0.1)%] were significantly higher in system F. Despite a tendency for respiratory frequency and peak inspired and expired flows, to be lower with system F, no significant differences in the measurements of ventilatory mechanics were detected. In conclusion, the ultrasonic flowmeters pose significantly lower resistive loads onto the respiratory system during ventilation above resting levels than Fleisch No 5 pneumotachometers. However, at the flowrates achieved during lobeline-induced hyperpnoea an in vitro calibration of the differential pressure-flow relationship allows correction for expiratory alinearity in system F. In addition, the performance of the Spiroson flowmeter is accurate in determining ventilatory mechanics at rest and during lobeline-induced hyperpnoea.

Animals↗
PubMed2000

Evaluation of accuracy of pulse oximetry in newborn calves.

In human medicine, pulse oximetry is widely used to measure non-invasively and accurately the percentage of oxygen saturation of arterial haemoglobin (SpO(2)). Recently, pulse oximetry has been used in calves, but its accuracy has not been evaluated in newborn calves. The purpose of this study was to evaluate the accuracy of a pulse oximeter in newborn calves by comparing SpO(2) with arterial oxyhaemoglobin saturation (SaO(2)) obtained by use of a blood gas analyser. Fifty-five newborn calves were investigated from birth to 20 days old. Pulse oximetry readings and arterial blood samples were performed 5, 15, 30, 45, 60 min, 2, 3, 6, 12, 24 h and 1 and 3 weeks after birth. The transmission-type sensors of the pulse oximeter were fixed at the recommended site in the bovine species (at the base of the calf tail, where the skin had been shaved and was not pigmented) and arterial blood samples were withdrawn from the subclavian artery and analysed for SaO(2). Five-hundred paired data of SaO(2) and mean SpO(2)(mSpO(2)) were collected. Linear regression of the pooled data indicated a highly significant correlation of mSpO(2) with SaO(2) (r = 0.87;P< 0.001; mSpO(2) = 15.8 + 0.84 SaO(2)). The overall data bias value was positive (+2.1%), which indicated that the pulse oximeter tended to overestimate the SaO(2). The bias value for each SaO(2) category tended to become higher for lower ranges of SaO(2). Precision was also lower when SaO(2) values were low. The lower the SaO(2) value, the higher the positive bias (overestimation) and the lower the precision. These results suggest that pulse oximetry provides a relatively accurate non-invasive, immediate and portable method to monitor SaO(2) and to evaluate objectively the pulmonary function effectiveness in newborn calves during their adaptation to extra-uterine life.

Aging↗
PubMed2000

Comparison between radioactive aerosol, technegas and krypton for ventilation imaging in healthy calves.

The use of lung scintigraphy in calves necessitates the validation of a ventilation (V) imaging agent compatible with clinical applications. This study aimed at defining the value of an inhaled radioactive aerosol (99mTc-DTPA) and a 'pseudogas' (Technegas) in the assessment of regional V in healthy conscious calves by comparing 99mTc-DTPA and Technegas deposition (D) images to V(V) images obtained from the steady-state inhalation of the short half-life krypton 81 (81mKr) gas. Images were compared by analysis of radioactivity distribution in computer-generated regions of interest within the right lung and D to V ratio images were generated in order to highlight areas of mismatching between 99mTc-DTPA or Technegas and 81mKr distributions. Results of this analysis showed that the 99mTc-DTPA aerosol droplets were unable to reach the lung parenchyma because of significant particle impaction in the major conducting airways. Better definition of the ventilated lung was obtained when using Technegas because of minimal deposition in conducting airways. Furthermore, the Technegas and 81mKr distribution patterns were highly equivalent.

Aerosols↗
PubMed2000

Validation and prognostic value of plasma lactate measurement in bovine respiratory disease.

The purpose of this study was to evaluate the accuracy of a portable blood lactate analyser for bovine blood and to study the relevance of plasma lactate concentration in the prognosis of bovine pulmonary disorders. Measurements with the portable analyser were highly correlated (R = 0.94, P<0.0001) with the measurements of the reference method but significantly different (P<0.0001). The portable apparatus slightly overestimated plasma lactate concentration compared to the reference method (bias = + 0.412). Plasma lactate measurements on 109 calves suffering from acute bronchopneumonia showed increasing lactate concentrations with severity of the disease. A plasma lactate concentration higher than 3.6 mmol/L or 4 mmol/L, measured with the reference method and the portable analyser respectively, appeared to be a reliable prognostic indicator for mortality within 24 h. Consequently, this measurement could be very helpful to decrease economic losses in cases of bovine respiratory disease, by avoiding unnecessary treatment costs on cattle with poor prognosis.

Animals↗
PubMed2000

Correlation between nuclear factor-kappaB activity in bronchial brushing samples and lung dysfunction in an animal model of asthma.

Asthma is a chronic inflammatory disease of the airways, in which many inflammatory genes are overexpressed. Transcription factor, nuclear factor-kappaB (NF-kappaB), which is thought to control the transcriptional initiation of inflammatory genes, has been poorly investigated in asthma. In the present report, bronchial cells (BCs), recovered by bronchial brushing in healthy and heaves-affected horses (i.e., an animal model of asthma), were assessed for NF-kappaB activity. Small amounts of active NF-kappaB were present in BCs of healthy horses, whereas high levels of NF-kappaB activity was found during crisis (i.e., acute airway obstruction) in all heaves-affected horses. Three weeks after the crisis, the level of NF-kappaB activity found in BCs of heaves-affected horses was highly correlated (p < 0.01) to the degree of residual lung dysfunction. Unexpectedly, active NF- kappaB complexes found in BCs of heaves-affected horses were mainly p65 homodimers, rather than classic p65-p50 heterodimers. At last, intercellular adhesion molecule-1 (ICAM-1) expression paralleled p65 homodimers activity in these cells. These results demonstrate that the kinetics of NF-kappaB activity is strongly related to the course of the disease and confirm the relevance of NF-kappaB as a putative target in asthma therapy. Moreover, uncommon p65 homodimers could transactivate, in BCs, a subset of genes, such as ICAM-1, characteristic of chronic airway inflammation.

Animals↗
PubMed2000

Effect of a 30-minute infusion of dobutamine hydrochloride on hind limb blood flow and hemodynamics in halothane-anesthetized horses.

OBJECTIVE: To evaluate the hemodynamic effects of dobutamine hydrochloride (0.5 microg/kg of body weight/min) in halothane-anesthetized horses. ANIMALS: 6 adult Thoroughbred horses. PROCEDURE: Anesthesia was induced by use of romifidine (100 microg/kg) and ketamine (2.2 mg/kg), IV. Anesthesia was maintained by halothane (end-tidal concentration 0.9 to 1.0%). Aortic, left ventricular, and right atrial pressures were measured, using catheter-mounted strain gauge transducers. Cardiac output (CO), velocity time integral, maximal aortic blood flow velocity and acceleration, and left ventricular preejection period and ejection time were measured from aortic velocity waveforms obtained by transesophageal Doppler echocardiography. Velocity waveforms were recorded from the femoral vessels, using Doppler ultrasonography. The time-averaged mean velocity and early diastolic deceleration slope (EDDS) were measured. Pulsatility index (PI) and volumetric flow were calculated. Microvascular perfusion was measured in the semimembranosus muscles by laser Doppler flowmetry. Data were recorded 60 minutes after induction of anesthesia (control) and at 15 and 30 minutes after start of an infusion of dobutamine (0.5 microg/kg/min). RESULTS: Aortic pressures were significantly increased during the infusion of dobutamine. No change was observed in the indices of left ventricular systolic function including CO. Femoral arterial flow significantly increased, and the PI and EDDS decreased. No change was observed in the femoral venous flow or in microvascular perfusion. CONCLUSIONS AND CLINICAL RELEVANCE: At this dosage, dobutamine did not alter left ventricular systolic function. Femoral blood flow was preferentially increased as the result of local vasodilatation. The lack of effect of dobutamine on microvascular perfusion suggests that increased femoral flow is not necessarily associated with improved perfusion of skeletal muscles.

Adrenergic beta-Agonists↗