Biomedical subjects

N E Robinson

Publications and source records attributed to N E Robinson.

At least 19 recordsLinked to original sources

PubMed1992

The role of muscarinic M1 and M2 receptors in airway constriction in the cat.

The role of prejunctional inhibitory and facilitatory muscarinic receptors was investigated in cats with tracheal hyperresponsiveness to vagal stimulation. Intrathoracic airway caliber (total lung resistance (RL) and dynamic compliance (Cdyn] and the diameter of tracheal ring 4 were measured during vagal stimulation and local acetylcholine (ACh) injection before and after administration of the M1 receptor antagonist pirenzepine or the M2 receptor antagonist gallamine. The responses of tracheal ring 4, RL, and Cdyn to ACh were unaltered by gallamine or pirenzepine. Changes in RL and Cdyn during vagal stimulation were enhanced by gallamine, but the magnitude of tracheal constriction was unchanged. Vagally induced tracheal constriction was decreased by pirenzepine in hyperresponsive but not in control cats. The M2 receptors limit intrathoracic airway constriction, but a functional role for M2 receptors in the cervical trachea could not be demonstrated. However, these data suggest that M1 excitatory receptors may play a role in vagally mediated tracheal hyperreactivity.

Animals↗

PubMed1992

Muscarinic receptor subtypes in equine tracheal smooth muscle.

Selective muscarinic receptor antagonists were used to identify muscarinic receptor subtypes in equine trachealis strips. The M1 receptor antagonist pirenzepine (10(-7) mol/L to 3 x 10(-5) mol/L) and the M3 receptor antagonist 4-diphenylacetoxy-N-methylpiperidine (4-DAMP, 10(-9) mol/L to 3 x 10(-7) mol/L3) dose dependently inhibited the contractile responses to electrical field stimulation (EFS) and exogenous acetylcholine (ACh). Schild plots yielded a pA2 value for pirenzepine vs ACh of 6.75 +/- 0.09, which is consistent with the affinity for M2 or M3 receptors, and a pA2 value for 4-DAMP vs ACh of 8.47 +/- 0.09, which is in agreement with the affinity for M3 receptors. The M2 receptor antagonist gallamine (10(-5) mol/L and 10(-4) mol/L) did not affect the response of trachealis to exogenous ACh and low-frequency EFS (0.1-2 Hz) but decreased the responses to high-frequency EFS (4-16 Hz). These results suggest that the muscarinic receptors mediating contractions induced by ACh in equine tracheal smooth muscle are of the M3 subtype. The lack of an increase in the response to EFS following gallamine suggests that functional prejunctional inhibitory M2 receptors are not present on the cholinergic nerves innervating equine tracheal smooth muscle.

Acetylcholine↗

PubMed1992

Exogenous but not endogenous PGE2 modulates pony tracheal smooth muscle contractions.

The modulatory role of prostaglandin E2 (PGE2) was examined in pony tracheal smooth muscle strips. Although exogenous PGE2 inhibited the contractile response to both electrical field stimulation (EFS) and acetylcholine (ACh) in a dose-dependent manner, the concentration required to inhibit the response to EFS (10 nM) was less than that required to inhibit the response to ACh (0.1 microM). Cyclooxygenase inhibition with aspirin or meclofenamate had no effect on either the response to EFS or to ACh even though PGE2 production was inhibited. Our results demonstrate that in ponies as in other species, exogenous PGE2 can inhibit the airway smooth muscle's response to EFS and ACh. However, the failure of cyclooxygenase inhibition to alter the response to EFS and ACh suggests that endogenous prostanoids do not exert a significant modulatory effect on pony tracheal smooth muscle in vitro.

Acetylcholine↗

PubMed1992

The inhibitory effect of furosemide on the contractile response of equine trachealis to cholinergic nerve stimulation.

The effects of furosemide on the responses of equine trachealis muscle with and without epithelium to electrical field stimulation (EFS) and exogenous acetylcholine (ACh) were investigated in organ baths. Tissues were pretreated with guanethidine and the parameters used for EFS were those previously demonstrated to activate postganglionic cholinergic neurons. In tissues with intact epithelium, furosemide (100 microM) shifted the frequency-response curve to the right. In the preparations without epithelium, furosemide did not affect the response to EFS. Neither in epithelium-on nor in epithelium-off tissues was the ACh dose-response curve affected by the administration of furosemide. We conclude that furosemide (100 microM) decreases the equine tracheal smooth muscle responses to EFS through inhibition of cholinergic neurotransmission, and that this effect is dependent on epithelium.

Acetylcholine↗

PubMed1992

Airway physiology.

The understanding of the mechanisms of dog and cat airway disease is in its infancy, because the clinical tools necessary to measure airway function in patients have not been readily available. The advent of lung function computers that can rapidly analyze flow-volume loops and calculate Cdyn and RL will make it easier to evaluate airway function in disease and to detect the effects of the newer specific receptor blockers. In the not-too-distant future, measurements of lung function will be used to prove the efficacy of new therapeutic agents for canine and feline airway disease and to guide the clinician in the use of these agents.

Airway Obstruction↗

PubMed1992

Evidence for the absence of a functional role for muscarinic M2 inhibitory receptors in cat trachea in vivo: contrast with in vitro results.

1. The effect of the selective muscarinic M2 receptor antagonist, gallamine and the selective M2 receptor agonist, pilocarpine, on airway constriction induced by vagal stimulation was studied in anaesthetized cats. In addition, the effect of gallamine on contraction of cat isolated tracheal and bronchi preparations induced by electrical field stimulation was also investigated. 2. In in vivo experiments, extrathoracic airway constriction was measured with an electromechanical caliper that was attached to the outer surface of tracheal ring 4. Intrathoracic airway constriction was determined by measuring the changes in total lung resistance and dynamic compliance during vagal stimulation. 3. Intravenous gallamine (0.1, 1, and 10 mg kg-1) augmented the rise in total lung resistance induced by vagal stimulation in a dose- and frequency-dependent manner. At stimulation frequencies of 8 and 12 Hz the fall in dynamic compliance provoked by vagal stimulation was also significantly increased by gallamine (10 mg kg-1). Gallamine was without effect on airway constriction induced by acetylcholine. 4. Vagal stimulation at 4 Hz produced significant tracheal constriction, but the amount of constriction did not change following injection of increasing doses of gallamine. Similarly, there was no difference in tracheal constriction at any frequency of stimulation (0.5-16 Hz) when frequency-response curves before and after gallamine injection (10 mg kg-1) were compared. 5. Pilocarpine (0.01-10 micrograms kg-1, i.v.) diminished changes in total lung resistance and dynamic compliance induced by vagal stimulation, an effect that was reversed by gallamine (10 mg kg-1, i.v.). Vagally-induced tracheal constriction was not significantly affected by any dose of pilocarpine, nor was it modified by gallamine (10mg kg- ') given subsequently.6. Atropine (0.5 mgkg-') completely blocked tracheal constriction induced by vagal stimulation, indicating that the changes in tracheal ring diameter provoked by stimulation were mediated by muscarinic receptors and that intravenous drugs could reach the cervical trachealis muscle.7. In vitro tissue bath studies demonstrated a significant leftward shift of the frequency-response curve to electrical field stimulation in both tracheal strips and bronchial rings following gallamine (10-4M) administration.8. Although the functional presence of muscarinic M2 autoreceptors was demonstrated in feline isolated tracheal and bronchial preparations, a corresponding functional role was not detected in cat trachea in vivo. This was despite repeated demonstration of muscarinic M2 receptor-mediated limitation of airway constriction of intrathoracic airways in vivo.

Acetylcholine↗

PubMed1992

Aerosol pirbuterol: bronchodilator activity and side effects in ponies with recurrent airway obstruction (heaves).

The dose of aerosol pirbuterol that could be administered safely to ponies (weight approximately 200 kg) was determined by observation for sweating, trembling and excitement and measurement of heart and respiratory rates during cumulative administration of the drug. Sweating, trembling and excitement were first observed following a dose of 2,400 micrograms and became more severe at 3,200 micrograms. These effects were accompanied by an increase in heart rate but not a change in respiratory rate. When 3200 micrograms was administered without prior administration of lower doses, side effects were trivial. This dose was therefore tested for its bronchodilator activity. Pulmonary function was evaluated in ponies that developed airway obstruction ('heaves') when housed in a barn and fed hay. Measurements were made when ponies were in clinical remission (Period A) and during an acute attack of airway obstruction (Period B). At Period A, pirbuterol had no effect on pulmonary function. Barn housing increased pulmonary resistance and decreased dynamic compliance. At Measurement Period B, pirbuterol administration significantly reduced pulmonary resistance and increased dynamic compliance and minute ventilation. These changes were significant 5 min after drug administration and lasted for the 30 min duration of the study. Vehicle administration had no effect on pulmonary function. It was concluded that aerosol pirbuterol has few undesirable side effects and is an effective bronchodilator in ponies with recurrent airway obstruction.

Aerosols↗

PubMed1992

Increased pulmonary production of immunoreactive 15-hydroxyeicosatetraenoic acid in an animal model of asthma.

Airway obstruction and hyperreactivity are characteristics of human asthma and of "heaves," a naturally occurring respiratory disorder of horses and ponies. We measured pulmonary function and plasma immunoreactive 15-hydroxyeicosatetraenoic acid (i15-HETE) concentrations in simultaneously collected carotid artery and right ventricle blood samples in five affected ponies and their age- and gender-matched control ponies. Measurements and sampling were performed before (Period A), during (Period B), and following recovery from (Period C) acute airway obstruction precipitated by housing ponies in a barn and exposing them to hay dust. Pulmonary resistance increased significantly, and dynamic compliance and PaO2 decreased significantly in affected ponies at Period B. Plasma i15-HETE concentrations were greater in carotid artery samples compared with right ventricle samples in affected ponies at each measurement period, suggesting that the lung was a source of i15-HETE. Carotid artery i15-HETE concentrations were significantly greater in affected ponies than in control ponies and increased at Period B. There was a significant negative correlation between changes in plasma i15-HETE and changes in dynamic compliance between measurement Periods A and B. We conclude that the lung is a source of i15-HETE in ponies with heaves, that these ponies produce greater quantities of i15-HETE than control ponies, and that exposing affected ponies to a barn environment produces acute airway obstruction and increased plasma concentrations of i15-HETE.

Animals↗

PubMed1992

Decreased airway mucosal prostaglandin E2 production during airway obstruction in an animal model of asthma.

Heaves is a respiratory disorder of horses and ponies characterized by bouts of acute airway obstruction and airway hyperresponsiveness. We measured prostaglandin E2 (PGE2) and 15-hydroxyeicosatetraenoic acid (15-HETE) production in vitro in tracheal epithelium obtained from six affected horses at the time of acute airway obstruction as compared with six matched control horses. Strips of epithelium and subepithelial tissue were prepared and stimulated with A23187, histamine, and bradykinin. The PGE2 and 15-HETE in media from strips was quantitated by radioimmunoassay. 15-HETE above the limits of accurate detection was found in epithelial strips of only two principal animals and in none of the control horses, and the amount of 15-HETE was not increased when strips were stimulated. Epithelial strips from affected horses tended to produce less PGE2 than did strips from control horses, and there was a significant correlation between epithelial PGE2 production and the time taken for affected animals to develop airway obstruction. Subepithelial tissue strips from control horses produced significantly more PGE2 in response to A23187 and bradykinin than did strips from affected horses. We conclude that equine tracheal epithelium is not a significant source of 15-HETE. Airway mucosal PGE2 production is reduced in horses with heaves, which suggests that a relative decrease in this bronchorelaxant substance may be a factor in the pathogenesis of this model of asthma.

Airway Obstruction↗

PubMed1992

Epithelial strips: an alternative technique for examining arachidonate metabolism in equine tracheal epithelium.

We have developed an alternative method for examining equine tracheal epithelial arachidonic acid (AA) metabolism that utilizes strips of pseudostratified columnar epithelium attached to a layer of elastic tissue 80 to 130 microns thick. We compared the responses of this preparation with those of enzymatically dispersed suspensions of tracheal epithelium obtained from the same animal. Strips incubated with [3H]AA incorporated 40.8 +/- 3.6% of added radioactivity and released 2.55 +/- 0.23% of incorporated radioactivity when stimulated with 5 microM A23187. Values for the cell suspension were 59.6 +/- 1.6% and 1.90 +/- 0.08%, respectively. Stimulation with 50 microM histamine or bradykinin resulted in significant release of free [3H]AA only from the strips. High-performance liquid chromatography radioactivity profiles of eicosanoids released following stimulation with 5 microM A23187 demonstrated peaks that coeluted with free AA, prostaglandin (PG) E2, and PGF2 alpha for the strips, and free AA, leukotriene B4, and 5-HETE for the cell suspensions. The absence of PGE2 production by cell suspensions was confirmed by assaying immunoreactive PGE2 in supernatants from unlabeled strips and suspensions stimulated with 5 microM A23187. Epithelial strips produced 10.3 +/- 1.3 ng PGE2/ml supernatant, whereas 5 x 10(6) cells in suspension produced less than 100 pg/ml. Despite the lack of PG production by the cell suspensions, immunocytochemical staining with an anti-PGH synthase antibody demonstrated the presence of PGH synthase in epithelial cells of both preparations. These data indicate that, in contrast to epithelial cell suspensions, epithelial strips synthesize cyclooxygenase metabolites and respond to peptide agonists.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1992

Exercise-induced pulmonary hemorrhage in horses with experimentally induced allergic lung disease.

The lungs of sensitized horses were exposed to aerosolized ovalbumin. Some horses (n = 4) were given ovalbumin in 1 lung only, whereas in others (n = 7), ovalbumin or vehicle were inoculated in the cranial, ventral, and caudal regions of the caudal lung lobe. Horses were exercised 5 hours after ovalbumin exposure. Immediately before exercise, endoscopy failed to reveal any abnormality. After exercise, endoscopic examination of horses subjected to unilateral ovalbumin exposure revealed extensive blood in airways leading to the exposed lung in all horses. Blood was not observed in the airways leading to the control lung. Mean (+/- SEM) minimum volume of the exposed and control lungs was 9.5 +/- 1.5 and 5.5 +/- 1.6 L, respectively; this difference was statistically significant (P less than 0.05). Bronchoscopy of horses subjected to regional ovalbumin or vehicle exposure and exercise revealed a small amount of blood-tinged fluid in the bronchi serving the regions of the lung inoculated with ovalbumin. Minimum volumes of such regions were not significantly different from one another. However, their minimum volume was significantly (P less than 0.05) larger than that of vehicle-inoculated regions. Gross and histologic examination confirmed inflammation and hemorrhage in the ovalbumin-exposed, but not the control lungs or lung regions. Thus, exercise can cause blood from an injured region of lung to appear in the larger airways. Regional differences in lung structure and function do not influence the appearance of blood in the airways.

Aerosols↗

PubMed1992

Effects of xylazine on airway function in ponies with recurrent airway obstruction.

The effect of IV administration of the alpha 2-adrenoceptor agonist xylazine hydrochloride (0.5 mg/kg of body weight) was examined in ponies with recurrent obstructive pulmonary disease, commonly called heaves. Six ponies with the disease (principals) were studied during clinical remission and during an acute attack of airway obstruction precipitated by stabling and feeding of dusty hay. Six control ponies were also studied. In principal ponies with airway obstruction, xylazine administration significantly (P < 0.05) decreased pulmonary resistance and increased dynamic compliance, but did not affect PaO2 or PaCO2. The alpha 2-antagonist yohimbine blocked the pulmonary effects of xylazine. Administration of saline solution was without effect in both groups of ponies at all periods and xylazine did not have effect in controls or in principals in clinical remission.

Airway Obstruction↗

PubMed1992

Histologic evaluation of nerve muscle pedicle graft used as a treatment for left laryngeal hemiplegia in standardbreds.

A nerve muscle pedicle (NMP) graft was placed in the cricoarytenoideus dorsalis (CAD) muscle of 6 horses with induced left laryngeal hemiplegia. The NMP graft was created by use of the first cervical nerve and omohyoideus muscle. In 1 horse (control), the first cervical nerve was transected after placement of the NMP graft. One year after the surgical procedure, horses were examined endoscopically and then anesthetized. While the larynx was observed endoscopically, the first cervical nerve was stimulated. Horses were subsequently euthanatized, and the larynx was harvested. Prior to anesthesia, the endoscopic appearance of the larynx of all horses was typical of laryngeal hemiplegia. During anesthesia, stimulation of the first cervical nerve produced vigorous abduction of the left arytenoid in principal horses but not in the control horse. The right cricoarytenoideus lateralis and CAD muscles were grossly and histologically normal. Also, the left cricoarytenoideus lateralis was atrophic in all horses as was the left CAD muscle of the control horse. In contrast, the left CAD muscle harvested from principal horses had evidence of reinnervation with type 1 or type 2 fiber grouping. One year after the NMP graft procedure, horses with left laryngeal hemiplegia had reinnervation of the left CAD muscle. In another study, reinnervation was sufficient to allow normal laryngeal function during exercise. Combined, these data suggest that the NMP graft procedure is a viable technique for the treatment of left laryngeal hemiplegia in horses.

Animals↗

PubMed1991

In vitro responses of airway smooth muscle from horses with recurrent airway obstruction.

The in vitro contractile and relaxant responses of tracheal smooth muscle strips (TSM) and third-generation bronchi (3B) of control horses and horses with recurrent obstructive disease (heaves) were compared. Acetylcholine (ACH) sensitivity of the diseased tissues was less than that of tissues from control horses, especially at the level of the third generation (EC50 controls 15 +/- 11 microM vs 81 +/- 17 microM for heaveys). Despite tracheal and bronchial hyporesponsiveness to ACH, these tissues from heavey horses were hyperresponsive to EFS. The inhibitory effect of isoproterenol and electrical field stimulation (EFS) was examined in histamine-precontracted airways pretreated with atropine (1 microM), indomethacin (3 microM), and phentolamine (1 microM). Precontracted tissues of both groups at both levels of airway demonstrated similar concentration-dependent relaxation in response to cumulative doses of isoproterenol (0.1 nM to 0.1 mM). EFS of precontracted tissues caused 80-90% relaxation in the TSM in both groups and 21% relaxation in 3B of the control group. Electrical field stimulation relaxation of precontracted tissues was not seen in the diseased 3B, suggesting a lack of inhibitory innervation. EFS of similarly precontracted tissues plus propranolol (1 microM) resulted in only 46% relaxation in the TSM of both groups but did not reduce the EFS relaxation of control 3B, suggesting the presence of both sympathetic and nonadrenergic noncholinergic nerves (NANC) in the trachea but only NANC in the 3B.

Acetylcholine↗

PubMed1991

Effects of furosemide on ponies with recurrent airway obstruction.

The effect of aerosol and intravenous administrations of furosemide was examined in ponies with recurrent obstructive pulmonary disease, commonly called 'heaves'. This recurrent airway disease bears many similarities to human asthma. Six ponies with the disease (principal animals) were studied during clinical remission and during an acute attack of airway obstruction precipitated by stabling and feeding dusty hay. Six control animals were also studied. Furosemide (1.0 mg/kg) or vehicle was administered by aerosol in the first study, and intravenously in a second study. In principal ponies with airway obstruction, furosemide administration significantly decreased pulmonary resistance and increased dynamic compliance, but had no effect on PaO2 or PaCO2. The time course and magnitude of lung function changes were similar following aerosol or intravenous drug administration. Vehicle was without effect in both groups of animals at all time periods and furosemide had no effect in controls or in principals in clinical remission.

Aerosols↗

PubMed1991

Beta-adrenergic receptor activity in ponies with recurrent obstructive pulmonary disease.

Pulmonary function measurements were made in control ponies and in ponies with recurrent obstructive pulmonary disease (principals) during clinical remission and during an attack of acute airway obstruction. The ponies were given beta-adrenergic antagonists and agonists to determine the role of beta receptors in recurrent obstructive pulmonary disease, and to determine the subtypes of beta receptors mediating bronchodilation in ponies. Aerosol administration of the beta antagonists, propranolol (beta 1 and beta 2), atenolol (beta 1), and butoxamine (beta 2) decreased dynamic compliance (Cdyn) and increased pulmonary resistance (RL) in the principal ponies during airway obstruction, but were without effect when the ponies were in clinical remission. Intravenous administration of atropine reversed the effect of atenolol on Cdyn and RL, but was without effect on the decrease in Cdyn and increase in RL observed after butoxamine administration. The beta antagonists did not affect airway function in the control ponies. The effect of beta blockade on Cdyn and RL suggests beta-adrenergic activation in the central and peripheral airways of principal ponies, mediated through both beta 2- and beta 1-adrenergic receptors. The aerosol beta agonists, isoproterenol (beta 1 and beta 2), and clenbuterol (beta 2) attenuated histamine-induced airway obstruction to a similar extent in control ponies that were given histamine IV. In addition, the beta 1 antagonist, atenolol, did not attenuate the bronchodilation observed with isoproterenol. We concluded that, although beta 1- and beta 2-adrenergic receptors exist in pony airways and are activated during acute airway obstruction, bronchodilation in response to beta agonists in ponies seems to be mediated primarily by beta 2-adrenergic receptors.

Aerosols↗

PubMed1991

In vitro responses of distal airways in horses with recurrent airway obstruction.

Distal airway segments (ID, 3 to 4 mm; length, 5 mm) from 2 groups of horses were isolated and suspended in tissue baths filled with Krebs solution, aerated with 5% CO2 in oxygen and maintained at 37 degrees C. Responses to exogenous acetylcholine, isoproterenol, or electrical field stimulation were compared. Control horses (n = 30) had no history of recurrent airway obstruction, whereas principal horses (n = 15) had recurrent airway obstruction and were studied during an acute episode of airway obstruction. Although the distal airways contracted in response to the cumulative half-logarithmic addition of acetylcholine (10(-10) M to 10(-3) M) in both groups, bronchi obtained from principals were less sensitive to acetylcholine than were bronchi obtained from controls. Tetdrodotoxin-sensitive electrical field stimulation-induced contractions were observed in both groups of airways, but the tension achieved in principal bronchi was less than in controls. All electrical field stimulation-induced contractions were abolished by atropine, indicating that the only excitatory innervation of equine distal airway is through the parasympathetic system. To examine the effect of isoproterenol and determine inhibitory innervation, bronchi were precontracted with histamine. Electrical field stimulation did not cause relaxation of precontracted bronchi in either group, thus indicating that distal airways lack inhibitory innervation. Isoproterenol caused similar, dose-dependent relaxation in both groups.

Acetylcholine↗

PubMed1991

Effects of bovine respiratory syncytial virus on airway function in neonatal calves.

Respiratory syncytial virus (RSV) infection causes severe lower respiratory tract disease in infants and calves. Neonatal respiratory tract infection in children often produces persistent changes in lung function. The specific objective of this study was to determine whether neonatal calves have transient or persistent alterations in pulmonary function and airway reactivity following RSV infection. Six 2- to 3-day-old Holstein bull calves were inoculated with 10 ml of bovine respiratory syncytial virus (BRSV) inoculum (10(2.7) to 10(3.8) cell culture infective doses/ml) intranasally and 10 ml of BRSV inoculum (10(4.8) to 10(5.9) cell culture infective doses/ml) intratracheally for 4 consecutive days, and 5 other calves were sham-inoculated. Prior to inoculation (day 0) and on days 4, 14, and 30 after the last inoculation, body weight (kg), dynamic compliance (Cdyn), pulmonary resistance (RL), and 2 indices of airway reactivity (effective dose [ED] 65Cdyn and ED200RL) were measured. Control calves gained weight progressively throughout the study, whereas RSV-inoculated calves failed to gain weight for 14 days, but equaled control calf weight by 30 days after inoculation. The Cdyn of control calves increased significantly by 30 days, but did not in the RSV-infected calves. Pulmonary resistance was increased significantly at 4, 14, and 30 days, but was unaffected by sham inoculation. The ED65Cdyn and ED200RL indicated an age-dependent increase in reactivity to histamine and an increase in responsiveness in the infected group beginning at 14 days and persisting until the end of the study.(ABSTRACT TRUNCATED AT 250 WORDS)

Airway Resistance↗