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A R Leff

Publications and source records attributed to A R Leff.

At least 163 records · Page 9Linked to original sources
PubMed1985

Autonomic response characteristics of porcine airway smooth muscle in vivo.

We studied the autonomic response characteristics of airways in 65 swine in vivo. Tracheal smooth muscle response was measured isometrically in situ; bronchial response was measured simultaneously as change in airway resistance and dynamic compliance. To determine the optimal resting length at which maximal tracheal contraction was obtained, length-tension studies were generated in four animals using maximal electrical stimulation of the vagus nerves determined from stimulus-response characteristics in eight other swine. Pharmacological studies were performed in 25 animals to determine the relative potency and intrinsic activity of agonists (acetylcholine greater than histamine much greater than norepinephrine) causing contraction of trachea and bronchial airways. In 13 swine, the effects of autonomic stimulation were studied by intravenous administration of dimethylphenylpiperazinium (DMPP) after muscarinic blockade with 1.5 mg/kg iv atropine. Tracheal contraction caused by topical application of 3.4 X 10(-4) mol histamine (13.4 +/- 1.54 g/cm) was 96 +/- 7.2% blocked by 25 micrograms/kg iv DMPP in adrenal-intact animals; minimal relaxation was demonstrated in adrenalectomized animals, indicating absence of substantial sympathetic innervation to porcine trachea. Nonadrenergic innervation was not demonstrated. After beta-adrenergic blockade, sympathetic stimulation caused alpha-adrenergic contraction in bronchial airways but not in trachea. These data define the unique response characteristics of the airways of swine and demonstrate their utility for acute experimental study of airway responses in vivo.

Acetylcholine↗
PubMed1985

Augmentation of parasympathetic contraction in tracheal and bronchial airways by PGF2 alpha in situ.

We studied the effect of exogenous prostaglandin F2 alpha (PGF2 alpha) on airway smooth muscle contraction caused by parasympathetic stimulation in 22 mongrel dogs in situ. Voltage (0-30 V, constant 20 Hz) and frequency-response (0-25 Hz, 25 V) curves were generated by stimulating the cut ends of both cervical vagus nerves. Airway response was measured isometrically as active tension (AT) in a segment of cervical trachea and as change in airway resistance (RL) and dynamic compliance (Cdyn) in bronchial airways. One hour after 5 mg/kg iv indomethacin, a cumulative frequency-response curve was generated in nine animals by electrical stimulation of the vagus nerves at 15-s intervals. Reproducibility was demonstrated by generating a second curve 7 min later. A third frequency-response curve was generated during active contraction of the airway caused by continuous intravenous infusion of 10 micrograms X kg-1 X min-1PPGF2 alpha. Additional frequency-response studies were generated 15 and 30 min after PGF2 alpha, when airway contractile response (delta RL = +2.8 +/- 0.65 cmH2O X 1(-1) X s; delta Cdyn = -0.0259 +/- 0.007 1/cmH2O) returned to base line. Substantial augmentation of AT, RL, and Cdyn responses was demonstrated in every animal studied (P less than 0.01 for all points greater than 8 Hz) 15 min after PGF2 alpha. At 30 min, response did not differ from initial base-line control. In four animals receiving sham infusion, all frequency-response curves were identical. We demonstrate that PGF2 alpha augments the response to vagus nerve stimulation in tracheal and bronchial airways. Augmentation does not depend on PGF2 alpha-induced active tone.

Animals↗
PubMed1985

Homeostatic regulation of bronchomotor tone by sympathetic activation during bronchoconstriction in normal and asthmatic humans.

It has been assumed previously that the sympathetic nervous system (SNS) serves to antagonize bronchoconstrictor stimuli. To assess the homeostatic regulatory effect elicited by exogenously induced bronchoconstriction, we studied the effect of inhaled methacholine on the SNS response in 12 normal and 9 asthmatic humans. Exogenous SNS response was assessed as change in plasma epinephrine and norepinephrine concentrations from basal levels during inhalation challenge. A 74 +/- 3% decrease in specific airway conductance (SGaw) (p less than 0.001) was induced in normal subjects and a 78 +/- 7% decrease in asthmatics by methacholine challenge (p less than 0.001). Neither plasma epinephrine nor norepinephrine increased significantly from basal concentrations in normal or asthmatic subjects after maximal challenge (p greater than 0.33). To determine if physiologically achievable epinephrine concentrations potentially could modulate bronchoconstriction, the effect of intravenously infused epinephrine was measured in 11 of these subjects. After the highest dose of methacholine, a 15-min intravenous infusion of epinephrine (0.06 micrograms/kg/min) caused an 85 +/- 7% increase in SGaw in normal subjects (p less than 0.02). In asthmatics, a 319 +/- 68% increase in SGaw (p less than 0.002) was observed with similar changes in plasma epinephrine. Plasma epinephrine concentrations after infusion were comparable to those obtained in 4 normal and 1 asthmatic subject undergoing 60-degree, head-up tilt 1 h after volume depletion with intravenously administered furosemide. We conclude that physiologic concentrations of epinephrine can modulate moderately severe bronchoconstriction. However, the SNS does not regulate bronchomotor tone during mild to moderate bronchoconstriction.

Adolescent↗
PubMed1985

Sympathetic modulation of biochemical and physiological response to immune degranulation in canine bronchial airways in vivo.

The effect of sympathetic stimulation on bronchial smooth muscle contractile response after mast cell degranulation with Ascaris suum antigen was studied in 36 natively allergic dogs in situ. Bronchial smooth muscle response was measured isometrically in a single right middle lobe bronchus. A dose of antigen causing maximal release of mediator was administered to the bronchus through the bronchial arterial circulation. Serial plasma histamine concentrations were determined at 15-s intervals after intra-arterial (i.a.) administration of antigen. Samples of blood were obtained simultaneously from right heart and femoral artery, and arteriovenous difference (AVd) in histamine concentration across the bronchus was determined during mast cell degranulation. In nine dogs showing bronchial mast cell degranulation to antigen challenge, bronchial smooth muscle contraction was 22.3 +/- 2.95 g and the mean AVd in histamine concentration across the bronchus was 188 +/- 41.5 ng/ml. Six other dogs having muscarinic blockade with 0.75-1.0 mg/kg intravenous atropine were given i.a. antigen after 1 min of steady-state sympathetic stimulation with intravenous 1,1-dimethyl-4-phenylpiperazinium iodide (DMPP). Sympathetic stimulation during Ascaris suum antigen challenge caused complete inhibition of bronchial smooth muscle contractile response to i.a. antigen (P less than 0.001), and a significant AVd in histamine concentration across the bronchus (9.8 +/- 16.0 ng/ml; P less than 0.01 vs. control) was not detected. Peak plasma histamine concentration in control dogs was 1,138 +/- 237 ng/ml vs. 310 +/- 135 ng/ml in animals receiving sympathetic stimulation (P less than 0.01). In four dogs undergoing systemic anaphylaxis to i.v. antigen, subsequent sympathetic stimulation with i.v. DMPP reduced bronchomotor tone to approximately 70% of base-line control. Exogenously induced sympathetic stimulation can substantially inhibit systemic mast cell degranulation to Ascaris suum antigen in allergic dogs. Maximal stimulation of the sympathetic nervous system causes substantial inhibition of respiratory mast cell secretion of histamine and bronchial smooth muscle contraction to circulating mediator.

Airway Resistance↗
PubMed1985

Tuberculosis control practices in major metropolitan health departments in the United States. 3. Standard of practice in 1984.

Twenty-eight metropolitan health departments in the United States reporting more than 200 cases annually were surveyed to determine the standard of practice in the control of pulmonary tuberculosis. The results were compared to previous surveys done in 1978 and 1980 to determine the impact of policy changes recommended by the American Thoracic Society, American College of Chest Physicians, and Centers for Disease Control and recent reports of innovative chemotherapeutic methods. A high degree of uniformity in chemoprophylaxis practices again was demonstrated. In contrast to our previous survey of 1980, most programs now use rifampin-containing regimens with short (less than 12 month) course chemotherapy as the primary initial treatment regimen for tuberculosis. Mean duration of treatment for tuberculosis decreased from 20.2 +/- 2.1 months in 1980 to 11.7 +/- 1.0 months in 1984. Intermittent chemotherapeutic regimens also were used more frequently in 1984. However, substantial variance from other recommended guidelines still is prevalent among the major metropolitan programs in the United States.

Adolescent↗
PubMed1984

Radioenzymatic assay for measurement of tissue concentrations of histamine: adaptation to correct for adherence of histamine to mechanical homogenizers.

Because adherence of histamine to glass is well-known, we tested for its adherence to a mechanical homogenizer commonly used in the extraction of histamine from tissue samples. During 60 sec of homogenization, 15% to 17% of the histamine originally present in the samples "disappeared," and the reason for the disappearance was reversible binding of histamine to the homogenizer. Adding trace amounts of [14C]histamine to each sample before homogenization and measuring the disappearance of radioactivity during homogenization permitted correction for binding to the homogenizer. This technique for correction was validated by the measurement of endogenous concentrations of histamine in the tracheal posterior membranes of six dogs (range of mean concentrations: 0.63 to 1.51 ng/mg wet weight) followed by the measurement of known amounts of exogenous histamine added before homogenization to tracheal tissue samples from the same dogs. In the latter samples, 96 +/- 13% (mean +/- SEM) of the histamine added was measured by our technique. We conclude that binding of histamine to mechanical homogenizers may be an important cause of inaccuracy of the enzymatic assay for the measurement of histamine concentrations in tissue but that such binding may but that such binding may be easily corrected for.

Adhesiveness↗
PubMed1984

Distribution of innervation and circulation in porcine cervical trachea.

The circulation and innervation to porcine cervical trachea were studied in 54 animals in situ. The antemortem response of porcine tracheal muscle was measured isometrically during selective injection of acetylcholine into the cranial thyroid arterial circulation. A predominantly unilateral (70.4%), rather than bilateral (3.7%), arterial circulation was identified; a cranial thyroid artery was not demonstrated in 25.9% of swine, suggesting dominant perfusion from the caudal thyroid circulation. After animals were killed, dye injection through the dominant cranial thyroid trunk demonstrated homogeneous perfusion of the muscle in all instances. In 20 of these animals, the distribution of parasympathetic innervation to porcine tracheal muscle was studied by selective electrical stimulation of the vagus nerves in situ. Tracheal smooth muscle response was measured isometrically, using settings (20 v, 20 Hz) causing maximal contractile force. Bilateral electrical stimulation caused active tracheal tension of 23.2 +/- 1.9 g/cm. Unilateral stimulation of the left vagus nerve caused 17.8 +/- 1.5 g/cm contraction, which was significantly greater than the response caused by selective stimulation of the right vagus nerve (12.1 +/- 1.6 g/cm; P less than 0.001). Innervation to porcine cervical trachea, although bilateral, is derived predominantly from the left vagus nerve; circulation is derived almost always from the left cranial thyroid artery.

Acetylcholine↗
PubMed1983

Physiological and pharmacological response of canine bronchial smooth muscle in situ.

We studied the isometric response of bronchial smooth muscle in a single third-order bronchus of 24 dogs in situ. Length-tension studies were performed in six dogs by repeated injection of 10(-5) mol acetylcholine (ACh) into the right bronchoesophageal artery, and the resting tension (30.6 +/- 6.9 g/cm) and length (0.76 +/- 0.14 cm) permitting maximal contraction were determined. In eight other dogs, dose-related bronchial contraction was obtained with 10(-10) to 10(-5) mol intra-arterial (ia) ACh. Supramaximal electrical stimulation of the right cervical vagus nerve and bronchial parasympathetic ganglion stimulation with ia 1-1-dimethyl-4-phenylpiperazinium (DMPP) also caused bronchial contraction. The maximal response to ia ACh (28.5 +/- 1.7 g/cm), supramaximal electrical stimulation (15.2 +/- 1.1 g/cm), and ia DMPP (10.5 +/- 3.0 g/cm) was blocked by an ia dose of atropine (1-5 micrograms/kg) that did not alter the sympathetic relaxation response in the trachea. In four dogs, the bronchial response to sympathetic activation was studied by intravenous (iv) bolus injection of DMPP after cholinergic blockade with atropine. DMPP (25 micrograms/kg iv) caused 9.5 +/- 2.2 g/cm bronchial relaxation, which was blocked completely by 2-4 mg/kg iv propranolol. In six other dogs, hypoxia induced by ventilation with pure nitrogen caused bronchial contraction, which was blocked by vagotomy, atropine, and hexamethonium. We report a sensitive method for selective measurement of bronchial smooth muscle response in a single resistance bronchus. This preparation preserves regional innervation and circulation and permits selective physiological stimulation in situ.

Acetylcholine↗
PubMed1983

Biochemical and physiological effects of compound 48/80 on canine trachea in vivo.

We studied changes in tracheal histamine content and tracheal muscle tension after degranulation of tracheal mast cells by compound 48/80 in 32 anesthetized dogs. In four dogs compound 48/80 caused an increase in tracheal tension [13 +/- 5 (SD) g/cm], while femoral arterial blood pressure decreased only 14 +/- 11%. Tracheal tissue histamine decreased 17 +/- 6% in five dogs receiving intra-arterial compound 48/80 (5 X 10(-3) to 10(-1) mg/kg). Chlorpheniramine, an H1-antagonist, selectively inhibited tracheal contraction to compound 48/80 and histamine. Cimetidine, an H2-antagonist, did not alter the response to intra-arterial histamine. In 11 dogs, the doses of both intra-arterial histamine and acetylcholine required to produce a threshold increase in tracheal tension of 8 g/cm were compared. Threshold doses for acetylcholine varied 10-fold, compared with 100-fold variation for histamine among these dogs. There was a significant correlation between increased tracheal tension produced by compound 48/80 and histamine (r = 0.62). We conclude that compound 48/80 causes a variable increase in tracheal tension in vivo because of marked variability in the H1-receptor response of tracheal smooth muscle to histamine and because of variability in the release of mediator from respiratory mast cells by compound 48/80.

Acetylcholine↗
PubMed1983

Parasympathetic and adrenergic contractile responses in canine trachea and bronchus.

We compared the sympathetic and parasympathetic contractile responses of tracheal and third-order bronchial smooth muscle simultaneously in 26 dogs in situ. Stimulus-response curves were generated by bilateral stimulation of the cervical vagus nerves in five dogs to determine the parameters (20 V, 15 Hz, 2-ms duration) causing maximal parasympathetic contraction in trachea and bronchus. In six adrenal-intact (ADi) and five adrenalectomized (ADx) dogs, sympathetically mediated alpha-adrenergic contraction was studied after muscarinic and beta-adrenergic blockade by administering intravenous (iv) 1,1-dimethyl-4-phenylpiperazinium iodide (DMPP). In ADi dogs, the maximal alpha-adrenergic contractile response to iv DMPP was 67.3 +/- 14.8% of the maximal parasympathetic response in trachea and 112 +/- 21% of the maximal parasympathetic response in bronchus (P less than 0.03). In ADx dogs, the maximal alpha-adrenergic-to-parasympathetic stimulation ratios were 17.6 +/- 1.3% in trachea and 41.4 +/- 2.5% in bronchus (P less than 0.001). Comparable relationships were also obtained in pharmacological studies of alpha-adrenergic and cholinergic responses in trachea and bronchus. We conclude that there is substantial heterogeneity in the physiological and pharmacological cholinergic and alpha-adrenergic contractile properties in trachea and bronchus. Relative to cholinergic contraction, both circulating catecholamines and sympathetic innervation cause substantially greater alpha-adrenergic contraction in bronchus than for tracheal smooth muscle.

Adrenergic Fibers↗
PubMed1983

Response of bronchial smooth muscle to mast cell degranulation in situ.

We studied the response of bronchial smooth muscle to mast cell degranulation with Ascaris suum antigen (AA) and compound 48/80 (48/80) in 26 mongrel dogs in situ. Bronchial smooth muscle response was measured isometrically in situ from a segment of the right middle lobe bronchus; tracheal response was monitored isometrically as a control. After intra-arterial (ia) injection of AA into the bronchial circulation, bronchial contraction preceded tracheal contraction by 19.2 +/- 4.6 s (P less than 0.002). Bronchial contraction to AA (21.7 +/- 3.4 g) was substantially greater than to 48/80 (10.5 +/- 1.8 g, P less than 0.05) corresponding to differences in maximal systemic histamine concentrations (146 +/- 24.1 vs. 1000 +/- 236 ng/ml, P less than 0.01). In 5 dogs, the effect of leukotriene D4 (LTD4) and FPL 55712 was studied. Injection of 10(-8) mol ia LTD4 caused no bronchial contraction. In four dogs, 10(-7) mol FPL 55712 caused no bronchial relaxation after initial precontraction during immune degranulation with AA; intravenous chlorpheniramine (5 mg/kg) caused 69.7 +/- 9.4% relaxation. We demonstrate a model that permits selective immune degranulation of a single major resistance bronchus in situ. We conclude that AA-induced degranulation in dogs caused bronchial contraction predominantly by secretion of preformed mediator.

Animals↗
PubMed1983

Comparative distribution of smooth muscle postsynaptic contractile responses in canine trachea and bronchus in vivo.

The response of canine tracheal and bronchial smooth muscle to i.a. administered agonists causing smooth muscle contraction was compared in 22 mongrel dogs in vivo. Tracheal and bronchial contractile responses were measured isometrically in situ in the same dogs. In nine dogs, dose-response curves were generated with i.a. acetylcholine and histamine (10(-10) to 10(-6) mol) in a 4-cm tracheal segment and a 1-cm segment of third order bronchus. The tracheal response to i.a. histamine was 36.5 +/- 4.48% of the response to equivalent doses of acetylcholine. In bronchus, the contraction caused by histamine was 81.0 +/- 2.83% of the cholinergic contractile response (P less than .001). In five dogs having beta adrenergic blockade with propranolol, tracheal contraction to 10(-8) to 10(-6) mol i.a. norepinephrine was 27.3 +/- 4.2% of the response to acetylcholine. However, in bronchus, contraction to norepinephrine was 218 +/- 16.6% of the response to equivalent doses of acetylcholine (P less than .001). Phentolamine (200-400 micrograms/kg i.a.) caused 79 to 100% blockade of the tracheal and bronchial response to i.a. norepinephrine. Cholinergic contraction was blocked specifically with 5 micrograms/kg i.a. of atropine. It is concluded that there is substantial heterogeneity in the contractile responses of canine trachea and bronchus in situ. Relative to cholinergic contraction, both histamine and alpha adrenergic stimulation cause substantially greater contraction of airway smooth muscle in the third order bronchus than in trachea.

Acetylcholine↗
PubMed1982

Measurement of airway response by isometric and nonisometric techniques in situ.

Because isometric systems differ substantially from methods of measuring airway smooth muscle tone that depend on airway diameter, we determined the sensitivity and significance of data derived from these different methods in 20 anesthetized dogs. The airway contractile response was measured directly from an isometric tracheal segment in situ and simultaneously as pulmonary resistance (RL) and dynamic compliance (Cdyn). The contractile response to intravenous (iv) methacholine (MC) (2.6 X 10(-11) to 2.6 X 10(-6) mol/kg) and norepinephrine (NE) (1.2 X 10(-11) to 1.2 X 10(-6) mol/kg) was measured in dose-response studies of beta-blocked and ganglion-blocked animals. A statistically significant change in isometric tracheal tension was first observed at 2.6 X 10(-10) mol/kg iv MC and 1.2 X 10(-9) mol/kg iv NE. Statistically significant changes in Cdyn and RL did not occur at doses less than 10(-8) mol/kg for either agonist. Substantial increase in isometric tracheal tension (greater than 10 g force/cm) occurred before any change in RL or Cdyn. These finding indicate that change in isometric tension reflects parallel changes in RL and Cdyn. For NE and MC, tracheal tension is a more sensitive and selective measurement of airway contraction than RL or Cdyn.

Airway Resistance↗
PubMed1982

Sympathetic inhibition of histamine-induced contraction of canine trachealis in vivo.

The effect of sympathetic stimulation on histamine-induced tracheal contraction was studied in 42 dogs in situ. After cholinergic blockade with atropine, dose-response curves to intra-arterial (ia) histamine (10(-10)-10(-6) mol) were performed in 11 adrenal-intact (ADi) and 5 adrenalectomized (ADx) dogs receiving steady-state sympathetic stimulation from continuous intravenous infusion (62.5-312 micrograms . kg-1 . min-1) of 1,1-dimethyl-4-phenylpiperazinium iodide (DMPP). In ADi dogs receiving maximal sympathetic prestimulation (312 micrograms . kg-1 . min-1 DMPP), tracheal tension barely exceeded base-line resting tension after 10(-6) mol ia histamine. In five dogs, tracheal tension after maximal sympathetic prestimulation exceeded base line for greater than or equal to 10(-8) mol ia histamine. In 12 other dogs, reversal of histamine-induced contraction by maximal sympathetic prestimulation was studied. Tracheal tension decreased 45.6 +/- 4.4 g/cm in four ADi dogs (P less than 0.001), 12.4 +/- 2.8 g/cm in four ADx dogs (P less than 0.02), and 2.2 +/- 2.5 g/cm in four control dogs receiving sham infusions (P greater than 0.90). No evidence was found for nonadrenergic relaxation of canine airway smooth muscle. We conclude that tracheal sympathetic nerves cause significant antagonism of histamine-induced contraction, which is augmented by adrenal secretion. We also report a pharmacological method for dose-related steady-state sympathetic stimulation of canine airways.

Adrenal Glands↗
PubMed1982

Characterization of tracheal mast cell reactions in vivo. Inhibition by a beta-adrenergic agonist.

In 12 anesthetized dogs, we tested the effects of pharmacologic beta-adrenergic stimulation on the severity of tracheal mast cell reactions in vivo (Am Rev Respir Dis 1979; 119:62). In control dogs, tracheal arterial injections of compound 48/80 produced arteriovenous differences in histamine concentrations across the trachea (35 +/- 15 ng/ml), but not the lung; this finding suggested selective degranulation of tracheal mast cells. Tracheal arteriovenous histamine differences correlated (r = 0.70) with tracheal contractions (12 +/- 4 g/cm) induced by compound 48/80 in these animals. In other dogs, injections of isoproterenol (10 micrograms/kg) before compound 48/80 prevented the development of both tracheal arteriovenous differences and contractions. We concluded that pharmacologic beta-adrenergic stimulation inhibited degranulation of tracheal mast cells. The preparation appears suitable for examining the effects of endogenous stimuli on the severity of mast cell reactions in the central airways of anesthetized dogs.

Adrenergic beta-Agonists↗
PubMed1981

Interrelationship between alpha- and beta-adrenergic agonists and histamine in canine airways.

To determine the interrelationship between adrenergic receptors in airway smooth muscle and histamine-induced airway constriction, we studied the responses of 26 parasympathectomized dogs to selective and mixed alpha- and beta-adrenergic stimulation in situ by means of an isometric tracheal smooth-muscle preparation. Intra-arterial (IA) phenylephrine (PE) caused dose-related tracheal contraction beginning at 10-8 mol; maximal active tension was 9.47 +/- 2.2 gm F/cm (mean +/- SD) at 10-5 mol. Pretreatment with propranolol augmented tracheal contraction to PE (maximum 35.5 +/- 3.2 gm F/cm). The contractile response to PE was blocked with a dose of phentolamine (200 microgram/kg IA), which did not alter the response to acetylcholine. Isoproterenol (ISO) caused dose-related tracheal relaxation beginning at 4.2 X 10-11 mol (maximum 43.2 +/- 19.6 gm F/cm). Norepinephrine (NE) also caused tracheal relaxation beginning at 1.2 X 10-6 mol, which was less than relaxation caused by ISO. Prestimulation with histamine did not augment the contractile response to PE but reduced maximal tracheal relaxation to NE ( p less than 0.001). It is concluded that selective alpha-adrenergic stimulation causes tracheal contraction. However, nonselective stimulation results in tracheal relaxation, even with a weak beta-agonist such as NE. Histamine does not augment alpha-adrenergic contraction as previously suggested but causes physiologic antagonism of beta-adrenergic relaxation of tracheal muscle.

Adrenergic alpha-Agonists↗