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C A Hirshman

Publications and source records attributed to C A Hirshman.

At least 19 recordsLinked to original sources
PubMed1992

Role of acetylcholinesterase in airway epithelium-mediated inhibition of acetylcholine-induced contraction of guinea-pig isolated trachea.

To seek evidence for the involvement of acetylcholinesterase activity in the modulatory influence of the airway epithelium, we examined responses to acetylcholine (ACh), bethanechol, histamine or KCl in isolated epithelium-intact and epithelium-denuded guinea-pig trachealis preparations. The concentration-response curves to ACh were shifted 26-fold to the left by epithelial denudation but the contractile response to KCl was not altered. The response to histamine in epithelium-denuded preparations increased 4-fold with no attenuation in the presence of physostigmine (30 nM). Physostigmine (30 nM) potentiated the response to ACh in epithelium-intact tissues more (about 26-fold) than in epithelium-denuded tissues (about 3.5-fold). Thus, in the presence of physostigmine removing the epithelium had only a slight effect (not statistically significant) on the potency of ACh to contract the trachea. Removing the epithelium had no effect on the potency of bethanechol, a muscarinic receptor agonist that is not a substrate for cholinesterases. Physostigmine itself contracted the trachealis muscle but the pD2 values and maximum responses in epithelium-intact and denuded preparations were not significantly different. The frequency-response curves to electrical field-stimulated cholinergic contractions were unaffected by removing the epithelium. In conclusion, the principal mechanism by which the epithelium inhibits contraction of guinea-pig trachea to exogenously applied ACh is via epithelium-derived acetylcholinesterase activity.

Acetylcholine↗
PubMed1992

Latex allergy.

Explore the source record for details and available documents.

Anaphylaxis↗
PubMed1992

Mechanism of action of atracurium on airways.

Histamine-releasing drugs may produce significant effects on airways in high-risk populations. To determine if clinically relevant doses of atracurium produce adverse effects on airways, we measured changes in airway resistance in the lung periphery of anesthetized Basenji-Greyhound dogs before and after intravenous (iv) administration of atracurium. A wedged bronchoscope technique was used to measure collateral system resistance (Rcs). After a stable baseline was obtained, atracurium (1.2 or 0.5 mg/kg) or histamine (200 micrograms) were administered as an iv bolus, and percent increase in Rcs was calculated. On separate days dogs were pretreated with the histamine 1 receptor antagonist, chlorpheniramine (0.2 mg/kg iv), with or without atropine (0.2 mg/kg iv) and ranitidine (0.75 mg/kg iv) and the experiment repeated. Histamine (200 micrograms) increased Rcs 97 +/- 24% at 30 s (8 sublobar segments), whereas a second dose increased Rcs 77 +/- 15%. Pretreatment with chlorpheniramine (0.2 mg/kg iv) totally prevented increases in Rcs (9 sublobar segments). Atracurium (1.2 mg/kg) increased Rcs to 174 +/- 35% at 3 min (14 sublobar segments), whereas 0.5 mg/kg had little effect (10 sublobar segments). A second bolus of atracurium (1.2 mg/kg) increased Rcs to only 54 +/- 14% (P less than 0.01). Chlorpheniramine pretreatment (0.2 mg/kg iv) reduced the response to the initial dose of atracurium to only 26 +/- 14% (10 sublobar segments). Pretreatment with a combination of atropine and chlorpheniramine (4 sublobar segments), or ranitidine and chlorpheniramine (5 sublobar segments), did not attenuate the increase in Rcs significantly more than chlorpheniramine pretreatment alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Airway Resistance↗
PubMed1992

Halothane inhibition of ion transport of the tracheal epithelium. A possible mechanism for anesthetic-induced impairment of mucociliary clearance.

Significant depression of mucociliary function occurs during general anesthesia. One possible mechanism to account for this effect is a change in ion and water transport across airway epithelium. To determine if anesthetics alter epithelial cell function, we used electrophysiologic techniques to measure the effects of halothane on ion transport of in vitro canine tracheal epithelial. Epithelial tissues were mounted in an Ussing chamber and the short-circuit current (Isc) (a measure of active ion transport) and transepithelial resistance were determined in the absence and presence of halothane. Halothane induced a rapid and reversible decrease in Isc that was dose-dependent. Four percent halothane reversibly decreased Isc from 90 +/- 11 to 39 +/- 6 microA/cm2 (n = 12; P = 0.001) and increased transepithelial resistance. Isoproterenol is a well-known activator of chloride secretion that acts via beta-adrenergic receptors and cyclic adenosine monophosphate (cAMP). Pretreatment with isoproterenol or dibutyryl cAMP (a cell permeable analogue of cAMP) increased the percent inhibition of Isc by 4% halothane. These effects are consistent with preferential inhibition of chloride secretion by halothane but rule out a primary action of halothane on the beta-adrenergic system. In the presence of indomethacin, which eliminates the contribution of chloride secretion to Isc, 4% halothane induced a much smaller but still significant inhibition. This suggests that sodium absorption is also affected. We conclude that halothane significantly decreases ion and water transport in canine epithelia and that impaired fluid secretion may contribute to decreased mucous clearance in the perioperative period.

Animals↗
PubMed1992

Methylprednisolone restores sensitivity to beta-adrenergic agonists in Basenji-Greyhound dogs.

This study investigated the effect of chronic methylprednisolone treatment on the ability of albuterol and aminophylline to inhibit methacholine-induced airway constriction in Basenji-Greyhound (BG) dogs in vivo. Pulmonary responsiveness to methacholine was measured in five untreated BG dogs and in the same dogs pretreated with albuterol or aminophylline (which has been shown in this model to release endogenous catecholamines). Each dog was studied before, during, and after daily subcutaneous methylprednisolone for 6 wk. Changes in pulmonary resistance and dynamic compliance with methacholine aerosol challenge were measured. Neither baseline pulmonary function nor pulmonary responsiveness to aerosolized methacholine was significantly altered by albuterol, aminophylline, or chronic methylprednisolone administration alone. However, pretreatment with albuterol or aminophylline significantly attenuated airway responses to methacholine in BG dogs chronically receiving methylprednisolone. Because the reduced sensitivity to albuterol and aminophylline was restored by chronic methylprednisolone treatment, we conclude that at least part of the beneficial effects of corticosteroids on airways in BG dogs is through modulation of beta-adrenergic function.

Adrenergic beta-Agonists↗
PubMed1992

M2 muscarinic receptors inhibit isoproterenol-induced relaxation of canine airway smooth muscle.

Classification of muscarinic receptors in the central airways has revealed the coexistence of M2 and M3 muscarinic receptors in this tissue, with the M2 subtype being predominant. Although M3 muscarinic receptors have been linked to airway smooth muscle contraction, a functional role for the M2 subtype in this tissue has been unclear. In nonairway smooth muscle, stimulation of the M2 muscarinic receptor has been shown to be associated with inhibition of adenylyl cyclase. In the present study, characterization of muscarinic receptors in canine tracheal smooth muscle confirmed that the majority of these muscarinic receptors were of the M2 subtype (89 +/- 3%), with a minor population of M3 receptors (11 +/- 3%). In functional studies, both isoproterenol and forskolin cause a dose-dependent relaxation of precontracted airway smooth muscle. In tissues precontracted with methacholine, 11-([[2-(diethylamino)methyl]-1-piperidinyl]acetyl)5,11- dihydro-6H-pyrido[2,3-6][1,4]benzodiazepine-6-one (AF-DX 116), a selective M2 antagonist, shifted dose-response curves to both isoproterenol and forskolin significantly to the left. In contrast, AF-DX 116 did not alter relaxation induced by the K+ channel opener BRL 38227. Furthermore, the ability of AF-DX 116 to enhance isoproterenol-induced relaxation appears to be limited to smooth muscle precontracted with muscarinic agonists because AF-DX 116 had no effect on isoproterenol dose-response curves in muscle strips precontracted with histamine. Hexahydrosiladifenidol (HHSiD), a selective antagonist for M3 receptors, did not shift the isoproterenol dose-response curve in muscle precontracted with methacholine. This study demonstrates that stimulation of M2 muscarinic receptors in canine airway smooth muscle plays an important role in functional antagonism by reducing the relaxation caused by agents such as isoproterenol and forskolin.

Animals↗
PubMed1991

Differential effect of glucocorticoids on pulmonary responses and eosinophils.

The persistent airway hyperresponsiveness of Basenji-Greyhound (BG) dogs to 10% citric acid (CA) is abolished by chronic administration of methylprednisolone (MP) and is accompanied by the disappearance of eosinophils from the bronchoalveolar lavage (BAL) fluid. To determine whether the disappearance of eosinophils from BAL fluid was temporally related to the loss of airway responsiveness to CA, we investigated the time course of the reduction in airway responsiveness to CA and correlated it with changes in cell profiles in BAL fluid in a group of BG dogs treated with MP for 1 to 7 days. Six dogs in separate studies were pretreated with MP (2 mg/kg/day) subcutaneously for either 1, 3 or 7 days. Each dog served as its own control for each set of studies. Under thiopental anesthesia, lung resistance (RL) was calculated from transpulmonary pressure and flow measurements prior to and 5 minutes following the completion of a 10% CA aerosol. BAL was performed on a separate occasion with the animals pretreated with MP for either 1, 7, 10 or 14 days. Baseline RL was not significantly different in each control and treatment group. The pulmonary response to CA challenge was diminished following 1, 3 and 7 days of MP pretreatment. Although eosinophils disappeared from the peripheral blood following 1 day of MP treatment, eosinophils in BAL did not begin decreasing until 10 days of MP pretreatment. This temporal dissociation between CA hyperresponsiveness and eosinophils in the BAL fluid suggests that epithelial damage by toxic products of eosinophils in the airway lumen does not play a direct role in citric acid induced airway hyperresponsiveness in BG dogs.

Aerosols↗
PubMed1991

Airway responsiveness in atopic dermatitis.

Twelve of 123 patients with atopic dermatitis (AD) were screened by questionnaire and spirometry for the absence of smoking, hay fever, and respiratory disorders. Seven of these 12 patients had a positive methacholine challenge test. None of eight patients with another skin disorder, psoriasis, screened in a similar fashion, had a positive methacholine challenge. We conclude that hyperresponsive airways are a frequent finding in patients with AD and that similar mechanisms may account for the cutaneous physiologic and pharmacologic abnormalities that have been observed in AD.

Adult↗
PubMed1991

Methylprednisolone prevents propranolol-induced airway hyperreactivity in the Basenji-greyhound dog.

To determine if corticosteroids would prevent beta-adrenergic-antagonist-induced increases in airway reactivity, we evaluated the ability of chronic methylprednisolone administration to prevent propranolol-induced airway hypereactivity to methacholine aerosol in the basenji-greyhound (BG) dog model of asthma. Initial studies included the measurement of lung resistance (RL) and dynamic compliance (Cdyn) with and without propranolol pretreatment in 5 BG and 5 mongrel dogs. A single dose of propranolol (2 mg/kg) did not significantly alter airway reactivity in the mongrels. The dose of methacholine needed to increase RL by 200% (ED200RL) was 0.20 +/- 0.05 mg/ml (mean +/- standard error of the mean [SEM]) in untreated and 0.18 +/- 0.04 mg/ml in propranolol-treated mongrels. In contrast, propranol significantly increased methacholine-reactivity in the BGs. The ED200RL for methacholine was 0.17 +/- 0.03 mg/ml in untreated and 0.05 +/- 0.02 mg/ml (P less than 0.05) in propranolol-treated BG dogs. Following the initial studies, the 5 BG dogs were given methylprednisolone (2 mg.kg-1.day-1) for 4 weeks, after which time propranolol no longer increased methylacholine reactivity in the BGs. The ED200RL was 0.16 +/- 0.03 mg/ml after 4 weeks of methylprednisolone and 0.22 +/- 0.06 mg/ml after propranolol administration in the BGs given 4 weeks of methylprednisolone treatment. The attenuation of propranolol-induced bronchoconstriction by corticosteroids may be a clinically useful intervention in asthmatic patients receiving beta-adrenergic antagonists in the perioperative period. However, further studies are needed to define the effective dose and duration of corticosteroid therapy that is needed.

Animals↗
PubMed1991

Contractile responses of guinea pig trachea to oxybarbiturates and thiobarbiturates.

To determine what mechanisms are involved in barbiturate-induced tracheal constriction and whether a relationship exists between barbiturate structure and the ability of the barbiturate to induce constriction, we compared the effects of thiamylal, thiopental, methohexital, pentobarbital, and phenobarbital at increasing airway tone in an intact guinea pig tracheal preparation in the presence and absence of cyclooxygenase and thromboxane synthetase inhibition. Whole tracheas were suspended between two cannulas in 50-ml tissue baths and perfused at a constant flow rate with Krebs-Henseleit solution. The contractile responses were assessed by measuring the pressure differential between the tracheal inlet and outlet ports. Barbiturates were added to the bath of each trachea, which was washed between each drug. Each drug was added to produce final bath concentrations of 10(-6), 10(-5), 10(-4), 10(-3), and 3 x 10(-3) M. Tracheas were also pretreated with meclofenamate (10(-6) M) (a cyclooxygenase inhibitor) and UK 37,248 (10(-8) to 10(-5) M) and OKY 046 (10(-9) to 10(-6) M) (thromboxane synthetase inhibitors), and the thiamylal protocol was repeated. All data were normalized to a concentration of carbachol (2 x 10(-6) M) that has been shown to produce maximum constriction in this preparation. Thiamylal and thiopental produced constriction beginning at 10(-4) M and reached a maximum at 10(-3) M (P less than 0.0001). Methohexital, pentobarbital, and phenobarbital did not produce any significant change in airway tone. Pretreatment with meclofenamate (10(-6) M), UK 37,248 (5 x 10(-5) M), and OKY 046 (10(-6) M) prevented thiamylal-induced tracheal constriction.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Mediators, initiating the inflammatory response, released in organ culture by full-thickness human skin explants exposed to the irritant, sulfur mustard.

Mediators released from injured human skin that initiate the inflammatory response have not been adequately identified. Organ culture of full-thickness skin explants enables us to do so, because injury to the skin can be made in vitro, eliminating the rapid leakage of serum and infiltration of leukocytes that occur in vivo. In our studies, the military vesicant sulfur mustard (SM) (10 microliters of a 0.01 to 1.0% dilution) was topically applied to injure the epidermis of the explant. Then, the explants were cultured in small Petri dishes, usually for 18 h at 36 degrees C, and the organ-culture fluids were assayed for various inflammatory mediators. We found that the culture fluids from SM-exposed and control explants contained similar amounts of angiotensin-converting enzyme, trypsin-like and chymotrypsin-like proteases, acid phosphatase, beta-glucuronidase, beta-galactosidase, lysozyme, deoxyribonuclease, ribonuclease, interleukin 1, and lactic dehydrogenase. However, the culture fluids from SM-exposed explants contained increased amounts of histamine and plasminogen-activating activity, and often prostaglandin E2, when compared to culture fluids from control explants. After 3 to 4 d in culture, full-thickness human skin explants, when exposed to 0.2% SM (but not when exposed to 1.0% SM), sometimes showed separation of the epidermis and increased collagenase activity (i.e., hydroxyproline release). Thus, histamine (from local mast cells), and prostaglandin E2 and plasminogen-activating activity (probably from both mast cells and epidermal cells) are apparently involved in early mediation of the inflammatory response.

Administration, Cutaneous↗
PubMed1991

Assessment of pulmonary airway reactivity with high-resolution CT.

The evaluation of airway reactivity plays a central role in the diagnosis of bronchial hyperreactivity and asthma. The authors used high-resolution computed tomography (HRCT) to assess airway reactivity and compared the results with simultaneously performed measurements of airway pressure (Paw). Ten anesthetized and ventilated dogs were studied in a control state, after saline aerosol application, and after histamine aerosol challenge. In each condition, Paw was determined and HRCT was performed at functional residual capacity. On the HRCT scans, the cross-sectional areas of airway lumina were measured by using a computer edging process. After histamine challenge, HRCT demonstrated a decrease in airway areas of 43% +/- 2% (mean +/- standard error) from baseline (control) and Paw increased 99% +/- 18%. Surprisingly, saline aerosol challenge also resulted in a significant decrease in airway areas (26% +/- 3%) from control, while Paw measurements did not change significantly. Airway reactivity varied between dogs and within dogs. The authors conclude that HRCT can depict the site and degree of airway reactions and thus represents a new tool to assess airway reactivity in vivo.

Animals↗
PubMed1991

Use of collateral airways to assess airway reactivity.

We investigated the correlation between collateral airway reactivity and other indexes of lung reactivity in response to aerosol and intravenous (iv) challenges. In four anesthetized mongrel dogs, we measured the peripheral airway resistance (Rp) to gas flow out of a wedged lung segment in different lobes on multiple occasions. We obtained dose-response curves of peripheral airways challenged with iv histamine or aerosols through the bronchoscope. During the same iv bolus challenge, whole lung airway pressure (Paw) responses to histamine were also measured. On separate occasions, changes in lung resistance (RL) were measured after the whole lung was challenged with a histamine aerosol. Reactivity was assessed from the dose-response curves for Rp and RL as the PD50 (dose required to produce a 50% increase); for changes in Paw we calculated the PD15 (dose required to produce a 15% increase over baseline). Results for Rp showed considerably more variability among different lobes in a given animal with the aerosol challenge through the bronchoscope than with the iv challenge. With aerosol challenge there were no significant differences in the mean PD50 for Rp among any of the animals. However, with the iv challenge two of the dogs showed significant differences from the others in reactivity assessed with Rp (P less than 0.01). Moreover, the differences found in the peripheral airways with iv challenge reflected differences found in whole lung reactivity assessed with either iv challenge (Paw vs. Rp, r2 = 0.96) or whole lung aerosol challenge (RL vs. Rp, r2 = 0.84). We conclude that the measurement of the collateral resistance response to iv challenge may provide a sensitive method for assessing airway reactivity.

Aerosols↗
PubMed1991

Calcium channel blockers modulate airway constriction in the canine lung periphery.

We studied the effect of two voltage-sensitive calcium channel blockers on Na2EDTA-induced bronchoconstriction in the canine lung periphery. A wedged bronchoscope technique was used to measure collateral system resistance before and after challenges with aerosolized Na2EDTA, hypocapnia, aerosolized acetylcholine, and increased flow of dry air in anesthetized mongrel dogs. Nifedipine, a dihydropyridine calcium channel blocker, reduced hypocapnia-induced bronchoconstriction by 88 +/- 6% (SE) but did not alter Na2EDTA-induced constriction. Verapamil, a phenylalkylamine calcium channel blocker, attenuated hypocapnia- and Na2EDTA-induced bronchoconstriction by 69 +/- 6 and 44 +/- 7%, respectively, but did not significantly alter responses to either acetylcholine or dry air challenge. We conclude that calcium influx through voltage-sensitive calcium channels, perhaps of the T subtype, has a limited role in the initiation of Na2EDTA-induced bronchoconstriction in the canine lung periphery.

Acetylcholine↗
PubMed1991

Functional antagonism of airway constriction in the canine lung periphery.

We studied the ability of a beta-adrenergic agonist (albuterol) to attenuate calcium chelator- and acetylcholine-induced airway constriction in the lung periphery of anesthetized mongrel and Basenji-Greyhound (BG) dogs. A wedged bronchoscope technique was used to measure collateral system resistance before and after challenges with aerosolized Na2EDTA and acetylcholine. Time course of the response to Na2EDTA differed significantly between mongrel and BG dogs. Peak response to challenge with 4% Na2EDTA occurred within 2 min for mongrel dogs and at 5 min for BG dogs. Albuterol (1 microgram/kg iv) significantly attenuated Na2EDTA-induced bronchoconstriction in both groups of animals (P less than 0.01, each group). Albuterol (1 microgram/kg iv) significantly attenuated acetylcholine-induced bronchoconstriction in mongrel (P less than 0.01) but not in BG dogs. We conclude that a qualitative difference exists in the mechanism of Na2EDTA-induced constriction in the lung periphery of BG compared with mongrel dogs. In addition, the lung periphery of BG dogs demonstrates reduced beta-adrenergic sensitivity with respect to a cholinergic challenge compared with mongrels, suggesting enhanced cholinergic inhibition of the beta-adrenergic system.

Acetylcholine↗