Basenji-Greyhound Dogs Research Articles

Carol Hirshman: Recipient of the 2000 Excellence in Research Award

Carol Hirshman: Recipient of the 2000 Excellence in Research Award

Is β-Adrenergic-Mediated Airway Relaxation of Salmeterol Antagonized by Its Solvent Xinafoic Acid?

Isolated case reports of asthmatic fatalities accompanied by the use of salmeterol have raised the question whether a paradoxical effect of salmeterol or its vehicle on the airways might contribute to these fatalities. We questioned whether salmeterol's solvent, xinafoic acid, has detrimental effects on the tone of airways or on beta-adrenoceptor binding. Basenji-greyhound dogs were anesthetized and their peripheral airways challenged with xinafoic acid via a wedged bronchoscope technique. Radioligand binding assays were performed in lung membranes prepared from these dogs. In contrast to a methacholine control, xinafoic acid (0.001 to 1.0 mg/mL) aerosolized into the peripheral airways of anesthetized dogs did not increase airway resistance. Xinafoate alone had no significant effect on the specific binding of 125I-cyanopindolol to lung membranes and did not affect the affinity of salmeterol for the beta-adrenoceptor in the absence or presence of xinafoate, respectively (-log concentration that inhibits 50% [IC50] of the high-affinity site, 7.7+/-0.15 and 7.9+/-0.27; -log IC50 of the low-affinity site = 5.6+/-0.44 and 5.3+/-0.28 [n = 4]). These findings suggest that xinafoic acid, the solvent for salmeterol, does not have direct airway irritant effects, does not bind to beta-adrenoceptors, and does not impair the binding of salmeterol to beta-adrenoceptors. Thus, xinafoate is unlikely to contribute to the worsening of airway symptoms in asthmatics using salmeterol xinafoate.

Dermal and airway responses to monoclonal antibodies specific for canine IgE

In order to understand mechanisms underlying variability of IgE-mediated responses in vivo, we compared effects of different monoclonal antibodies to IgE on dermal and airway responses in a group of atopic dogs. Using intradermal testing, fourteen antibodies were screened in Basenji-Greyhound dogs. For further comparisons between dermal and airway responses, we selected the two antibodies that stimulated the greatest and least dermal responses, respectively. These antibodies bound to IgE with similar affinities (4.1 ± 0.2 · 10 9 and 1.5 ± 0.2 · 10 10 M −1). Dose-response curves to intradermal testing were constructed for these two antibodies. On a separate occasion, peripheral airway resistance (Rp) was determined before and after aerosol challenge with an antibody or saline in the same dogs. For one antibody (affinity 4.1 ± 0.2 · 10 9 M −1), Rp reached a maximum (407 ± 142% above baseline; mean ± SE, n = 6) 10 to 15 min after challenge, while maximum responses to saline (62 ± 16% above baseline, p < 0.01) occurred immediately after aerosol delivery. Responses to the other antibody were similar ( p = 0.068) to responses to saline. The magnitude of skin responses did not predict the magnitude of airway responses. These findings suggest that differences in affinities, alone, do not predict magnitude of responsiveness to the anti-IgE antibody and that mechanisms underlying skin and airway responses may differ qualitatively and/or quantitatively.

Glucocorticoid treatment decreases muscarinic receptor expression in canine airway smooth muscle.

Corticosteroids upregulate the beta-adrenergic pathway, but little is known about corticosteroid regulation of muscarinic pathways. Basenji-greyhound (BG) dogs treated for 3 days with methylprednisolone (MPS) but not deoxycorticosterone (DOC) had decreased numbers of muscarinic receptors in airway smooth muscle homogenates as determined by radioligand binding with 1-[3H]quinuclidinyl benzilate (vehicle control, 578 +/- 53 fmol/mg protein; MPS, 290 +/- 22 fmol/mg protein; DOC, 565 +/- 141 fmol/mg protein). Competition radioligand binding with the M2-selective antagonist tripitramine showed a decrease in both the M2 and M3 muscarinic receptors with no changes in receptor affinities (M2: vehicle control, 478 +/- 41 fmol/mg protein; MPS, 265 +/- 20 fmol/mg protein, M3: vehicle control, 89 +/- 13 fmol/mg protein; MPS, 25 +/- 16 fmol/mg protein). In vitro treatment of airway smooth muscle from control BG dogs with MPS had no effect on muscarinic receptor number, despite increased expression of beta-adrenergic receptors. Thus glucocorticoids indirectly decrease the expression of M2 and M3 muscarinic receptors in airway smooth muscle, which, in part, may account for their beneficial effects in the treatment of asthma.

Impaired activation of adenylyl cyclase in lung of the Basenji-greyhound model of airway hyperresponsiveness: decreased numbers of high affinity beta-adrenoceptors.

1. To evaluate mechanisms involved in the impaired beta-adrenoceptor stimulation of adenylyl cyclase in tissues from the Basenji-greyhound (BG) dog model of airway hyperresponsiveness, we compared agonist and antagonist binding affinity of beta-adrenoceptors, beta-adrenoceptor subtypes, percentage of beta-adrenoceptors sequestered, and coupling of the beta-adrenoceptor to Gs alpha in lung membranes from BG and control mongrel dogs. We found that lung membranes from the BG dog had higher total numbers of beta-adrenoceptors with a greater percentage of receptors of the beta 2 subtype as compared to mongrel lung membranes. 2. Agonist and antagonist binding affinity and the percentage of beta-adrenoceptors sequestered were not different in BG and mongrel dog lung membranes. However, the percentage of beta-adrenoceptors in the high affinity state for agonist was decreased in BG lung membranes suggesting an uncoupling of the receptor from Gs alpha. 3. Impaired coupling between the beta-adrenoceptor and G protein documented by the decreased numbers of beta-adrenoceptors in the high affinity state in BG lung membranes, is a plausible explanation for the reduced stimulation of adenylyl cyclase and the resultant reduction in airway smooth muscle relaxation in this model.

Basenji-greyhound dog: increased m2 muscarinic receptor expression in trachealis muscle

Airway smooth muscle from asthmatic humans and from the Basenji-greyhound dog (BG) dog is hyporesponsive to beta-adrenergic agonist stimulation. Because adenylyl cyclase is under dual regulation in airway smooth muscle, we compared muscarinic receptor-coupled inhibition of adenylyl cyclase in airway smooth muscle from BG and mongrel dogs. Inhibition of forskolin-stimulated adenylyl cyclase activity by the muscarinic M2 agonist oxotremorine was greater in airway smooth muscle membranes from BG compared with mongrel controls. Quantitative immunoprecipitation studies showed increased numbers of m2 but not m3 muscarinic receptors in the BG airway smooth muscle. The enhanced ability of muscarinic agonists to inhibit adenylyl cyclase in BG airway smooth muscle may be due to the greater numbers of muscarinic m2 receptors, which may account in part for impaired airway smooth muscle relaxation in the BG model of airway hyperresponsiveness.

Reduced adenylyl cyclase activation with no decrease in β-adrenergic receptors in basenji greyhound leukocytes: Relevance to β-adrenergic responses in airway smooth muscle

Mononuclear leukocytes (MNLs) have been used as a model of β-adrenergic responsiveness of airway smooth muscle, but the relevance of this model remains controversial. The basenji greyhound (BG) dog model of airway hyperresponsiveness shares some features with human asthma, and airway smooth muscle shows a selective impairment in isoproterenol-stimulated adenylyl cyclase activity. In this study, MNL membranes were obtained from these same dogs, and the β-adrenergic receptor–adenylyl cyclase cascade function was compared with that in airway smooth muscle. β-Adrenergic receptor numbers and affinities for iodine 125–cyanopindolol were similar in the two dog groups (receptor numbers [B max] = 441 ± 101 and 447 ± 61 fmol/mg protein and dissociation constant [K d] = 269 ± 44 and 312 ± 60 pmol/L for mongrel and BG MNLs, respectively). Quantities of the G sα protein were not different in the membranes as determined by immunoblotting. Stimulation of adenylyl cyclase by isoproterenol (100 μmol/L) was impaired in MNL membranes of BG membranes (22% ± 4% increase over guanosine triphosphate [10 μmol/L]) compared with mongrel membranes (47% ± 8.6% increase over guanosine triphosphate [10 μmol/L], p < 0.05). Stimulation of adenylyl cyclase by prostaglandin E 1 (10 μmol/L), NaF (10 mmol/L), or forskolin (10 μmol/L) did not differ in membranes from the two groups. No difference was found in the lymphocyte subsets in the two groups as determined by flow cytometry. These findings are qualitatively similar to studies of trachealis muscle membranes from these same dogs. We have found a selective impairment of isoproterenol stimulation of adenylyl cyclase in membranes prepared from MNLs of the BG dog, which was previously found in airway smooth muscle membranes despite no decrease in numbers of β-adrenergic receptors. (J A LLERGY C LIN I MMUNOL 1995;95:860-7.)

Prevention of bronchoconstriction by an orally active local anesthetic.

Stimulation of airway irritant receptors produces reflex bronchoconstriction that can be prevented by pretreatment with anticholinergic drugs or local anesthetics delivered by aerosol or intravenously. We compared therapeutic doses of an orally administered local anesthetic, mexiletine hydrochloride, and intravenously administered lidocaine at blocking histamine-induced bronchoconstriction in five basenji-greyhound dogs, using high-resolution computed tomography (HRCT) to directly measure changes in airway size. In the dogs given placebo, a histamine infusion decreased airway area to 61 +/- 2% (mean +/- SEM) of control (p < 0.01). Mexiletine pretreatment completely prevented histamine-induced airway constriction, with an airway area that was 94 +/- 4% of the control value during the histamine infusion (p = 0.07 compared with baseline). Mexiletine serum levels were therapeutic (1.7 +/- 0.3 mg/L). Similarly, pretreatment with lidocaine significantly blunted the airway constriction provoked by intravenous histamine. In lidocaine-pretreated dogs, histamine decreased airway area to 79 +/- 4% of baseline (p < 0.01). As in the case of mexiletine, lidocaine serum levels were also therapeutic (2.4 +/- 0.3 mg/L). Mexiletine was more effective than lidocaine at preventing histamine-induced bronchoconstriction (p = 0.02). These data suggest that orally administered local anesthetics may be useful in preventing irritant-induced bronchoconstriction in humans.

Decreased ion transport by tracheal epithelium of the basenji-greyhound dog

The Basenji-Greyhound (BG) dog model shows altered beta-adrenergic function in both airway smooth muscle and leukocytes. To investigate a possible beta-adrenergic pathway defect in airway epithelial cells of BG dogs, we studied the electrophysiological behavior of tracheal epithelia in vitro and measured tracheal electrical potentials in vivo. Baseline short-circuit currents of isolated tracheal epithelia from BG (n = 6) and mongrel control dogs (n = 7) were 18.7 +/- 3.4 and 43.7 +/- 4.2 microA/cm2, respectively (P = 0.001). Significant differences between short-circuit currents of BG and control epithelia persisted after inhibition of Cl- secretion by indomethacin or stimulation by isoproterenol or dibutyryl adenosine 3',5'-cyclic monophosphate. In vivo tracheal potentials were also significantly less (P = 0.01) in BG dogs (-22.3 +/- 2.5 mV; n = 12) than in control dogs (-32.5 +/- 2.6 mV; n = 10), and intravenous indomethacin reduced the tracheal potential of BG dogs but had no effect in control animals. There was no correlation in BG dogs between tracheal potential and the dose of methacholine required to double total lung resistance. These data suggest that ion transport by tracheal epithelium is decreased in BG dogs, that this difference is not due to diminished beta-adrenergic activity, and that cyclooxygenase products are important in maintaining tracheal potential in vivo in this model.

Corticosteroid withdrawal restores responses to calcium chelators and enhances cholinergic responsiveness.

To investigate the importance of the inflammatory response in acute peripheral airway constriction, we measured peripheral airway responses to calcium chelators and acetylcholine in anesthetized Basenji-Greyhound (BG) dogs before, during, and after chronic corticosteroid treatment. A wedged bronchoscope technique was used to measure peripheral airway resistance before and after aerosol challenge with 4% Na2EDTA or acetylcholine (10 micrograms/ml) in contralateral lungs. After the initial measurements, five BG dogs received long-term treatment with methylprednisolone (2 mg/kg/d, subcutaneously), and five dogs were not treated and served as controls. Four weeks of methylprednisolone treatment almost totally abolished responses to Na2EDTA, but responses to acetylcholine did not change significantly. After discontinuing corticosteroid therapy, responses to Na2EDTA returned to levels found before corticosteroid treatment; responses to acetylcholine were significantly enhanced. We conclude that chronic corticosteroid treatment reduces acute response to calcium chelators and that withdrawal of corticosteroid therapy is associated with enhanced cholinergic responsiveness.

Importance of prostanoids in calcium chelator-induced airway constriction

To elucidate the mechanism of calcium chelator-induced airway constriction, we examined the relationship between prostanoids and histamine in bronchoalveolar lavage (BAL) fluid and the magnitude of airway constriction in peripheral airways of anesthetized Basenji-Greyhound dogs. A wedged bronchoscope technique was used to measure collateral system resistance (Rcs) before and after aerosol challenges. Sublobar segments were challenged either with acetylcholine or with Na2EDTA in the presence or absence of meclofenamate sodium (3 mg/kg iv) or methylprednisolone (2 mg.kg-1.day-1). After measurements of Rcs, BAL was performed, and the fluid was analyzed for prostanoids with the use of gas chromatography-mass spectrometry. Sublobar segments challenged with Na2EDTA showed increased concentrations of prostaglandin (PG) D2 but no increases in PGE2, PGF2 alpha, 9 alpha,11 beta-PGF2, 6-keto-PGF1 alpha, thromboxane B2, or histamine. There was a strong relationship (r = 0.84, P = 0.005) between changes in Rcs after Na2EDTA and concentrations of PGD2 in BAL fluid. Acetylcholine, which increased Rcs to a similar degree as Na2EDTA did, produced no significant increase in prostanoid concentrations. Changes in Rcs after Na2EDTA and concentrations of PGD2 were reduced in the presence of meclofenamate or methylprednisolone. These data support the idea that the mechanism of calcium chelator-induced bronchoconstriction involves the release of bronchoconstricting prostanoids.

Impaired β-adrenergic Receptor Activation of Adenylyl Cyclase in Airway Smooth Muscle in the Basenji-Greyhound Dog Model of Airway Hyperresponsiveness

Previous studies in human asthmatics have suggested a defect in the beta-adrenergic pathway leading to cyclic adenosine monophosphate (cAMP) generation. Although these studies have suggested normal or increased numbers of beta-adrenergic receptors, limitations in the quantity of tissue available have not allowed further delineation of the biochemical or molecular mechanisms of human asthma. The basenji-greyhound (BG) dog model of nonspecific airway hyperreactivity displays similarities to human asthma, and altered functional response to beta-adrenergic agonists has been previously shown in airway tissue from this model. We have now correlated this functional impairment in beta-adrenergic response with a decreased generation of cAMP in response to isoproterenol. Organ bath studies and adenylyl cyclase assays of trachealis muscle revealed impaired responses to isoproterenol in the BG dog as compared with control dogs. Pretreatment of muscle strips from BG dogs with isoproterenol had no effect on subsequent dose-response curves to methacholine (pD2 = 7.17 +/- 0.13, 7.34 +/- 0.12, and 7.14 +/- 0.17 for control, 10(-6) M isoproterenol, and 10(-5) M isoproterenol, respectively), while muscle strips from mongrel dogs had a significant shift in methacholine responses after isoproterenol pretreatment (pD2 = 7.91 +/- 0.23, 7.48 +/- 0.29, and 6.98 +/- 0.33 for control, 10(-6) M isoproterenol, and 10(-5) M isoproterenol, respectively). Adenylyl cyclase activity in response to isoproterenol was 54% in the BG trachealis membranes as compared with mongrels. Functional and biochemical responses to forskolin, NaF, prostaglandin, and dibutyryl cAMP, and the quantity of G,alpha were similar in the BG and control dogs.(ABSTRACT TRUNCATED AT 250 WORDS)

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)

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.

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.

Differential effect of glucocorticoids on pulmonary responses and eosinophils

The persistent airway hyperresponsivenes oof 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 (R l) 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 R l was not significantly different in each control annd 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.

Effect of inhibitors on histamine release from mast cells recovered by bronchoalveolar lavage in Basenji-Greyhound and Mongrel dogs

Studies of rodent mast cells have demonstrated that subpopulations differ in regard to their response to inhibitors of histamine release. To determine whether such compounds have different effects on mast cells from Basenji-Greyhound (BG) dogs with airway hyperreactivity and from mongrel dogs, we investigated the effect of cromolyn sodium, nedocromil sodium, theophylline, and quercetin on calcium ionophore A23187-induced histamine release from mast cells recovered by bronchoalveolar lavage. Mast cells recovered from BG and mongrel dogs were similar in respect to morphology and spontaneous and calcium ionophore-induce histamine release. Histamine release from mast cells from both BG and mongrel dogs was inhibited by quercetin (10(-4) M) and nedocromil sodium (5 x 10(-5) M). In contrast, only the histamine release from mast cells recovered from mongrel dogs was inhibited by cromolyn sodium (10(-4) M) and theophylline (5 x 10(-3) M). Thus, mast cells that are similar in regard to morphology and response to histamine liberators may differ in their response to inhibitors of histamine release.

Reduced sensitivity to beta-adrenergic agonists in Basenji-Greyhound dogs

To investigate the inhibitory effects of beta-adrenergic agonists and aminophylline on pulmonary responsiveness, we evaluated the ability of albuterol and aminophylline to attenuate pulmonary responses to aerosol challenge with methacholine and histamine in intact Basenji-Greyhound (BG) and selected mongrel dogs. Pulmonary responses were measured in untreated dogs and in dogs pretreated with albuterol (1 and 2.5 micrograms/kg) or aminophylline. Before aerosol challenge, baseline pulmonary resistance (RL) and dynamic compliance (Cdyn) were not significantly different between the BGs and the mongrels. In the untreated dogs, pulmonary responses to methacholine and histamine aerosols were not different between the BGs and the mongrels. Pretreatment with albuterol (1 microgram/kg) or aminophylline significantly attenuated the pulmonary response to methacholine in the mongrels but was without effect in the BGs. Albuterol (2.5 micrograms/kg) significantly attenuated the pulmonary response to methacholine in the BGs and the mongrels; however, this attenuation was significantly greater (P less than 0.05) in the mongrels than in the BGs. In response to histamine challenge, no differences were seen between the BGs and the mongrels in the control state (no pretreatment) or after pretreatment with albuterol or aminophylline. This study demonstrates that in BGs pulmonary responsiveness to methacholine but not histamine is resistant to inhibition by beta-adrenergic agonists. This may result from a qualitative or quantitative defect in either the cholinergic or beta-adrenergic receptor or to an abnormality distal to the receptors in the signal transduction mechanism at a site where the two signals interact.

Pulmonary Reactivity to Methacholine during β-adrenergic Blockade

Pulmonary reactivity to methacholine after equipotent beta-blocking doses of propranolol and esmolol was compared in seven basenji-greyhound dogs during thiopental-fentanyl anesthesia. Equipotent doses of esmolol and propranolol were determined by both heart rate effects and by isoproterenol response curves. Propranolol (2 mg/kg) was administered intravenously as a bolus dose and esmolol (0.4-0.5 mg.kg-1.min-1) was administered by continuous infusion. Both esmolol and propranolol significantly decreased heart rate and mean arterial pressure (P less than 0.001). Baseline pulmonary resistance and dynamic compliance did not change after the administration of either propranolol or esmolol. However, propranolol significantly shifted the methacholine dose-response curve to the left so that methacholine (0.3 mg/ml) increased pulmonary resistance by 7.9 +/- 0.97 cmH2O.l-1.s-1 (mean +/- SEM of seven dogs) after pretreatment with propranolol but only 4.4 +/- 0.89 cmH2O.l-1.s-1 (P less than 0.05) without propranolol pretreatment (control). Esmolol, however, did not significantly shift the methacholine dose-response curve. Methacholine (0.3 mg/ml) increased resistance 4.0 +/- 0.89 cmH2O.l-1.s-1 during esmolol administration. This study shows that at equipotent beta 1-blocking doses, propranolol, but not esmolol, produces significant increases in pulmonary reactivity to methacholine.

Attenuation of Histamine-Induced Airway Constriction by Albuterol during Halothane Anesthesia

The effect of albuterol (a beta 2 specific adrenergic agonist) on airway reactivity to histamine aerosol challenge was evaluated during halothane anesthesia and thiopental-fentanyl anesthesia in five Basenji Greyhound dogs. Responses to histamine aerosol challenges (0.01, 0.03, 0.1, 0.3, 1.0, and 3.0 mg/ml) were measured during thiopental-fentanyl anesthesia and during halothane anesthesia in the presence and absence of iv albuterol (2.5 micrograms/kg). Prior to aerosol challenges, baseline pulmonary resistance (RL) and dynamic compliance (Cdyn) did not differ in the four conditions. Albuterol significantly attenuated the pulmonary response to histamine during thiopental-fentanyl anesthesia. Although halothane itself significantly attenuated the pulmonary response to histamine, this response was further attenuated by the addition of albuterol. This study suggests that albuterol is effective in attenuating bronchoconstriction during both thiopental-fentanyl and halothane anesthesia. As the effects of albuterol and halothane on the airways are additive, beta-adrenergic agonists such as albuterol are the agents of choice to treat bronchospasm in patients anesthetized with inhalational anesthetics.