L. Yerger

Functional depression of H2 histamine receptors in sheep with experimental allergic asthma

We tested the hypothesis that airway hyperresponsiveness to histamine in the allergic sheep is related to functional depression of H2 histamine receptors. Thirteen of 32 sheep responded with bronchoconstriction to inhaled Ascaris suum antigen (allergic sheep), and the remainder served as controls (nonallergic sheep). In the allergic sheep, 50 and 100 breaths of 5% histamine solution increased mean pulmonary resistance (RL) to 235% and 438% of baselines, respectively. The corresponding values in nonallergic sheep were 200% and 211%, indicating a greater response to the higher dose of histamine in allergic sheep. Selective H1-receptor stimulation with 50 breaths of histamine (pretreatment with the H2-receptor antagonist metiamide) failed to enhance the effect of histamine in allergic sheep (mean RL increased to 239% of baseline) whereas it enhanced the histamine response in nonallergic sheep (RL increased to 438% of baseline). Selective H2-receptor stimulation (pretreatment with the H1-receptor antagonist chlorpheniramine) caused histamine to decrease RL by 31% in the nonallergic sheep group; it blocked but did not reverse the histamine effect in the allergic sheep. Similar observations were made in a different group of animals when selective H1- or selective H2-receptor stimulation was produced by 100 breaths of histamine. The cutaneous wheal response to intradermal histamine dilutions of 0.0001. 0.001, 0.01, and 1 mg/ml was similar in both groups. In nonallergic sheep, both chlorpheniramine and metiamide blunted the cutaneous wheal response. In allergic animals, only chlorpheniramine blunted the cutaneous wheal response, whereas metiamide was without effect. We conclude that airway hyperresponsiveness to histamine in allergic sheep is related to a functional depression of H2 receptors and that such a defect is observed both in the airways as well as in the skin.

Changes in airway permeability and responsiveness after exposure to ozone

The purpose of this investigation was to examine the relationship between airway responsiveness and the permeability of histamine through the airways in conscious sheep after exposure to ozone (O3). Airway responsiveness was assessed by measuring the change from baseline in mean pulmonary flow resistance following a controlled 2-min inhalation challenge with 1% histamine, containing 200 microCi/ml of [3H]histamine. The rate of appearance of the [3H]histamine in the plasma during inhalation challenge was used to estimate airway permeability. To perturb the airways, conscious sheep were exposed to either 0.5 or 1.0 ppm O3 for 2 hr via an endotracheal tube. Airway responsiveness and airway permeability were measured prior to and 1 day after exposure. In six sheep exposed to 0.5 ppm O3, increased airway responsiveness and airway permeability were observed 1 day after exposure. Four of seven sheep exposed to 1.0 ppm O3 had enhanced airway responsiveness and airway permeability, while the remaining three sheep showed corresponding decreases in airway responsiveness and airway permeability. Since the O3-induced directional changes in airway responsiveness paralleled the directional changes in airway permeability in both the positive and negative directions, it was concluded that changes in airway responsiveness to inhaled histamine following exposure to O3 may be related to concomitant changes in airway permeability to this agent.

Effects of Nitric Acid on Carbachol Reactivity of the Airways in Normal and Allergic Sheep

The airway effect of a 4-hr exposure (via a Plexiglas hood) to 1.6 ppm nitric acid vapor were evaluated in seven normal and seven allergic sheep, i.e., animals that have a history of reacting with bronchospasm to inhalation challenge with Ascaris suum antigen. The nitric acid vapor was generated by ultrasonic nebulization of a 2% nitric acid solution. Airway effects were assessed by measuring the change in specific pulmonary flow resistance before and after a standard inhalation challenge with 2.5% carbachol aerosol. Nitric acid exposure did not produce bronchoconstriction in either group. Pre-exposure increases in specific pulmonary flow resistance after carbachol inhalation were 68% (SD +/- 13%) and 82% (SD +/- 35%) for the normal and allergic sheep, respectively. Within 24 hr, the largest post exposure increased in specific pulmonary flow resistance for the normal and allergic sheep were 108% [SD +/- 51% (P less than .06)] and 175% [SD +/- 87% (P less than .02)], respectively. We conclude that a short-term exposure to nitric acid vapor at levels below the industrial threshold limit (2 ppm), produces airway hyperreactivity to aerosolized carbachol in allergic sheep.

Inhibition of antigen-induced bronchoconstriction by methylprednisolone succinate☆

We investigated whether the glucocorticoid methylprednisolone succinate mg/kg) could prevent antigen-induced bronchoconstriction in conscious sheep. Ten allergic ewes were subjected to inhalation challenge with Ascaris suum antigen, with and without methylprednisolone pretreatment, administered intravenously either 20 min or 3 hr before antigen challenge. Antigen challenge alone resulted in increased airflow resistance, pulmonary hyperinflation, and decreases in dynamic lung compliance and arterial oxygen tension. Methylprednisolone administered 20 min before antigen challenge had no effect on these antigen-induced changes. In contrast, administration of methylprednisolone 3 hr before antigen challenge effectively prevented all the responses to antigen challenge. We suggest that pretreatment with glucocorticoids can attenuate airway anaphylaxis if sufficient time is allowed between the pretreatment and the antigen challenge.