ovalbumin and methoctramine

We examined the density of muscarinic acetylcholine receptor (mACh-R) subtypes (M1R, M2R and M3R) in guinea pig lung. The density of M3R in the lung tissue of ovalbumin (OA)-sensitized guinea pigs was higher than that in the control group. However, no difference was observed in the affinity of M3R between the sensitized and the control lungs. No difference was observed in the density and affinity of M1R and M2R in sensitized and control lungs. Pilocarpine, which is an M2R stimulant, increased the density of M3R in the lung tissue and the rate of the increase in sensitized guinea pigs was less than that in the control group. In contrast, methoctranine, which is an M2R antagonist, decreased the density of M3R and the rate ofthis decrease was the same in the sensitized and control groups. These results suggest that, in OA-sensitized guinea pigs, a dysfunction of M2R leads to the abnormal density of M3R.

Topics: Animals; Asthma; Diamines; Gallamine Triethiodide; Guinea Pigs; Membranes; Muscarinic Agonists; Nicotinic Antagonists; Ovalbumin; Parasympatholytics; Pilocarpine; Receptor, Muscarinic M2; Receptor, Muscarinic M3; Receptors, Muscarinic

M2 muscarinic receptors limit acetylcholine release from the pulmonary parasympathetic nerves. M2 receptors are dysfunctional in antigen-challenged guinea pigs, causing increased vagally mediated bronchoconstriction. Dysfunction of these M2 receptors is due to eosinophil major basic protein, which is an antagonist for M2 receptors. Histamine-induced bronchoconstriction is composed of a vagal reflex in addition to its direct effect on airway smooth muscle. Because hyperreactivity to histamine is seen in antigen-challenged animals, we hypothesized that hyperreactivity to histamine may be due to increased vagally mediated bronchoconstriction caused by dysfunction of M2 receptors. In anesthetized, antigen-challenged guinea pigs, histamine-induced bronchoconstriction was greater than that in control guinea pigs. After vagotomy or atropine treatment, the response to histamine in antigen-challenged animals was the same as that in control animals. In antigen-challenged animals, blockade of eosinophil influx into the airways or neutralization of eosinophil major basic protein prevented the development of hyperreactivity to histamine. Thus hyperreactivity to histamine in antigen-challenged guinea pigs is vagally mediated and dependent on eosinophil major basic protein.

Topics: Animals; Antibodies; Antigens; Atropine; Blood Proteins; Bronchoconstriction; Diamines; Eosinophil Granule Proteins; Eosinophils; Guinea Pigs; Histamine; Integrin alpha4beta1; Integrins; Muscarinic Agonists; Muscarinic Antagonists; Ovalbumin; Receptor, Muscarinic M2; Receptors, Lymphocyte Homing; Receptors, Muscarinic; Ribonucleases; Vagotomy; Vagus Nerve

We investigated the effects of subtype-selective muscarinic receptor antagonists upon aerosol antigen-induced bronchoconstriction in anesthetized guinea pigs. Neither pirenzepine (muscarinic M1 receptor-selective), 4-methylpiperidine methiodide (4-DAMP, muscarinic M3 receptor-selective), [N-iminomethyl-N'-[(2-hydroxy-2-phenyl-2-cyclohexyl)-ethyl] piperazine HCl (DAC-5945, muscarinic M3 receptor-selective), ipratropium or atropine inhibited bronchoconstriction, but methoctramine (muscarinic M2 receptor-selective) produced a dose-dependent increase in bronchoconstriction (up to 46%). Methoctramine also produced increases in bronchoconstriction induced by aerosols of histamine (up to 45%) and platelet activating factor (up to 118%), demonstrating nonspecific airway hyperresponsiveness. This effect of methoctramine was not inhibited by atropine, DAC-5945 or vagotomy and could not be attributed to altered arachidonic acid metabolism or beta-adrenergic antagonism. However, propranolol prevented methoctramine-induced airway hyperresponsiveness, suggesting that this effect resulted from the reported ganglionic blocking activity of methoctramine. In conclusion, muscarinic receptors do not appear to play an important role in antigen-induced bronchoconstriction in anesthetized guinea pigs. Furthermore, caution should be exercised in using methoctramine to characterize the roles of muscarinic receptors in airway inflammatory responses in vivo.

Topics: Aerosols; Albuterol; Animals; Arachidonic Acid; Atropine; Bronchial Hyperreactivity; Bronchoconstriction; Diamines; Drug Synergism; Gallamine Triethiodide; Guinea Pigs; Histamine; Male; Muscarinic Antagonists; Ovalbumin; Parasympatholytics; Piperazines; Piperidines; Platelet Activating Factor; Propranolol; Receptors, Muscarinic