Viral infection induces dependence of neuronal M2 muscarinic receptors on cyclooxygenase in guinea pig lung.

Abstract

Inhibitory M 2 muscarinic receptors on parasympathetic nerve endings in the lungs decrease release of acetylcholine, inhibiting vagally induced bronchoconstriction. Neuronal M 2 receptor function can be studied using selective agonists and antagonists such as pilocarpine and gallamine. In pathogenfree guinea pigs indomethacin (1 mg/kg) did not alter the effect of either gallamine or pilocarpine, thus in pathogen free animals neuronal M 2 muscarinic receptors function independently of cyclooxygenase products. However, in guinea pigs infected with virus, (which causes temporary loss of M 2 receptor function), and then allowed to recover for 8 wk (to allow recovery of M 2 receptors), indomethacin prevented both gallamine's potentiation and pilocarpine's inhibition of vagally induced bronchoconstriction. This new effect of indomethacin was not blocked by the addition of a 5-lipoxygenase inhibitor, AA861. However, the selective COX II inhibitor, L-745,337, had the same effect as indomethacin. Since exposure to ozone also caused neuronal M 2 receptors to become dependent upon cyclooxygenase the effects of viral infection are likely to be due to inflammation. Thus, despite apparent recovery of normal M 2 receptor function after viral infection or ozone, linkage of these receptors is chronically altered such that they become largely dependent on the activity of COX II. ( J. Clin. Invest. 1996. 98:299-307. )

Neuromuscular Blocking Agents' Differential Bronchoconstrictive Potential in Guinea Pig Airways

“…We used a well-established guinea pig model of airway responses that has been used for more than 25 yr for the measurement of changes in airway tone. 5,6,[11][12][13][14][15][16] This model uses intraperitoneal urethane (1.7 Ϯ 0.2 g/kg) as the anesthetic technique because this anesthetic is known to not effect pulmonary nerve function and the anesthetic effect is known to have a duration of at least 10 h. 17 Depth of anesthesia was monitored by changes in respiratory rate and response to foot pinch before paralysis. Surgical intervention did not begin until there was an absence of response to foot pinch (withdrawal).…”

“…Peak Ppi has been used in this model for many years as a reflection of changes in airway tone. 5,6,[11][12][13][14][15][16] Paralysis standardizes chest wall compliance and a constant volume ventilator standardizes inspiratory volume such that changes in airway tone are reflected in changes in peak Ppi.…”

“…Both vagus nerves were tightly tied but not cut, and the distal ends were placed on shielded electrodes immersed in a pool of liquid mineral oil. 5,6,[11][12][13][14][15][16] All pressure transducers were connected to a Biopac MP100A acquisition system, and data were continuously captured using Acknowledge software, version 3.7.3 (Biopac Systems, Inc.).…”

“…In the current study, using an established guinea pig in vivo model, 5,6,[11][12][13][14][15][16] we measured the ability of muscle relaxants to (1) enhance vagal nerve induced increases in Ppi by prejunctional M2 muscarinic receptor antagonism, 5,18,19,30 (2) prevent vagally induced bradycardia due to cardiac M2 muscarinic receptor antagonism, (3) antagonize or enhance intravenous acetylcholine's effect on Ppi via postjunctional M3 muscarinic receptor effects, or (4) promote an increase in Ppi via the release of histamine.…”

Anticholinergic Agents

“…27 It is important to stress that despite apparent recovery of normal M 2 Dysfunctional M 2 receptors and obstruction of receptor function after viral infection, linkage of these airways receptors is chronically altered, such that they become largely dependent on the activity of Cox II. 28 Drugs such as atropine and ipratropium, which block M 2 receptors on the nerves, which normally inhibit prejunctional M 2 receptors and those on smooth release of ACh, are dysfunctional after ozone exmuscle with equal efficacy (M 3 ), increase ACh release posure, as demonstrated by the failure of the muswhich may then overcome the post-junctional blockcarinic agonist pilocarpine to inhibit, and the failure ade. The action of ipratropium bromide at the auof the M 2 antagonist gallamine to potentiate, vagallytoinhibitory M 2 receptor may limit its use in the treatment of obstructive airways disease.…”