Neuronal M₂ muscarinic receptor function in guinea-pig lungs is inhibited by indomethacin

The function of M₂ muscarinic autoreceptors on pulmonary parasympathetic nerves was investigated in the absence and presence of cyclooxygenase inhibitors in vivo. Guinea pigs were anesthetized, paralyzed, and artificially ventilated. Pulmonary inflation pressure, heart rate, and blood pressure were recorded. Electrical stimulation of vagus nerves produced bronchoconstriction (measured as an increase in pulmonary inflation pressure) and bradycardia. In control guinea pigs, pilocarpine (1 to 100 μg/kg) given intravenously stimulated inhibitory M₂ muscarinic receptors on pulmonary parasympathetic nerves, thus attenuating vagally induced bronchoconstriction. Conversely, blockade of these autoreceptors by the selective M₂ antagonist gallamine (0.1 to 10 mg/kg given intravenously) potentiated vagally induced bronchoconstriction. Separate groups of animals were given either indomethacin or naproxen. These cyclooxygenase inhibitors potentiated vagally induced bronchoconstriction. Furthermore, in those animals pretreated with either indomethacin or [+] naproxen, pilocarpine did not inhibit and gallamine did not potentiate vagally induced bronchoconstriction. In the heart, the effects of pilocarpine and gallamine on M₂ muscarinic receptors were not altered by either cyclooxygenase inhibitor. Neither intravenously administered indomethacin (1 mg/kg) nor [+] naproxen (5 mg/kg) altered baseline pulmonary inflation pressure or baseline heart rate in the treated guinea pigs. These studies demonstrate that inhibitory M₂ muscarinic receptors on pulmonary parasympathetic nerves do not function in the presence of cyclooxygenase inhibitors. Loss of M₂ receptor function may contribute to aspirin-induced airway hyperresponsiveness.