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

Inhibitory M2 muscarinic receptors on parasympathetic nerve endings in the lungs decrease release of acetylcholine, inhibiting vagally induced bronchoconstriction. Neuronal M2 receptor function can be studied using selective agonists and antagonists such as pilocarpine and gallamine. In pathogen-free guinea pigs indomethacin (1 mg/kg) did not alter the effect of either gallamine or pilocarpine, thus in pathogen free animals neuronal M2 muscarinic receptors function independently of cyclooxygenase products. However, in guinea pigs infected with virus, (which causes temporary loss of M2 receptor function), and then allowed to recover for 8 wk (to allow recovery of M2 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 M2 receptors to become dependent upon cyclooxygenase the effects of viral infection are likely to be due to inflammation. Thus, despite apparent recovery of normal M2 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.

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 micrograms/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.

Interaction of nondepolarizing muscle relaxants with M2 and M3 muscarinic receptors in guinea pig lung and heart.

BACKGROUND: Neuromuscular blocking agents such as gallamine and pancuronium bind to muscarinic cholinergic receptors and alter parasympathetically mediated airway caliber and heart rate. In the lungs, acetylcholine induces bronchoconstriction via M3 muscarinic receptors on airway smooth muscle, whereas in the heart M2 muscarinic receptors mediate bradycardia. Moreover, release of acetylcholine from parasympathetic nerves in the lung is decreased by inhibitory M2 receptors on the nerves, which represent a negative feedback system. Blockade of these receptors potentiates vagally induced bronchoconstriction, which may be clinically important if the M3 receptors on airway muscle are not blocked. These experiments were designed to examine the effects of the newer, nondepolarizing muscle relaxants pipecuronium, doxacurium, and mivacurium on pulmonary and cardiac muscarinic receptors. METHODS: Guinea pigs were anesthetized with urethane, paralyzed with succinylcholine, and their lungs mechanically ventilated. Pulmonary inflation pressure and heart rate were measured before and after electrical stimulation of both vagus nerves to evaluate prejunctional M2 muscarinic receptor function and after intravenous acetylcholine to evaluate postjunctional M3 and M2 receptor function in the presence of increasing concentrations of pancuronium, mivacurium, pipecuronium, and doxacurium. RESULTS: Pancuronium was an antagonist for M2 and M3 muscarinic receptors. Mivacurium was a more potent antagonist of M3 than M2 receptors. Pipecuronium was an antagonist of M2 but not M3 receptors. Doxacurium was not an antagonist of either M2 or M3 muscarinic receptors. Only pancuronium and pipecuronium potentiated vagally induced bronchoconstriction. With pipecuronium, the potentiation occurred at concentrations greater than those used clinically. CONCLUSIONS: Although pipecuronium is an M2 receptor antagonist with no M3 receptor antagonist properties, potentiation of reflex-induced bronchoconstriction is unlikely, because this effect occurred only at doses greater than those used clinically.