A muscarinic agonist inhibits reflex bronchoconstriction in normal but not in asthmatic subjects

Abstract

Muscarinic receptors of the M2 subtype, which inhibit acetylcholine release from cholinergic nerves (autoreceptors), have been described in animal and human bronchi in vitro. We investigated whether these receptors may be involved in feedback inhibition of cholinergic reflex bronchoconstriction induced by sulfur dioxide (SO2) in seven nonasthmatic atopic subjects and in six mild asthmatic subjects. In a control experiment, total respiratory resistance (Rrs) was increased by 30 +/- 5% in nonasthmatic and by 60 +/- 18% in asthmatic subjects. In nonasthmatic subjects, pilocarpine, an agonist of muscarinic M2-autoreceptors, increased Rrs by 15 +/- 5% and addition of SO2 increased Rrs to 21 +/- 5% above base line, which was not significantly greater than after pilocarpine alone. Histamine gave a comparable bronchoconstriction (25 +/- 3% increase in Rrs) and SO2 further increased Rrs to 39 +/- 6% above base line (P less than 0.05). Thus pilocarpine appears to inhibit SO2-induced bronchoconstriction in nonasthmatic subjects, and this effect is not explained by an increase in airway tone. In asthmatic subjects, pretreatment with pilocarpine increased Rrs by 31 +/- 8% and SO2 further increased Rrs to 88 +/- 17% above base line. SO2 alone gave a 60 +/- 18% increase in Rrs. Our results suggest that feedback inhibitory muscarinic receptors may be present on cholinergic nerves in normal airways and that there may be a dysfunction of this feedback mechanism in asthmatic airways. This might be contributory to exaggerated cholinergic reflex bronchoconstriction in asthma.

Hyperinsulinemia Potentiates Airway Responsiveness to Parasympathetic Nerve Stimulation in Obese Rats

“…Loss of M 2 receptor function has been described in asthma (21,23) and is a common feature of many different animal models of airway hyperresponsiveness, including acute infection with parainfluenza virus (24), sensitization and challenge with antigen (26,33), acute exposure to ozone (25), and acute exposure to organophosphate pesticides (39). M 2 muscarinic receptor function is measured in vivo in this study using the selective agonist pilocarpine.…”

“…Dysfunctional M 2 muscarinic receptors on airway parasympathetic nerves result in airway hyperresponsiveness in humans with asthma (21)(22)(23) and in animal models of asthma (24)(25)(26). Here we used a polygenic model of diet-induced obesity to test whether obesity increases insulin that subsequently decreases neuronal M 2 receptor function, resulting in airway hyperresponsiveness to vagus nerve stimulation.…”

Pancuronium masks the prejunctional muscarinic autoreceptor in guinea pig tracheal smooth muscle

“…Clinical experiments by Minette el al. (9) indicated that prejunctional inhibitory muscarinic receptors may protect against parasympathetic stimuli in healthy subjects, whereas these receptors seemed to be dysfunctional in mild asthmatics. When pancuronium causes the inhibitory muscarinic receptor response to vanish in vivo and this receptor plays a protective role, one may wonder why the use of pancuronium in lung surgery has not resulted in any bronchospasms or asthmatic attacks.…”

“…The prejunctional autoreceptor has been characterized with selective muscarinic antagonists, and appeared to be an Mr like receptor, which differs in the guinea-pig from the cardiac type M2 receptor in its relatively high affinity for hexahydrosiladiphenidol (6), Prejunctional muscarinic autoreceptors in human airways are of special interest, as they might play a role in the etiology of asthma (9). The first evidence for the presence and functionality of prejunctional muscarinic autoreceptors in human airways came from a study in which pilocarpine and gallamine were used as selective agents to demonstrate the prejunctional autoreceptor in electrical field stimulation (EFS) experiments (4), Although one may question the usefulness of pilocarpine as a selective agonist in this approach (5), the possibility of a role of an inhibitory muscarinic receptor in human airways is important enough to perform further investigation.…”

The effect of allosteric antagonists in modulating muscarinic M2‐receptor function in guinea‐pig isolated trachea

“…This is of particular interest given that activation of prejunctional muscarinic M2-receptors inhibits acetylcholine release from cholinergic nerves and that the function of these receptors in the lung is attenuated in virus-infected (Fryer & Jacoby, 1991) and ovalbumin-sensitized (Fryer & Wills-Karp, 1991;Fryer & Jacoby, 1992) guinea-pigs in vivo. Furthermore, muscarinic M2-receptor function appears to be altered in asthma (Minette et al, 1989). It would appear that the function of muscarinic M2-receptors might be modulated during an inflammatory response .…”