Is There Loss of a Protective Muscarinic Receptor Mechanism in Asthma?
Various types of agonists are capable of contracting the airway smooth muscle through different mechanisms of action.1 Among these agents, histamine and methacholine are the most widely used in the investigation of airway hyperreactivity. The pharmacodynamic properties of these agents have shown that histamine acts through H1 and H2 receptors, whereas methacholine stimulates muscarinic receptors on smooth muscle and possibly on autonomic ganglia. Repetitive stimulation of histamine receptors elicits tachyphylaxis in vitro and in vivo, whereas repetitive administration of methacholine generally has not shown any tachyphylaxis. Although the mechanism of action of these two agonists in terms of specific receptor stimulation and blockade by specific receptor antagonist is well established, any interaction between these two agonists if not well known. buy glucotrol online
The classic mode of mediator action has been described in terms of agonist-antagonist interaction at the receptor level. Recently, Ishii and Kato10 have proposed a new type of drug interaction at the cellular level, ie, “functional antagonism” between agonists for two distinct receptor system, exhibiting physiologic responses in the same direction (smooth muscle contraction). These authors observed a suppression of H! histamine-receptor function by prior stimulation of muscarinic receptors in the longitudinal muscle of guinea pig ileum. Although such an interaction, so far, has not been described in airway smooth muscle, Minette and Barnes7 have observed that the muscarinic agonist, pilocarpine, attenuated the contractile responses to electrical field stimulation in the guinea pig airway smooth muscle possibly via stimulation of inhibitory M2-muscarinic receptors. Since airway effects of histamine, in part, are mediated indirectly via stimulation of vagal reflex, we wondered if muscarinic receptor stimulation in vivo would cause a suppression of airway effects of histamine. Thus, the aim of this study was to determine whether airway muscarinic receptor stimulation with aerosolized methacholine would influence the subsequent bronchoconstrictor responses to histamine. Since airway hyperresponsiveness to methacholine and histamine is a hallmark of bronchial asthma, we also studied any possible differences in methacholine-histamine interaction between normal and asthmatic subjects.