Role of muscarinic m2 receptors in regulating [beta]-adrenergic
responsiveness in maturing rabbit airway smooth muscle.
Schramm, Craig M., Nereida C. Arjona, Michael M. Grunstein.
Pediatric Pulmonary Division, University of Connecticut School of
Medicine, Farmington, CT 06030, and The Joseph Stokes, Jr. Research
Institute of the Children's Hospital of Philadelphia, Department of
Pediatrics, University of Pennsylvania School of Medicine,
Philadelphia, PA 19104
APStracts 2:0127L, 1995.
Muscarinic M2 and M3 receptor subtypes have been pharmacologically
distinguished in airway smooth muscle. Whereas M3 receptors have been
associated with smooth muscle contraction, M2 receptors have been
implicated in Gi protein-coupled inhibition of adenylyl cyclase. To
determine whether the role of M2 receptors varies with age in
tracheal smooth muscle (TSM), dose-dependent relaxation responses to
isoproterenol were compared in TSM isolated from 3-day-old and adult
rabbits pre-contracted with acetylcholine (ACh) in the absence
(control) and presence of an M2 receptor antagonist (gallamine or
methoctramine). From sustained half-maximal ACh contractions, adult
TSM were 5.6-fold less sensitive than 3-day-old tissues to
isoproterenol-induced relaxation. Furthermore, the magnitude of
muscarinic functional antagonism of isoproterenol-mediated TSM
relaxation, assessed by varying the initial degree of ACh-induced
contraction, significantly increased with age. In gallamine- and
methoctramine-treated tissues, the relaxation-response curves to
isoproterenol were shifted to the left in both 3-day-old and adult
TSM. In contrast, pretreatment with either M2 receptor antagonist had
no significant effect on the magnitude of muscarinic functional
antagonism at either age. Moreover, Western blot analysis of G
[alpha]i common and specific subunit expression in TSM membranes
demonstrated qualitatively similar levels in 3-day-old and adult TSM.
Collectively, these findings provide new evidence that: 1) there
exist inherent age-dependent differences in both the airway relaxant
responsiveness to [beta]-adrenoceptor stimulation and muscarinic
functional antagonism of [beta]-adrenergic relaxation; and 2) the
latter are attributed to mechanisms other than ontogenetic alteration
in M2 receptor function or Gi protein expression in maturing rabbit
TSM.
Received 3 February 1995; accepted in final form 6 July 1995.
APS Manuscript Number L38-5.
Article publication pending Am. J. Physiol. (Lung Cell. Mol.
Physiology).
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on 10 August 1995.