Muscarinic excitation-contraction coupling mechanisms in tracheal and bronchial smooth muscles.
We investigated the mechanisms underlying muscarinic excitation-contraction coupling in canine airway smooth muscle using organ bath, fura 2 fluorimetric, and patch-clamp techniques. Cyclopiazonic acid (CPA) augmented the responses to submaximal muscarinic stimulation in both tracheal (TSM) and bronchial smooth muscles (BSM), consistent with disruption of the barrier function of the sarcoplasmic reticulum. During maximal stimulation, however, CPA evoked substantial relaxation in TSM but not BSM. CPA reversal of carbachol tone persisted in the presence of tetraethylammoium or high KCl, suggesting that hyperpolarization is not involved; CPA relaxations were absent in tissues preconstricted with KCl alone or by permeabilization with beta-escin, ruling out a nonspecific effect on the contractile apparatus. Peak contractions were sensitive to inhibitors of tyrosine kinase (genistein) or Rho kinase (Y-27632). Sustained responses were dependent on Ca(2+) influx in TSM but not BSM; this influx was sensitive to Ni(2+) but not La(3+). In conclusion, there are several mechanisms underlying excitation-contraction coupling in airway smooth muscle, the relative importance of which varies depending on tissue and degree of stimulation.
Janssen
L J
LJ
Asthma Research Group, Firestone Institute for Respiratory Health, St. Joseph's Hospital, Hamilton, Ontario, Canada L8N 4A. janssenl@mcmaster.ca
Wattie
J
J
Lu-Chao
H
H
Tazzeo
T
T
D000818:Animals; D001980:Bronchi / Q000502:physiology*; D016535:Bronchial Hyperreactivity / Q000503:physiopathology; D002118:Calcium / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000037:antagonists & inhibitors / Q000378:metabolism; D002217:Carbachol / Q000494:pharmacology; D002712:Chlorides / Q000378:metabolism; D018679:Cholinergic Agonists / Q000494:pharmacology; D004285:Dogs; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019833:Genistein / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology*; D009126:Muscle Relaxation / Q000187:drug effects / Q000502:physiology; D009130:Muscle, Smooth / Q000502:physiology*; D018408:Patch-Clamp Techniques; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011976:Receptors, Muscarinic / Q000502:physiology*; D012519:Sarcoplasmic Reticulum / Q000201:enzymology; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D014132:Trachea / Q000502:physiology*; D054460:rho-Associated Kinases
D002118:Calcium; D000252:Calcium-Transporting ATPases; D002217:Carbachol; D002712:Chlorides; D018679:Cholinergic Agonists; D004791:Enzyme Inhibitors; D019833:Genistein; D007211:Indoles; D047908:Intracellular Signaling Peptides and Proteins; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011976:Receptors, Muscarinic; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D054460:rho-Associated Kinases; C000543:cyclopiazonic acid