cGMP modulation of Ca2+ sensitivity in airway smooth muscle.
A beta-escin-permeabilized canine tracheal smooth muscle preparation was used to test the hypothesis that cGMP decreases Ca2+ sensitivity in airway smooth muscle primarily by inhibiting the membrane receptor-coupled mechanisms that regulate Ca2+ sensitivity and not by inhibiting Ca2+/calmodulin activation of the contractile proteins. 8-Bromo-cGMP (100 microM) had no effect on the free Ca2+ concentration-response curves generated in the absence of muscarinic receptor stimulation. In the presence of 100 microM ACh plus 10 microM GTP, 8-bromo-cGMP (100 microM) caused a rightward shift of the free Ca2+ concentration-response curve, significantly increasing the EC50 for free Ca2+ from 0.35 +/- 0.03 to 0.75 +/- 0.06 microM; this effect of 8-bromo-cGMP was concentration dependent from 1 to 100 microM. 8-Bromo-cGMP (100 microM) decreased the level of regulatory myosin light chain (rMLC) phosphorylation for a given cytosolic Ca2+ concentration but had no effect on the amount of isometric force produced for a given level of rMLC phosphorylation. These findings suggest that cGMP decreases Ca2+ sensitivity in canine tracheal smooth muscle primarily by inhibiting the membrane receptor-coupled mechanisms that modulate the relationship between cytosolic Ca2+ concentration and rMLC phosphorylation.
Jones
K A
KA
Departments of Anesthesiology and Physiology and Biophysics, Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55905, USA.
Wong
G Y
GY
Jankowski
C J
CJ
Akao
M
M
Warner
D O
DO
D000818:Animals; D002118:Calcium / Q000502:physiology*; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000494:pharmacology / Q000502:physiology*; D004285:Dogs; D005260:Female; D066298:In Vitro Techniques; D007537:Isometric Contraction / Q000187:drug effects; D008297:Male; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology*; D018994:Myosin Light Chains / Q000378:metabolism; D009994:Osmolar Concentration; D010766:Phosphorylation / Q000187:drug effects; D011976:Receptors, Muscarinic / Q000502:physiology; D013268:Stimulation, Chemical; D014132:Trachea / Q000187:drug effects / Q000502:physiology*
D018994:Myosin Light Chains; D011976:Receptors, Muscarinic; C016276:8-bromocyclic GMP; D006152:Cyclic GMP; D002118:Calcium