Role of protein kinase C in nonsensitized and passively sensitized human isolated bronchial smooth muscle.
To examine the role of protein kinase C (PKC) activation in the control of the mechanical activity of human isolated bronchial smooth muscle obtained at thoracotomy, the effect of the phorbol ester phorbol 12,13-dibutyrate (PDB) was evaluated. PDB produced slowly developing and sustained contractions that were reduced 1) by the PKC inhibitor staurosporine and 2) after long-term (12 h) exposure to PDB, which downregulates PKC. Moreover, the inactive phorbol ester 4 alpha-phorbol 12,13 didecanoate had no contractile effect. Removal of external Ca2+ or addition of the Ca(2+)-channel antagonist verapamil reduced the PDB-induced contraction. Passive sensitization of human isolated bronchial rings, i.e., incubation overnight of tissues in serum from atopic asthmatic patients, decreased the maximal response to PDB to 28.9 +/- 8% of the maximal response to acetylcholine (ACh) when compared with that of paired nonsensitized rings, i.e., tissues incubated overnight in serum from normal subjects (46.7 +/- 9.4% of the maximal response to ACh, n = 5, P < 0.05). The decrease in the response to PDB induced by either long-term preexposure to PDB or passive sensitization was reversed when both types of tissues were allowed to recover unstimulated for 3 h before PDB application. These results show that 1) PKC activation induces maintained contractions in human isolated airway smooth muscle that are largely dependent on extracellular calcium; 2) passive sensitization alters the PKC-mediated response in a way similar to that induced by prolonged stimulation of PKC.
Rossetti
M
M
Laboratoire de Physiologie, Université de Bordeaux II, France.
Savineau
J P
JP
Crevel
H
H
Marthan
R
R
D000470:Alkaloids / Q000494:pharmacology*; D000485:Allergens; D001249:Asthma / Q000503:physiopathology*; D001980:Bronchi / Q000187:drug effects / Q000502:physiology* / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D006801:Humans; D007116:Immunization, Passive; D066298:In Vitro Techniques; D009119:Muscle Contraction / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology* / Q000503:physiopathology; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology*; D010703:Phorbol Esters / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019311:Staurosporine; D013997:Time Factors; D014700:Verapamil / Q000494:pharmacology
D000470:Alkaloids; D000485:Allergens; D010703:Phorbol Esters; C008876:phorbol-12,13-didecanoate; D015240:Phorbol 12,13-Dibutyrate; D014700:Verapamil; D011493:Protein Kinase C; D019311:Staurosporine