Potentiation of beta-adrenoceptor function in bovine tracheal smooth muscle by inhibition of protein kinase C.
To examine the role of contractile agonist-induced activation of protein kinase C (PKC) in functional antagonism of airway smooth muscle contraction by beta-adrenoceptor agonists, we examined the effects of the specific PKC-inhibitor GF 109203X (2-[1-(3-dimethylaminopropyl)-1H-indol-3-yl]-3-(1H-indol-3-yl) maleimide) on isoprenaline-induced relaxation of bovine tracheal smooth muscle contracted by various concentrations of methacholine and histamine. In the absence of GF 109203X, the potency of isoprenaline (pD(2)) was gradually reduced at increasing methacholine- and histamine-induced smooth muscle tones, but the maximal relaxation (E(max)) was decreased only at higher concentrations of methacholine. In the presence of GF 109203X, pD(2) values were significantly increased for both methacholine- and histamine-induced contractions. Moreover, isoprenaline E(max) values in the presence of high concentrations of methacholine were also increased. Although both methacholine- and histamine-induced contractions were slightly reduced by GF 109203X, the changes in isoprenaline pD(2) could only partially be explained by reduced contractile tone. In contrast to isoprenaline, forskolin-induced relaxations were not affected by GF 109203X. The results indicate that PKC activation contributes to the reduced beta-adrenergic responsiveness induced by methacholine and histamine, which may involve uncoupling of the beta-adrenoceptor from the effector system. Since many mediators and neurotransmitters in allergic airway inflammation can activate PKC, this cross talk may be important in the reduced bronchodilator response of patients with severe asthma.
Boterman
Mark
M
Department of Molecular Pharmacology, University Centre for Pharmacy, A. Deusinglaan 1, 9713 AV Groningen, The Netherlands. M.Boterman@rug.nl
Elzinga
Carolina R S
CR
Wagemakers
David
D
Eppens
Pauline B
PB
Zaagsma
Johan
J
Meurs
Herman
H
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D002417:Cattle; D005576:Colforsin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006632:Histamine / Q000494:pharmacology; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology*; D007545:Isoproterenol / Q000494:pharmacology; D008301:Maleimides / Q000494:pharmacology*; D016210:Methacholine Chloride / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects*; D009126:Muscle Relaxation / Q000187:drug effects; D009130:Muscle, Smooth / Q000502:physiology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011943:Receptors, Adrenergic, beta / Q000502:physiology*; D014132:Trachea / Q000502:physiology
D000318:Adrenergic beta-Agonists; D004791:Enzyme Inhibitors; D007211:Indoles; D008301:Maleimides; D011943:Receptors, Adrenergic, beta; D016210:Methacholine Chloride; D005576:Colforsin; D006632:Histamine; D011493:Protein Kinase C; D007545:Isoproterenol; C070515:bisindolylmaleimide I