Protein kinase C induced changes in human airway smooth muscle tone: the effects of Ca2+ and Na+ transport.
Activation of protein kinase C by phorbol 12,13-dibutyrate (PDB) (1 nM-3 microM) caused a concentration-dependent contractile response in human isolated bronchus. The mean maximal contraction was 26 +/- 4.4% (n = 11) of that induced by acetylcholine (1 mM). The contraction was increased by the presence of the Ca2+ ionophore (A23187) to 47 +/- 6% (n = 7, P < 0.05) by the Ca2+ channel agonist, Bay K 8644 to 59.5 +/- 4.5% (n = 4, P < 0.05) and by KCl to 47.4 +/- 6%, while it was unaffected by carbachol (28.7 +/- 6.8%, n = 4, P > 0.05). The Ca2+ channel antagonist, verapamil (1 microM) significantly reduced the contraction from 32.3 +/- 4.9 to 12.5 +/- 1% (n = 4, P < 0.05) and in the presence of nifedipine (1 microM), the contractile response was abolished. A single concentration of 10 microM PDB produced a biphasic response-relaxation (6 +/- 1%) followed by contraction (76 +/- 4%, n = 4) which was greater than that produced when responses were obtained cumulatively. The relaxation response was inhibited by the addition of a Na-/K+ exchange antagonist, ouabain (10 microM) which also markedly potentiated the contractile response to 110 +/- 10% (n = 4, P < 0.05). These results suggest that the protein kinase C-mediated contraction in human airway smooth muscle is dependent on extracellular Ca2+ influx. Protein kinase C may also phosphorylate Na+/K(+)-ATPase resulting in a relaxation response.
Yang
K X
KX
Department of Pharmacology, University of Sydney, NSW, Australia.
Black
J L
JL
D000584:Amiloride / Q000494:pharmacology; D001980:Bronchi / Q000187:drug effects* / Q000502:physiology; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects* / Q000502:physiology; D009543:Nifedipine / Q000494:pharmacology; D010042:Ouabain / Q000494:pharmacology; D015240:Phorbol 12,13-Dibutyrate / Q000008:administration & dosage; D011493:Protein Kinase C / Q000378:metabolism*; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors*; D014700:Verapamil / Q000494:pharmacology
D002121:Calcium Channel Blockers; D015240:Phorbol 12,13-Dibutyrate; D010042:Ouabain; D000584:Amiloride; D014700:Verapamil; D011493:Protein Kinase C; D000254:Sodium-Potassium-Exchanging ATPase; D009543:Nifedipine