Mechanism of protein kinase C potentiation of airway beta-adrenergic relaxation.
To evaluate the regulatory action of protein kinase C (PKC) on airway beta-adrenergic function, the relaxant effects of isoproterenol (ISO) and 8 bromo-cyclic AMP (BrcAMP) were examined in tracheal smooth muscle (TSM) segments half-maximally contracted with acetylcholine in the absence (control) and presence of PKC activation with the phorbol ester, 12-deoxyphorbol 13-isobutyrate (DPB). Relative to control tissues, TSM treated with 0.1 microM DPB depicted significantly enhanced maximal relaxation and sensitivity to ISO but not to BrcAMP. The enhancing effect of DPB on ISO responsiveness was completely inhibited in the presence of the PKC antagonist H-7. Inhibition of the Na(+)-K+ pump with either ouabain or K(+)-free buffer diminished the TSM relaxant response to ISO but not to BrcAMP. Inhibition of the Na(+)-K+ pump also ablated the DPB-induced potentiation of beta-adrenoceptor responsiveness. Collectively, these data demonstrate that: 1) PKC activation enhances TSM relaxant responsiveness to beta-adrenoceptor stimulation; 2) inhibition of the airway Na(+)-K+ pump markedly blunts the relaxant response to beta-adrenoceptor stimulation; and 3) inhibition of the Na(+)-K+ pump abolishes the above potentiating effect of DPB on beta-adrenoceptor-mediated relaxation of rabbit TSM. Thus, the above findings provide new evidence that PKC activation enhances the airway relaxant response to beta-adrenoceptor stimulation, and that the latter effect is dependent on potentiated stimulation of the airway electrogenic Na(+)-K+ pump.
Schramm
C M
CM
Pediatric Pulmonary Division, Univ. of Connecticut School of Medicine, Farmington 06030, USA.
Grunstein
M M
MM
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D046508:Culture Techniques; D004789:Enzyme Activation; D007545:Isoproterenol / Q000494:pharmacology; D009126:Muscle Relaxation / Q000502:physiology*; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology*; D010703:Phorbol Esters / Q000494:pharmacology; D011493:Protein Kinase C / Q000502:physiology*; D011817:Rabbits; D011943:Receptors, Adrenergic, beta / Q000502:physiology*; D000254:Sodium-Potassium-Exchanging ATPase / Q000494:pharmacology; D014132:Trachea
D010703:Phorbol Esters; D011943:Receptors, Adrenergic, beta; D015124:8-Bromo Cyclic Adenosine Monophosphate; C039067:12-deoxyphorbol 13-isobutyrate; D011493:Protein Kinase C; D000254:Sodium-Potassium-Exchanging ATPase; D007545:Isoproterenol