title: Inhibition of hepatic alpha 1-adrenergic effects and binding by phorbol myristate acetate.
abstract: Treatment of isolated hepatocytes with the tumor-promoting agent, 4 beta-phorbol 12 beta-myristate 13 alpha-acetate (PMA) produced a time- and dose-dependent, non-competitive inhibition of alpha 1-adrenergic responses, including the activation of phosphorylase, increase in Ca2+ efflux, increase in free cytosolic Ca2+, and release of myo-inositol-1,4,5-P3. The actions of [8-arginine] vasopressin (AVP) on liver cells were also inhibited by PMA, but the inhibition could be overcome by high AVP concentrations. No significant inhibition of beta-adrenergic and glucagon-mediated activation of phosphorylase was induced by PMA and no inhibitory or synergistic effects of PMA were observed on the dose-dependent activation of phosphorylase by the Ca2+ ionophore A23187. In radioligand binding studies, PMA did not directly interfere with [3H]prazosin specific binding, the displacement of [3H]prazosin by (-)-norepinephrine nor with [3H]AVP specific binding to purified liver plasma membranes. Plasma membranes prepared from livers perfused with PMA exhibited a 30-44% reduction in [3H]prazosin binding capacity. Under identical conditions [3H]AVP binding was unchanged. The alpha 1-receptors remaining in membranes from PMA-treated livers had equivalent affinities for [3H]prazosin and (-)-norepinephrine, and were unaffected in terms of coupling to guanine nucleotide-regulating proteins as indicated by the ability of guanosine 5'-(beta, gamma-imido)triphosphate to promote the conversion of the remaining alpha 1-receptors into a low affinity state. These data indicate that tumor promoters are potent antagonists of alpha 1-adrenergic and vasopressin (low dose) responses in liver. It is proposed that PMA acting via protein kinase C (which presumably mediates the action of PMA) exerts its inhibitory action on alpha 1-adrenergic responses at the alpha 1-adrenergic receptor itself and also at a site close to or before myo-inositol-1,4,5-P3 release.
authors.forename: C J
authors.initials: CJ
authors.lastname: Lynch
authors.forename: R
authors.initials: R
authors.lastname: Charest
authors.forename: S B
authors.initials: SB
authors.lastname: Bocckino
authors.forename: J H
authors.initials: JH
authors.lastname: Exton
authors.forename: P F
authors.initials: PF
authors.lastname: Blackmore
mesh_terms: D000818:Animals; D000001:Calcimycin / Q000494:pharmacology; D002118:Calcium / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004837:Epinephrine / Q000494:pharmacology; D005934:Glucagon / Q000494:pharmacology; D015544:Inositol 1,4,5-Trisphosphate; D007295:Inositol Phosphates / Q000378:metabolism; D008099:Liver / Q000187:drug effects*; D010646:Phentolamine / Q000494:pharmacology; D010704:Phorbols / Q000494:pharmacology*; D010762:Phosphorylase a / Q000378:metabolism; D011433:Propranolol / Q000494:pharmacology; D011493:Protein Kinase C; D011494:Protein Kinases / Q000378:metabolism; D051381:Rats; D011942:Receptors, Adrenergic, alpha / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D013997:Time Factors; D014667:Vasopressins / Q000494:pharmacology
chemical_list: D007295:Inositol Phosphates; D010704:Phorbols; D011942:Receptors, Adrenergic, alpha; D014667:Vasopressins; D000001:Calcimycin; D015544:Inositol 1,4,5-Trisphosphate; D005934:Glucagon; D011433:Propranolol; D000242:Cyclic AMP; D010762:Phosphorylase a; D011494:Protein Kinases; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium; D004837:Epinephrine; D010646:Phentolamine