Modulatory effect of the adrenergic system upon fibroblast proliferation: participation of beta 3-adrenoceptors.
1. The beta3-adrenoceptor agonist ZD 7114, like the non-selective beta-adrenoceptor agonist isoprenaline, but unlike the beta1-adrenoceptor agonist dobutamine and the beta2-adrenoceptor agonist salbutamol, produced an increment on mouse embryonic fibroblast proliferation. The half-maximal stimulation of cell growth occurred at substantially lower concentrations with the beta3-adrenoceptor agonist (EC50: 5.5 x 10(-8) m) than with isoprenaline (EC50: 1.25 x 10(-6) m). 2. The selective beta3-adrenoceptor antagonist SR 5923 OA prevented the beta3-stimulated fibroblast proliferation. Conversely, practolol and butoxamine did not prevent fibroblast growth. 3. Additionally, a decrease of cAMP was obtained in fibroblasts cells upon stimulation with isoprenaline and ZD 7114. 4. The expression of beta-adrenoreceptors on fibroblast cells was also studied by radioligand binding. The Ki values in the presence of beta1- and beta2-adrenoceptor antagonist was two-fold higher than the Ki values for beta3 adrenoceptor antagonist indicating the presence of A3-receptor subtype. 5. Inhibitors of different intracellular coupling pathways including phospholipase C (U 73122), protein kinase C (staurosporine), calcium/calmodulin (trifluoroperazine) and calcium channel (verapamil), prevented the stimulatory actions of the selective beta3-adrenoceptor agonist ZD 7114. 6. The presence of beta3-adrenoceptors on embryonic mouse fibroblast cells may play a role in the modulation of cell growth and biologic activity. The mechanism by which ZD 7114 triggers cell proliferation and function, involves the activation of phospholipase C, PKC, calcium/calmodulin and the influx of calcium.
Anesini
C
C
Pharmacology Unit, School of Dentistry, University of Buenos Aires, Marcelo T de Alvear 2142 (1122), Capitol Federal Buenos Aires, Argentina.
Borda
E
E
D000322:Adrenergic Agonists / Q000378:metabolism / Q000494:pharmacology; D018674:Adrenergic Antagonists / Q000378:metabolism / Q000494:pharmacology; D058667:Adrenergic beta-3 Receptor Agonists; D058673:Adrenergic beta-3 Receptor Antagonists; D000818:Animals; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D005347:Fibroblasts / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D022702:Receptors, Adrenergic, beta-3 / Q000378:metabolism*
D000322:Adrenergic Agonists; D018674:Adrenergic Antagonists; D058667:Adrenergic beta-3 Receptor Agonists; D058673:Adrenergic beta-3 Receptor Antagonists; D022702:Receptors, Adrenergic, beta-3; D000242:Cyclic AMP