Stimulation of beta-adrenoceptors inhibits calcium-dependent potassium-channels in mouse macrophages.
K+ efflux in mouse macrophages exhibited a rate constant (kK) of 0.67 +/- 0.04 (h)-1 (mean +/- SEM of 16 experiments). This was strongly stimulated by increasing concentrations of the Ca2+ ionophore A23187 up to a maximal value of 4.01 +/- 0.25 (h)-1 with an IC50 of 7.6 +/- 1.9 microM (mean +/- SEM of 6 experiments). Similar results were obtained with the Ca2+ ionophore ionomycin. Binding experiments with 3H-dihydroalprenolol revealed a high density of beta-adrenergic receptors (97.5 +/- 5.2 fmol/mg protein) with apparent dissociation constant of 2.03 +/- 0.06 nM. Isoproterenol at a concentration of 10(-6)-10(-5) M induced a two- to threefold stimulation of endogenous levels of cyclic AMP (cAMP). A23187-stimulated K+ efflux was partially inhibited by stimulation of adenylate cyclase with isoproterenol, forskolin or, PGE1; exogenous cAMP; and inhibition of phosphodiesterase with MIX (1-methyl-3-isobutylxanthine). Maximal inhibition of K+ efflux was obtained by simultaneous addition of isoproterenol and MIX. In dose-response curves, the isoproterenol-sensitive K+ efflux was half-maximally inhibited (IC50) with 2-5 X 10(-10) M of isoproterenol concentration. Propranolol was able to completely block the effect of isoproterenol, with an IC50 of about 1-2 X 10(-7) M. Isoproterenol and MIX were also able to partially inhibit ionomycin-stimulated K+ efflux. Isoproterenol and MIX did not inhibit A23187-stimulated K+ efflux in an incubation medium where NaCl was replaced by sucrose (or choline), suggesting the involvement of an Na+:Ca2+ exchange mechanism. Our results show that stimulation of beta-adrenoceptors in mouse macrophages counterbalances the opening of K+ channels induced by the calcium ionophore A23187. This likely reflects a decrease in cytosolic free calcium content via a cAMP-mediated stimulation of Na+:Ca2+ exchange.
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D000001:Calcimycin / Q000494:pharmacology; D002118:Calcium / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism; D004082:Dihydroalprenolol / Q000378:metabolism; D004987:Ethers / Q000494:pharmacology; D005260:Female; D007473:Ion Channels / Q000187:drug effects / Q000378:metabolism*; D015759:Ionomycin; D007545:Isoproterenol / Q000494:pharmacology; D007700:Kinetics; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D011188:Potassium / Q000378:metabolism*; D011433:Propranolol / Q000494:pharmacology; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000502:physiology*
D004987:Ethers; D007473:Ion Channels; D011943:Receptors, Adrenergic, beta; D000001:Calcimycin; D015759:Ionomycin; D004082:Dihydroalprenolol; D011433:Propranolol; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; D007545:Isoproterenol; D011188:Potassium; D002118:Calcium; D015056:1-Methyl-3-isobutylxanthine