Effects of local anesthetics of guanyl nucleotide modulation of the catecholamine-sensitive adenylate cyclase system and on β-adrenergic receptors |
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Authors: | Vladimir L Voeikov Robert J Lefkowitz |
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Institution: | Howard Hughes Medical Institute Laboratory, Departments of Medicine and Biochemistry, Duke University Medical Center, Durham, NC 27710, U.S.A. |
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Abstract: | Tetracaine and other local anesthetics exert multiple actions on the catecholamine-sensitive adenylate cyclase system of frog erythrocyte membranes. Tetracaine (0.2–2.0 mM) reduces the responsiveness of adenylate cyclose to (a) guanyl-5′-yl-imidodiphosphate and (b) isoproterenol in the presence of GTP or guanyl-5′-yl-imidodiphosphate. Local anesthetics did not affect (a) basal enzyme activity, and (b) enzyme responsiveness to NaF. Tetracaine inhibited stimulation of adenylate cyclase by guanyl-5′-yl-imidodiphosphate over the whole range of nucleotide concentrations. By contrast, inhibition by tetracaine of isoproterenol activity in the presence of GTP was significant only if GTP concentrations exceeded 10?7 M.Tetracaine also competitively inhibited binding of both the antagonist 3H]-dihydroalprenolol and the agonist 3H]hydroxybenzylisoproterenol to β-adrenergic receptors. However, it was twice as potent in inhibiting 3H]-hydroxybenzylisoproterenol as 3H]dihydroalprenolol binding. The greater potency for inhibition of agonist binding was due to the ability of the anesthetics to promote dissociation of the high-affinity nucleotide sensitive state of the β-adrenergic receptor induced by agonists.Other local anesthetics mimicked the effects of tetracaine on adenylate |
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Keywords: | Anesthetic Guanyl nucleotide Catecholamine Adenylate cyclase β-Adrenergic receptor Gpp(NH)p guanyl-5′-yl-imidodiphosphate cyclic AMP cyclic adenosine 3′ 5′-monophosphate |
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