Abstract
The effects of sevoflurane on the beta-adrenoceptor (beta AR) system, consisting of the receptor, stimulatory guanosine triphosphate (GTP) binding protein (Gs), and adenylate cyclase (AC), were studied in rat myocardial membrane. Cyclic adenosine monophosphate (cAMP) production rate was measured as cAMP generation stimulated by l-isoproterenol, guanosine 5"-O-(3-thiotriphosphate) (GTP gamma S), and forskolin, respectively. The receptor studies were performed by using the dihydroalprenolol ([3H]DHA) binding method. Nonspecific binding was determined in the presence of l-propranolol. beta AR binding capacity determined by the maximum number of binding sites (Bmax) and the dissociation constant (Kd) for [3H]DHA were calculated. beta AR affinity for agonists was assessed by an inhibition constant (Ki), calculated from the concentration of l-isoproterenol to produce half-maximum inhibition of [3H]DHA binding (IC50). At 2.0 mM sevoflurane, cAMP production rate was significantly depressed by 87.1% +/- 4.8% with l-isoproterenol and by 79.4% +/- 7.0% with GTP gamma S, but not significantly depressed by forskolin. In the presence of 0-2.0 mM sevoflurane, Kd for [3H]DHA and Ki for l-isoproterenol increased in a concentration-dependent manner, whereas Bmax remained unchanged. The ratio of high affinity state against the high and low affinity state of the adrenoceptor decreased significantly from 0.60 +/- 0.15 to 0.35 +/- 0.12. We conclude that sevoflurane might depress the beta AR signal transduction system by reducing ligand-receptor bindings and disrupting the relationship between the receptor and Gs.
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