Effects of bolorile anesthetics in isolated myocordial beta-adrenergic receptor transmission

本文研究了七氟醚对大鼠心肌细胞膜上由受体、刺激性GTP结合蛋白(Gs)和腺苷环化酶(AC)组成的β-肾上腺素能受体(BetaAR)系统的影响。分别用1-异丙肾上腺素、5-O-(3-硫代三磷酸)鸟苷(GTP-GammaS)和Forsklin刺激cAMP生成。受体研究采用二氢阿普洛尔([~3H]DHA)结合法。在1-心得安存在下，确定非特异性结合。计算了由最大结合位点数(Bmax)和[^3 H]DHA的解离常数(Kd)决定的βAR结合容量。根据1-异丙肾上腺素对[~3H]DHA结合的半最大抑制作用的抑制常数(I_1)来评价激动剂的β-AR亲和力。(1)在0~2.0 mM的七氟醚存在下，[~H]DHA的Kd和KI对1-异丙肾上腺素的Kd呈浓度依赖性增加，而Bmax保持不变。高亲和力状态与肾上腺素受体高、低亲和力状态之比从0.60±0.15降至0.35±0.12。(2)七氟醚浓度为2.0 mM时，1-异丙肾上腺素显著抑制cAMP生成率87.1±4.8%，+-GT抑制79.4%；七氟醚可能通过减少受体与受体的结合，破坏受体与Gs之间的关系，从而抑制β-AR信号转导系统。

The effects of sevoflurane on the beta-adrenoceptor (betaAR) system consisting of the receptor, stimulatory 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 1-isoproterenol, guanosine 5-O- (3-thiotriphoshate) (GTPgammaS) and forskolin, repectively. The receptor studies were carried out by using the dihydroalprenolol ( [^3H] DHA) binding method. Non-specific binding was determined in the presence of 1-propranolol. betaAR binding capacity determined by the maximal number of binding sites (Bmax) and the dissociation constant (Kd) for [^3H] DHA were calculated. betaAR affinity for agonists was assessed by an inhibition constant (Ki) , which was calculated from the concentration of 1-isoproterenol to produce half-maximal inhibition of [^3H] DHA binding (IC_<50>).(1) In the presence of 0-2.0mM sevoflurane, Kd for [^3H] DHA and Ki for 1-isoproterenol increased in a concentration-dependent manner, while Bmax remained unchanged. The ratio of high affinity state against the high and low affinity state of the adrenoceptor decreased significantly from 0.60 <plus-minus> 0.15 to 0.35 <plus-minus> 0.12.(2) At 2.0 mM sevoflurane concentration, cAMP production rate was significantly depressed by 87.1 <plus-minus> 4.8% with 1-isoproterenol and by 79.4 <plus-minus> 7.0% with GTPgammaS,but not significantly depressed by forskoWe conclude that sevoflurane might depress the betaAR signal transduction system by reducing ligand-receptor bindings and disrupting the relationship between the receptor and Gs.