Fuder H, Bath F, Wiebelt H, Muscholl E
Naunyn Schmiedebergs Arch Pharmacol. 1984 Jan;325(1):25-33. doi: 10.1007/BF00507050.
Rat isolated perfused hearts with the right sympathetic nerves intact were loaded with 3H-(-)-noradrenaline. The nerves were stimulated with trains of 180 pulses at 3 Hz and at 10 min intervals. The overflow of 3H-noradrenaline and 3H-metabolites was determined by liquid scintillation spectrometry. Clonidine (IC50 17 nM), oxymetazoline (IC50 63 nM), and alpha-methylnoradrenaline (apparent IC50 35 nM, determined in the presence of cocaine and propranolol) decreased the stimulation-evoked overflow of 3H-noradrenaline by 26, 49, and 78%, respectively, but not methoxamine up to 100 microM (propranolol present). Oxymetazoline and alpha-methyl-noradrenaline did not cause desensitization of the presynaptic adrenoceptors when present at their IC80 for 33 min. At a perfusion rate of 7 ml/min, yohimbine 1 microM enhanced the stimulation-evoked 3H-noradrenaline overflow by 26% in the absence, and by 58% in the presence of cocaine. Phentolamine 1 microM increased it by 69% when the neuronal reuptake was blocked. The increase by the antagonists faded with successive period of nerve stimulations, and was positively correlated with the biophase concentration of noradrenaline as reflected by the amount of 3H-noradrenaline released into the perfusate per nerve stimulation. At a perfusion rate of 1.8 ml/min (neuronal reuptake blocked), yohimbine 1 microM increased the overflow by 127%. The results indicate that the alpha 2-adrenoceptor-mediated autoinhibition in the rat perfused heart depends on the clearance of transmitter from the biophase via neuronal reuptake and diffusion into the vascular space. Reduction of either elimination pathway enhances the biophase concentration of noradrenaline, thus increasing the autoinhibition of release.
将右交感神经完整的大鼠离体灌注心脏用3H-（-）-去甲肾上腺素进行负载。以3Hz的频率每隔10分钟施加180个脉冲的串刺激神经。通过液体闪烁光谱法测定3H-去甲肾上腺素和3H-代谢产物的溢出量。可乐定（IC50为17 nM）、奥昔麻黄碱（IC50为63 nM）和α-甲基去甲肾上腺素（在可卡因和普萘洛尔存在的情况下测定的表观IC50为35 nM）分别使刺激诱发的3H-去甲肾上腺素溢出量降低26%、49%和78%，但高达100μM的美托咪啶（存在普萘洛尔）则没有此作用。奥昔麻黄碱和α-甲基去甲肾上腺素在其IC80浓度下存在33分钟时，不会引起突触前肾上腺素能受体脱敏。在灌注速率为7ml/min时，1μM育亨宾在不存在可卡因时使刺激诱发的3H-去甲肾上腺素溢出量增加26%，在存在可卡因时增加58%。当神经元再摄取被阻断时，1μM酚妥拉明使其增加69%。拮抗剂引起的增加随着神经刺激的连续周期而消退，并且与去甲肾上腺素的双相浓度呈正相关，这可通过每次神经刺激释放到灌注液中的3H-去甲肾上腺素的量来反映。在灌注速率为1.8ml/min（神经元再摄取被阻断）时，1μM育亨宾使溢出量增加127%。结果表明，大鼠灌注心脏中α2-肾上腺素能受体介导的自身抑制取决于递质通过神经元再摄取和扩散进入血管空间而从双相中的清除。任何一种消除途径的减少都会增加去甲肾上腺素的双相浓度，从而增强释放的自身抑制。
