Molderings G J, Likungu J, Göthert M
Institut für Pharmakologie and Toxikologie, Rheinische Friedrich-Wilhelms-Universität Bonn, Germany.
Naunyn Schmiedebergs Arch Pharmacol. 1999 Aug;360(2):157-64. doi: 10.1007/s002109900043.
Segments of human right atrial appendages preincubated with [3H]noradrenaline and superfused with physiological salt solution containing desipramine and corticosterone were used to examine whether the cardiac sympathetic nerves are endowed with cannabinoid receptors and to further study pharmacological properties of presynaptic imidazoline receptors. The cannabinoid CB1 receptor agonists CP55,940, HU210 and anandamide inhibited evoked [3H]noradrenaline release. The inhibition by CP55,940 and anandamide was abolished by the CB1 receptor antagonists SR141716A (1 microM) and LY320135 (1 microM). Rauwolscine at the imidazoline receptor-blocking concentration of 30 microM abolished the inhibitory effect of CP55,940 and anandamide. After blockade of alpha2-adrenoceptors with 1 microM rauwolscine, the imidazoline binding site ligand S23230, which is the (-)-enantiomer of the racemic oxazoline derivative S22687, exhibited low potency in inhibiting electrically evoked [3H]noradrenaline release (pIC30%=4.96), whereas the (+)-enantiomer S23229 and the racemate S22687 were ineffective. In the presence of 30 microM rauwolscine, S23230 did not significantly inhibit evoked release. The imidazoline receptor-mediated inhibitory effect of BDF 6143 and aganodine on evoked [3H]noradrenaline release was abolished by 1 microM SR141716A and by 1 microM LY320135. The inhibitory effect of moxonidine on evoked [3H]noradrenaline release, which is exclusively mediated via activation of alpha2-autoreceptors, was not antagonized by 1 microM SR141716A. In conclusion, inhibitory cannabinoid CB1 receptors are present on the sympathetic axon terminals of human atrial appendages. Presynaptic imidazoline receptors share the property of other receptors in that they can be stereoselectively activated. The cross-antagonism of imidazoline receptor agonists/antagonists with CB1 receptor antagonists/agonists suggests that these receptors may have certain binding domains in common or that they interact with each other in an unknown manner.
将预先用[3H]去甲肾上腺素孵育并灌注含有地昔帕明和皮质酮的生理盐溶液的人右心耳片段用于研究心脏交感神经是否具有大麻素受体，并进一步研究突触前咪唑啉受体的药理学特性。大麻素CB1受体激动剂CP55,940、HU210和花生四烯乙醇胺抑制诱发的[3H]去甲肾上腺素释放。CB1受体拮抗剂SR141716A（1 microM）和LY320135（1 microM）消除了CP55,940和花生四烯乙醇胺的抑制作用。咪唑啉受体阻断浓度为30 microM的利血平消除了CP55,940和花生四烯乙醇胺的抑制作用。在用1 microM利血平阻断α2-肾上腺素能受体后，咪唑啉结合位点配体S23230（外消旋恶唑啉衍生物S22687的（-）-对映体）在抑制电诱发的[3H]去甲肾上腺素释放方面效力较低（pIC30% = 4.96），而（+）-对映体S23229和外消旋体S22687无效。在存在30 microM利血平的情况下，S23230并未显著抑制诱发释放。BDF 6143和阿加诺定对诱发的[3H]去甲肾上腺素释放的咪唑啉受体介导的抑制作用被1 microM SR141716A和1 microM LY320135消除。莫索尼定对诱发的[3H]去甲肾上腺素释放的抑制作用（仅通过α2-自身受体的激活介导）未被1 microM SR141716A拮抗。总之，抑制性大麻素CB1受体存在于人心耳的交感神经轴突末端。突触前咪唑啉受体具有其他受体的特性，即它们可以被立体选择性激活。咪唑啉受体激动剂/拮抗剂与CB1受体拮抗剂/激动剂的交叉拮抗作用表明，这些受体可能具有某些共同的结合域，或者它们以未知方式相互作用。
