Donoso M Verónica, Aedo Felipe, Huidobro-Toro J Pablo
Centro de Regulación Celular y Patología Prof J.V. Luco, Departamento de Fisiología, Unidad de Regulación Neurohumoral, P. Universidad Católica de Chile, Santiago, Chile.
J Neurochem. 2006 Mar;96(6):1680-95. doi: 10.1111/j.1471-4159.2006.03671.x.
The pre-synaptic sympathetic modulator role of adenosine was assessed by studying transmitter release following electrical depolarization of nerve endings from the rat mesenteric artery. Mesentery perfusion with exogenous adenosine exclusively inhibited the release of norepinephrine (NA) but did not affect the overflow of neuropeptide Y (NPY), establishing the basis for a differential pre-synaptic modulator mechanism. Several adenosine structural analogs mimicked adenosine's effect on NA release and their relative order of potency was: 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine hydrochloride = 1-[2-chloro-6-[[(3-iodophenyl)methyl]amino]-9H-purin-9-yl]-1-deoxy-N-methyl-beta-d-ribofuranuronamide = 5'-(N-ethylcarboxamido)adenosine >> adenosine > N(6)-cyclopentyladenosine. The use of selective receptor subtype antagonists confirmed the involvement of A(2A) and A(3) adenosine receptors. The modulator role of adenosine is probably due to the activation of both receptors; co-application of 1 nM 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine hydrochloride plus 1 nM 1-[2-chloro-6-[[(3-iodophenyl)methyl]amino]-9H-purin-9-yl]-1-deoxy-N-methyl-beta-D-ribofuranuronamide caused additive reductions in NA released. Furthermore, while 1 nM of an A(2A) or A(3) receptor antagonist only partially reduced the inhibitory action of adenosine, the combined co-application of the two antagonists fully blocked the adenosine-induced inhibition. Only the simultaneous blockade of the adenosine A(2A) plus A(3) receptors with selective antagonists elicited a significant increase in NA overflow. H 89 reduced the release of both NA and NPY. We conclude that pre-synaptic A(2A) and A(3) adenosine receptor activation modulates sympathetic co-transmission by exclusively inhibiting the release of NA without affecting immunoreactive (ir)-NPY and we suggest separate mechanisms for vesicular release modulation.
通过研究大鼠肠系膜动脉神经末梢电去极化后的递质释放，评估了腺苷的突触前交感神经调节作用。用外源性腺苷灌注肠系膜仅抑制去甲肾上腺素（NA）的释放，但不影响神经肽Y（NPY）的溢出，从而建立了一种差异性突触前调节机制的基础。几种腺苷结构类似物模拟了腺苷对NA释放的作用，其相对效价顺序为：2-p-（2-羧乙基）苯乙氨基-5'-N-乙基羧酰胺基腺苷盐酸盐 = 1-[2-氯-6-[[（3-碘苯基）甲基]氨基]-9H-嘌呤-9-基]-1-脱氧-N-甲基-β-D-呋喃核糖酰胺 = 5'-（N-乙基羧酰胺基）腺苷 >> 腺苷 > N（6）-环戊基腺苷。使用选择性受体亚型拮抗剂证实了A（2A）和A（3）腺苷受体的参与。腺苷的调节作用可能是由于两种受体的激活；共同应用1 nM 2-p-（2-羧乙基）苯乙氨基-5'-N-乙基羧酰胺基腺苷盐酸盐加1 nM 1-[2-氯-6-[[（3-碘苯基）甲基]氨基]-9H-嘌呤-9-基]-1-脱氧-N-甲基-β-D-呋喃核糖酰胺导致释放的NA额外减少。此外，虽然1 nM的A（2A）或A（3）受体拮抗剂仅部分降低了腺苷的抑制作用，但两种拮抗剂的联合共同应用完全阻断了腺苷诱导的抑制。只有用选择性拮抗剂同时阻断腺苷A（2A）加A（3）受体才会引起NA溢出的显著增加。H-89降低了NA和NPY两者的释放。我们得出结论，突触前A（2A）和A（3）腺苷受体激活通过仅抑制NA的释放而不影响免疫反应性（ir）-NPY来调节交感神经共同传递，并且我们提出了囊泡释放调节的不同机制。
