Burgdorf C, Richardt D, Kurz T, Seyfarth M, Jain D, Katus H A, Richardt G
Medizinische Klinik II, Universitätsklinikum Lübeck, Ratzeburger Allee 160, 23538, Lubeck, Germany.
Cardiovasc Res. 2001 Mar;49(4):713-20. doi: 10.1016/s0008-6363(00)00309-6.
Numerous studies support the concept of impaired postischemic sympathetic neurotransmission in the heart. We hypothesized that postischemic neuronal dysfunction (neuronal stunning) is caused by a transient suppression of exocytotic norepinephrine (NE) release from sympathetic nerve terminals. Furthermore, we assessed the role of presynaptic adenosine-receptors and alpha2-adrenoceptors in neuronal stunning.
Exocytotic NE release was induced by two electrical field stimulations (S(1) and S(2)) in isolated perfused rat hearts. S(1) was performed under baseline conditions and S(2) either during or following intervention. Results are expressed as mean S(2)/S(1) ratios+/-S.E.M. Stepwise increase of global ischemic periods (10, 20, and 30 min) induced a progressive suppression of NE release in the postischemic hearts, which was reversible during reperfusion. Both the degree and duration of NE suppression was dependent on the extent of the preceding ischemic period. Following 10-min ischemia complete recovery of NE release was achieved after 5-min reperfusion (1.07+/-0.12), whereas 5-min reperfusion did not restore NE release after 30 min (0.36+/-0.07) of ischemia. The adenosine-receptor antagonists 8-phenyltheophylline (8-PT; non-selective) and 8-cyclopentyl-1,3-dipropylxanthine (DPCPX; adenosine A1-receptor subtype selective) significantly increased NE release after 30-min ischemia and 5-min reperfusion (0.78+/-0.06 and 0.64+/-0.07), while in the same experimental protocol blockade of alpha2-adrenoceptors by yohimbine failed to restore the postischemic release (0.24+/-0.06). In non-ischemic hearts the adenosine analogue R(-)N(6)-(2-phenylisopropyl)adenosine (R-PIA) resulted in a marked suppression of NE release (0.61+/-0.07). The inhibitory effect of R-PIA and 2-chloro-N(6)-cyclopentyladenosine (CCPA; adenosine A1-receptor subtype selective agonist) persisted 5 min after cessation of R-PIA (0.62+/-0.05) and CCPA (0.58+/-0.04). Activation of alpha2-adrenoceptors by 5-bromo-N-(4,5-dihydro-1H-imidazol-2-yl)-6-quinoxalinamine (UK 14,304) also caused a reduction of NE release (0.50+/-0.02), but the release increased to control levels 5 min after cessation of UK 14,304 (0.90+/-0.06).
The results establish the phenomenon of neuronal stunning in terms of a postischemic suppression of exocytotic NE release and provide evidence that neuronal stunning is mediated by endogenous adenosine through activation of presynaptic adenosine A1-receptors.
大量研究支持心脏缺血后交感神经传递受损的概念。我们假设缺血后神经元功能障碍（神经元晕厥）是由交感神经末梢去甲肾上腺素（NE）释放的胞吐作用短暂受抑制所致。此外，我们评估了突触前腺苷受体和α2 -肾上腺素受体在神经元晕厥中的作用。
在离体灌注大鼠心脏中，通过两次电场刺激（S(1)和S(2)）诱导NE的胞吐释放。S(1)在基线条件下进行，S(2)在干预期间或之后进行。结果以平均S(2)/S(1)比值±标准误表示。整体缺血时间（10、20和30分钟）的逐步增加导致缺血后心脏中NE释放的逐渐抑制，在再灌注期间这种抑制是可逆的。NE抑制的程度和持续时间取决于先前缺血期的程度。缺血10分钟后，再灌注5分钟NE释放完全恢复（1.07±0.12），而缺血30分钟后再灌注5分钟未能恢复NE释放（0.36±0.07）。腺苷受体拮抗剂8 -苯基茶碱（8 - PT；非选择性）和8 -环戊基 - 1,3 -二丙基黄嘌呤（DPCPX；腺苷A1受体亚型选择性）在缺血30分钟和再灌注5分钟后显著增加NE释放（0.78±0.06和0.64±0.07），而在相同实验方案中育亨宾阻断α2 -肾上腺素受体未能恢复缺血后释放（0.24±0.06）。在非缺血心脏中，腺苷类似物R(-)N(6)-(2 -苯异丙基)腺苷（R - PIA）导致NE释放显著抑制（0.61±0.07）。R - PIA和2 -氯 - N(6)-环戊基腺苷（CCPA；腺苷A1受体亚型选择性激动剂）的抑制作用在停止给药后5分钟仍持续存在（R - PIA为0.62±0.05，CCPA为0.58±0.04）。5 -溴 - N-(4,5 -二氢 - 1H -咪唑 - 2 -基)-6 -喹喔啉胺（UK 14,304）激活α2 -肾上腺素受体也导致NE释放减少（0.50±0.02），但在停止UK 14,304给药5分钟后释放增加至对照水平（0.90±0.06）。
这些结果证实了神经元晕厥现象表现为缺血后NE释放的胞吐作用受抑制，并提供证据表明神经元晕厥是由内源性腺苷通过激活突触前腺苷A1受体介导的。
