Du X J, Dart A M, Riemersma R A, Oliver M F
Department of Medicine, University of Edinburgh, Scotland, UK.
Circ Res. 1990 Apr;66(4):950-6. doi: 10.1161/01.res.66.4.950.
The effect of ischemia on cholinergic presynaptic inhibition of exocytotic norepinephrine release was studied in the innervated perfused rat heart. In normoxic hearts, vagal nerve stimulation significantly reduced exocytotic norepinephrine overflow to 75% of control values. This inhibitory effect was not affected by 3 minutes of low-flow ischemia (67% of control overflow values), but was attenuated or abolished by 10-minute low-flow ischemia or by 1-, 3-, and 5-minute stop-flow ischemia (107%, 85%, 101%, and 120% of control overflow values, respectively). The alpha-adrenergic antagonist phentolamine could completely or partly restore the failure of vagally induced inhibition of norepinephrine overflow in hearts with 1-, 3-, and 5-minute stop-flow ischemia (72%, 73%, and 85% of control overflow values, respectively). The muscarinic agonist methacholine substantially inhibited norepinephrine overflow to 18% of control overflow values in normoxic hearts. This effect was also significantly attenuated by 10-minute low-flow ischemia or by 1-, 3-, and 5-minute stop-flow ischemia (46%, 38%, 53%, and 55% of control overflow values, respectively). The cholinesterase inhibitor physostigmine did not restore the methacholine-induced inhibition of norepinephrine overflow after 3-minute stop-flow ischemia to normoxic level (55% vs. 17%). These results indicate that myocardial ischemia interferes with endogenous and exogenous cholinergic presynaptic inhibition of norepinephrine overflow in the rat heart. The extent of this attenuation depends on the severity and duration of ischemia. Reduced exocytotic acetylcholine release, which is at least in part due to an enhanced adrenergic presynaptic modulation, and dysfunction of presynaptic muscarinic receptors are suggested as two possible mechanisms.
在受神经支配的灌注大鼠心脏中，研究了缺血对胆碱能突触前抑制去甲肾上腺素释放的影响。在正常氧合的心脏中，迷走神经刺激可使去甲肾上腺素的胞吐溢出显著降低至对照值的75%。这种抑制作用不受3分钟低流量缺血的影响（为对照溢出值的67%），但在10分钟低流量缺血或1、3和5分钟停流缺血后减弱或消失（分别为对照溢出值的107%、85%、101%和120%）。α-肾上腺素能拮抗剂酚妥拉明可完全或部分恢复在1、3和5分钟停流缺血心脏中迷走神经诱导的去甲肾上腺素溢出抑制失败的情况（分别为对照溢出值的72%、73%和85%）。毒蕈碱激动剂乙酰甲胆碱在正常氧合心脏中可将去甲肾上腺素溢出显著抑制至对照溢出值的18%。在10分钟低流量缺血或1、3和5分钟停流缺血后，这种作用也显著减弱（分别为对照溢出值的46%、38%、53%和55%）。胆碱酯酶抑制剂毒扁豆碱在3分钟停流缺血后未能将乙酰甲胆碱诱导的去甲肾上腺素溢出抑制恢复至正常氧合水平（分别为55%对17%）。这些结果表明，心肌缺血会干扰大鼠心脏中内源性和外源性胆碱能对去甲肾上腺素溢出的突触前抑制。这种减弱的程度取决于缺血的严重程度和持续时间。提示至少部分由于增强的肾上腺素能突触前调制导致的胞吐乙酰胆碱释放减少以及突触前毒蕈碱受体功能障碍是两种可能的机制。
