Du X J, Riemersma R A, Fox K A, Dart A M
Baker Medical Research Institute, Melbourne, Australia.
Circulation. 1993 Oct;88(4 Pt 1):1885-92. doi: 10.1161/01.cir.88.4.1885.
Propranolol and lidocaine are effective antiarrhythmic drugs in myocardial ischemia and infarction. As sympathetic nerve activation and norepinephrine release in ischemic hearts are arrhythmogenic, we tested the possibility that both agents inhibit neural norepinephrine release following sympathetic activation in the ischemic environment.
The model used was an in situ perfused innervated rat heart. Norepinephrine release was induced by electrical stimulation of the left cervicothoracic stellate ganglion and analyzed using radioenzymatic assay or high-performance liquid chromatography. In normoxically perfused hearts, evoked norepinephrine release was not affected by either of the two agents at doses of 1 to 10 mumol/L when extracellular K+ concentration was 4 mmol/L but dose-dependently reduced at 10 mmol/L K+ (D,L-propranolol: -53 +/- 4% at 1 mumol/L and -64 +/- 6% at 10 mumol/L K+, lidocaine: -37 +/- 11% at 0.1 mumol/L, -67 +/- 5% at 1 mumol/L, and -75 +/- 6% at 10 mumol/L). At 10 mmol/L K+, norepinephrine release was not affected by timolol or atenolol (both 10 mumol/L but was equally inhibited by D- or L-propranolol at 10 mumol/L (-56 +/- 5% and -53 +/- 9%, respectively), indicating a beta-blocking-independent mechanism. In hearts with metabolic acidosis (pH 6.85) at K+ of 4 mmol/L, neural norepinephrine release was also reduced by propranolol at 10 mumol/L (-37%). Finally, in hearts perfused with 4 mmol/L K+ and subjected to 6-minute periods of ischemia, neural norepinephrine release was similarly suppressed by D,L-propranolol (-38 +/- 6% at 0.1 mumol/L, -44 +/- 5% at 1 mumol/L, and -78 +/- 3% at 10 mumol/L) or lidocaine (-39 +/- 7% at 0.1 mumol/L, -58 +/- 9% at 1 mumol/L, and -91 +/- 3% at 10 mumol/L).
These data indicate that propranolol and lidocaine inhibit neural norepinephrine release via a Na+ channel-blocking mechanism that is synergistic with changes induced by ischemia, primarily raised extracellular K+. This mechanism may contribute to the anti-ischemic and antiarrhythmic properties of both agents in acute myocardial ischemia, which induces increased extracellular K+ and sympathetic activation.
普萘洛尔和利多卡因是治疗心肌缺血和梗死的有效抗心律失常药物。由于缺血心脏中交感神经激活和去甲肾上腺素释放会引发心律失常，我们测试了这两种药物在缺血环境下交感神经激活后抑制神经去甲肾上腺素释放的可能性。
使用的模型是原位灌注有神经支配的大鼠心脏。通过电刺激左颈胸星状神经节诱导去甲肾上腺素释放，并使用放射酶法或高效液相色谱法进行分析。在正常氧合灌注的心脏中，当细胞外钾离子浓度为4 mmol/L时，1至10 μmol/L剂量的两种药物均不影响诱发的去甲肾上腺素释放，但在10 mmol/L钾离子时呈剂量依赖性降低（D，L - 普萘洛尔：1 μmol/L时为 - 53 ± 4%，10 μmol/L钾离子时为 - 64 ± 6%；利多卡因：0.1 μmol/L时为 - 37 ± 11%，1 μmol/L时为 - 67 ± 5%，10 μmol/L时为 - 75 ± 6%）。在10 mmol/L钾离子时，噻吗洛尔或阿替洛尔（均为10 μmol/L）不影响去甲肾上腺素释放，但10 μmol/L的D - 或L - 普萘洛尔同样抑制去甲肾上腺素释放（分别为 - 56 ± 5%和 - 53 ± 9%），表明存在非β受体阻断机制。在钾离子浓度为4 mmol/L且伴有代谢性酸中毒（pH 6.85）的心脏中，10 μmol/L的普萘洛尔也可降低神经去甲肾上腺素释放（ - 37%）。最后，在灌注4 mmol/L钾离子并经历6分钟缺血的心脏中，D，L - 普萘洛尔（0.1 μmol/L时为 - 38 ± 6%，1 μmol/L时为 - 44 ± 5%，10 μmol/L时为 - 78 ± 3%）或利多卡因（0.1 μmol/L时为 - 39 ± 7%，1 μmol/L时为 - 58 ± 9%，10 μmol/L时为 - 91 ± 3%）同样抑制神经去甲肾上腺素释放。
这些数据表明，普萘洛尔和利多卡因通过一种与缺血诱导的变化（主要是细胞外钾离子升高）协同的钠通道阻断机制抑制神经去甲肾上腺素释放。这种机制可能有助于这两种药物在急性心肌缺血中的抗缺血和抗心律失常特性，急性心肌缺血会导致细胞外钾离子增加和交感神经激活。
