Tölg R, Kurz T, Ungerer M, Schreieck J, Görge B, Richardt G
Medizinische Klinik II der Medizinischen Universität zu Lübeck, Germany.
Naunyn Schmiedebergs Arch Pharmacol. 1997 Jul;356(1):62-8. doi: 10.1007/pl00005029.
Although it is generally accepted that adrenergic influences contribute to arrhythmias during myocardial ischemia, it is still a matter of debate whether these arrhythmogenic effects are mediated via alpha- or beta-adrenergic receptors and which particular receptor subtype is involved. Controversial results may be due to ancillary properties of the adrenergic receptor antagonists used to resolve this question. Therefore, we compared the influence of various, structurally different alpha- and beta-adrenoceptor blocking agents on the occurrence of ventricular fibrillation in rat isolated hearts. Regional ischemia was induced by ligature of the left coronary artery and ECG was monitored over 30 min of coronary occlusion. Myocardial ischemia precipitated ventricular fibrillation in a well reproducible manner with an incidence of about 80% in control hearts. Racemic propranolol (0.1-1 micromol/l) concentration-relatedly reduced the incidence of ventricular fibrillation from 71% in controls to 10%, whereas the beta-adrenoceptor blocking agents atenolol (10 micromol/l) and timolol (1 micromol/l) did not influence the occurrence of arrhythmias. Moreover, both stereoisomers of propranolol were equipotent in suppressing ischemia-induced ventricular fibrillation, indicating an action of propranolol independent of its beta-adrenoceptor blocking properties. Unselective antagonism of alpha-adrenoceptors by phentolamine decreased the incidence of ventricular fibrillation from 90% to 58% at 0.1 micromol/l and totally suppressed ventricular fibrillation at 1 micromol/l. The alpha1-selective antagonists prazosin and HEAT concentration-dependently (0.1-10 micromol/l) reduced the incidence of ventricular fibrillation from 83% to 0%, whereas the alpha2-selective antagonist RX 821002 revealed no antiarrhythmic effect. Furthermore, subtype specific antagonism of alpha1A-adrenoceptors by WB 4101 clearly reduced the occurrence of ventricular fibrillation in a concentration-dependent manner (0.01-1 micromol/l) from 66% to 17%. Conversely, CEC, known to block the alpha1B-adrenoceptor subtype, possessed no antifibrillatory effect. In conclusion, the contribution of catecholamines to ischemia-induced arrhythmias in rat isolated heart is primarily mediated via WB 4101-sensitive alpha1-adrenergic activation. Beta- and alpha2-adrenoceptor blockade did not affect ventricular fibrillation in this model. The antifibrillatory action of propranolol was rather due to ancillary properties of this agent.
虽然人们普遍认为肾上腺素能影响在心肌缺血期间会导致心律失常，但这些致心律失常作用是通过α-还是β-肾上腺素能受体介导的，以及涉及哪种特定的受体亚型，仍是一个有争议的问题。有争议的结果可能归因于用于解决该问题的肾上腺素能受体拮抗剂的辅助特性。因此，我们比较了各种结构不同的α-和β-肾上腺素能受体阻断剂对大鼠离体心脏室颤发生的影响。通过结扎左冠状动脉诱导局部缺血，并在冠状动脉闭塞30分钟内监测心电图。心肌缺血以良好的可重复性方式引发室颤，对照心脏中的发生率约为80%。消旋普萘洛尔（0.1 - 1微摩尔/升）与浓度相关地将室颤发生率从对照组的71%降低至10%，而β-肾上腺素能受体阻断剂阿替洛尔（10微摩尔/升）和噻吗洛尔（1微摩尔/升）不影响心律失常的发生。此外，普萘洛尔的两种立体异构体在抑制缺血诱导的室颤方面具有同等效力，表明普萘洛尔的作用与其β-肾上腺素能受体阻断特性无关。酚妥拉明对α-肾上腺素能受体的非选择性拮抗作用在0.1微摩尔/升时将室颤发生率从90%降至58%，并在1微摩尔/升时完全抑制室颤。α1选择性拮抗剂哌唑嗪和HEAT浓度依赖性地（0.1 - 10微摩尔/升）将室颤发生率从83%降至0%，而α2选择性拮抗剂RX 821002未显示抗心律失常作用。此外，WB 4101对α1A-肾上腺素能受体的亚型特异性拮抗作用以浓度依赖性方式（0.01 - 1微摩尔/升）明显降低室颤的发生，从66%降至17%。相反，已知可阻断α1B-肾上腺素能受体亚型的CEC没有抗纤颤作用。总之，儿茶酚胺对大鼠离体心脏缺血诱导的心律失常的作用主要通过WB 4101敏感的α1-肾上腺素能激活介导。在该模型中，β-和α2-肾上腺素能受体阻断不影响室颤。普萘洛尔的抗纤颤作用相当程度上归因于该药物的辅助特性。
