Lathers C M, Spivey W H, Levin R M
Department of Pharmacology, Medical College of Pennsylvania, Philadelphia 19129.
J Clin Pharmacol. 1988 Aug;28(8):736-45. doi: 10.1002/j.1552-4604.1988.tb03208.x.
The effect of no drug or timolol (5 mg/kg, PO, for 1, 2, or 8 weeks on postganglionic cardiac sympathetic neural discharge, blood pressure, heart rate and beta-receptor density after acute coronary occlusion of the left anterior descending artery was compared. Beta-receptor density, determined by binding of 3H-dihydroalprenolol, was examined in the myocardium (LA = left atrium, RA = right atrium, LV1 = proximal and LV2 = distal left anterior descending artery distribution, LV3 = posterior left ventricle, S = septum, and RV = right ventricle). In control cats (no coronary occlusion or timolol) beta-receptor density of LV2 and LV3 was greater (P less than .05) than LA, RA, LV1, and RV. LV3 was greater (P less than .05) than S and RA, and LA was less than S. Longer treatment with timolol increased beta-receptor density. When compared with no timolol, beta-receptor density was greater in RA after 8 weeks and in LV1 after 2 weeks and not different in LV2 and S. Beta-receptor density and LV3 and RV were greater after 8 weeks than after 1 week or no timolol. Spearman rank correlation coefficients between dose and beta-receptor density revealed an increase (P less than .05) for all heart areas. Heart rate did not vary before timolol and was decreased after all doses of timolol. Timolol increased the mean times to coronary occlusion-induced death although the increase was not statistically significant. Timolol did not prevent postganglionic cardiac sympathetic neural discharge associated with arrhythmia. Timolol may increase beta-receptor density and decrease synaptic norepinephrine, causing a decreased release per cardiac sympathetic nerve impulse. Alternatively, molecules of timolol may accumulate in nerve endings and be released in greater concentrations at the receptors. This could explain the protection against coronary occlusion-induced arrhythmia and death.
比较了在左前降支急性冠状动脉闭塞后，不使用药物或使用噻吗洛尔（5毫克/千克，口服，持续1、2或8周）对节后心脏交感神经放电、血压、心率和β受体密度的影响。通过3H-二氢阿普洛尔结合测定β受体密度，在心肌中进行检测（LA = 左心房，RA = 右心房，LV1 = 左前降支近端分布区，LV2 = 左前降支远端分布区，LV3 = 左心室后壁，S = 室间隔，RV = 右心室）。在对照猫（无冠状动脉闭塞或噻吗洛尔）中，LV2和LV3的β受体密度高于（P <.05）LA、RA、LV1和RV。LV3高于（P <.05）S和RA，且LA低于S。噻吗洛尔的较长时间治疗增加了β受体密度。与未使用噻吗洛尔相比，8周后RA的β受体密度更高，2周后LV1的β受体密度更高，而LV2和S的β受体密度无差异。8周后的β受体密度在LV3和RV高于1周后或未使用噻吗洛尔时。剂量与β受体密度之间的Spearman等级相关系数显示所有心脏区域均增加（P <.05）。使用噻吗洛尔前心率无变化，所有剂量的噻吗洛尔后心率均降低。噻吗洛尔增加了冠状动脉闭塞诱导死亡的平均时间，尽管增加无统计学意义。噻吗洛尔不能预防与心律失常相关的节后心脏交感神经放电。噻吗洛尔可能增加β受体密度并减少突触去甲肾上腺素，导致每个心脏交感神经冲动的释放减少。或者，噻吗洛尔分子可能在神经末梢积累并以更高浓度在受体处释放。这可以解释对冠状动脉闭塞诱导的心律失常和死亡的保护作用。
