Hester R K, Chen Z, Becker E J, McLaughlin M, DeSantis L
Department of Medical Pharmacology and Toxicology, College of Medicine, Texas A&M University Health Science Center, College Station.
Surv Ophthalmol. 1994 May;38 Suppl:S125-34. doi: 10.1016/0039-6257(94)90056-6.
The vascular relaxing properties of three beta adrenoceptor antagonists, betaxolol, carteolol and timolol, currently used in the treatment of glaucoma, were characterized, compared and contrasted in the porcine long posterior ciliary artery. Isolated arterial ring segments precontracted with increased extracellular KCl (plus 40 mM) or the thromboxane analog, U-46619 (3 x 10(-7) M), were relaxed in a concentration-dependent fashion by betaxolol, carteolol, timolol or nitroprusside. In vessel segments depolarized with increased extracellular KCl, EC50 values indicated that the intrinsic relaxant sensitivity to betaxolol was equal to that of nitroprusside, six-fold greater than that of carteolol, and ten-fold greater than that of timolol. Similarly, the maximum relaxation occurring at equimolar concentrations (10(-4) M) for the beta adrenoceptor antagonists was betaxolol > carteolol = timolol. Qualitatively similar results were noted in ring segments of the rabbit external iliac artery precontracted with increased extracellular KCl (plus 30 mM). Under conditions in which specific receptor-linked events are absent and voltage-gated Ca++ entry is maximized, the Ca++ concentration response relationship in porcine long posterior ciliary artery was shifted to the right in an apparent competitive manner by betaxolol, reflecting a 5.6-fold reduction in the sensitivity to Ca++. Conversely, nitroprusside reduced the Ca++ sensitivity three-fold in a noncompetitive fashion; not only shifting the Ca++ concentration response relationship to the right, but also depressing the maximum by 57%. Porcine long posterior ciliary arterial segments precontracted to a similar degree with U-46619, in which voltage-gated Ca++ entry is only one component of many specific cell signalling transduction mechanisms contributing to the precontraction, exhibited a sensitivity to betaxolol that was six-fold less than to nitroprusside, but two-fold greater than to timolol and 20-fold greater than to carteolol. These results are consistent with an obvious direct vascular relaxing capacity for beta adrenoceptor antagonists that primarily represents a capacity for inhibiting voltage-gated Ca++ entry in vascular smooth muscle. Additionally, the differential potencies of these three beta adrenoceptor antagonists characterized in this study suggests that this property is much more likely to contribute to any potentially beneficial effects of betaxolol than carteolol or timolol.
对目前用于治疗青光眼的三种β肾上腺素能受体拮抗剂倍他洛尔、卡替洛尔和噻吗洛尔的血管舒张特性进行了表征，并在猪的睫状后长动脉中进行了比较和对比。用增加的细胞外氯化钾（加40 mM）或血栓素类似物U-46619（3×10⁻⁷ M）预收缩的离体动脉环段，可被倍他洛尔、卡替洛尔、噻吗洛尔或硝普钠以浓度依赖性方式舒张。在用增加的细胞外氯化钾使血管段去极化的情况下，半数有效浓度（EC50）值表明，对倍他洛尔的内在舒张敏感性与硝普钠相当，比卡替洛尔高6倍，比噻吗洛尔高10倍。同样，β肾上腺素能受体拮抗剂在等摩尔浓度（10⁻⁴ M）时产生的最大舒张程度为倍他洛尔>卡替洛尔 = 噻吗洛尔。在用增加的细胞外氯化钾（加30 mM）预收缩的兔髂外动脉环段中也观察到了定性相似的结果。在不存在特定受体相关事件且电压门控Ca²⁺内流最大化的条件下，倍他洛尔使猪睫状后长动脉中的Ca²⁺浓度反应关系以明显的竞争性方式向右移动，这反映出对Ca²⁺的敏感性降低了5.6倍。相反，硝普钠以非竞争性方式使Ca²⁺敏感性降低了3倍；不仅使Ca²⁺浓度反应关系向右移动，还使最大值降低了57%。用U-46619预收缩到相似程度的猪睫状后长动脉段，其中电压门控Ca²⁺内流只是导致预收缩的许多特定细胞信号转导机制之一，对倍他洛尔的敏感性比对硝普钠低6倍，但比对噻吗洛尔高2倍，比对卡替洛尔高20倍。这些结果与β肾上腺素能受体拮抗剂明显的直接血管舒张能力一致，这种能力主要表现为抑制血管平滑肌中电压门控Ca²⁺内流的能力。此外，本研究中表征的这三种β肾上腺素能受体拮抗剂的不同效力表明，与卡替洛尔或噻吗洛尔相比，这种特性更有可能促成倍他洛尔的任何潜在有益作用。
