Department of Physiology, University of Puerto Rico-School of Medicine, GPO Box 365067, San Juan, PR, 00936-5067, USA.
Department of Anesthesiology, University of Puerto Rico-School of Medicine, GPO Box 365067, San Juan, PR, 00936-5067, USA.
Sci Rep. 2021 May 10;11(1):9852. doi: 10.1038/s41598-021-89338-6.
Diabetics have a higher risk of developing cerebral vasospasms (CVSP) after subarachnoid hemorrhagic stroke than non-diabetics. Serotonin (5-HT) is one of the key vasoconstrictors released in the hemorrhagic blood and an important contributor to the etiology of CVSP. The combination of the ryanodine receptor blocker dantrolene and the Ca2+ channel blocker nimodipine significantly reduces phenylephrine (PHE)-induced vascular contraction in both diabetic and nondiabetic rats, but the effectiveness of this drug combination in reducing 5-HT-induced contraction is unknown. Dose-response curves for the 5-HT-induced contraction (from 0.1 nM to 100 µM) were performed on aortic rings from diabetic and non-diabetic rats after a 30-min incubation period with dantrolene, nimodipine, and both drugs in combination. In diabetic rats, 10 μM of dantrolene alone failed to reduce 5-HT-induced maximal contraction (E), but 50 μM reduced this parameter by 34% (n = 7, p < 0.05). In non-diabetic rats, by contrast, dantrolene did not modify the vascular response to 5-HT. 50 nM of nimodipine alone, however, reduced this parameter by 57% in diabetic rats (n = 10, p < 0.05), and by 34% in non-diabetic rats (n = 10, p < 0.05). In addition, concomitant administration of dantrolene and nimodipine reduced vascular reactivity to a similar extent in both diabetic (~ 60% reduction, n = 10, p < 0.05) and non-diabetic rats (~ 70% reduction, n = 10, p < 0.05). Moreover, the combination of nimodipine with the higher concentration of dantrolene significantly increased the EC values for the 5-HT-induced contraction curves in both diabetics (from 10.31 ± 1.17 µM to 19.26 ± 2.82; n = 10, p < 0.05) and non-diabetic rats (5.93 ± 0.54 µM to 15.80 ± 3.24; n = 10, p < 0.05). These results suggest that simultaneous administration of dantrolene and nimodipine has a synergistic effect in reducing 5-HT-induced vascular contraction under both diabetic and non-diabetic conditions. If our findings with rats are applicable to humans, concomitant administration of these drugs may represent a promising alternative for the management of CVSP in both diabetics and non-diabetics.
糖尿病患者蛛网膜下腔出血后发生脑血管痉挛（CVSP）的风险高于非糖尿病患者。5-羟色胺（5-HT）是出血性血液中释放的关键血管收缩剂之一，也是 CVSP 发病机制的重要因素。使用ryanodine 受体阻滞剂丹曲林钠和 Ca2+通道阻滞剂尼莫地平联合治疗可显著降低糖尿病和非糖尿病大鼠中苯肾上腺素（PHE）诱导的血管收缩，但这种药物联合治疗降低 5-HT 诱导收缩的效果尚不清楚。在丹曲林钠、尼莫地平及两药联合作用 30min 后，对糖尿病和非糖尿病大鼠的主动脉环进行 5-HT 诱导收缩（从 0.1nM 到 100μM）的量效曲线。在糖尿病大鼠中，单独使用 10μM 丹曲林钠不能降低 5-HT 诱导的最大收缩（E），但 50μM 可降低 34%（n=7，p<0.05）。相比之下，在非糖尿病大鼠中，丹曲林钠并不改变血管对 5-HT 的反应。单独使用 50nM 尼莫地平可使糖尿病大鼠的该参数降低 57%（n=10，p<0.05），而非糖尿病大鼠降低 34%（n=10，p<0.05）。此外，丹曲林钠和尼莫地平联合使用可使糖尿病（60%降低，n=10，p<0.05）和非糖尿病大鼠（70%降低，n=10，p<0.05）的血管反应降低到相似程度。此外，尼莫地平与较高浓度的丹曲林钠联合使用可显著增加糖尿病（从 10.31±1.17μM 增加到 19.26±2.82μM；n=10，p<0.05）和非糖尿病大鼠（从 5.93±0.54μM 增加到 15.80±3.24μM；n=10，p<0.05）的 5-HT 诱导收缩曲线的 EC 值。这些结果表明，在糖尿病和非糖尿病条件下，丹曲林钠和尼莫地平联合使用对降低 5-HT 诱导的血管收缩具有协同作用。如果我们在大鼠身上的发现适用于人类，那么同时使用这些药物可能是治疗糖尿病和非糖尿病患者 CVSP 的一种有前途的选择。
