Hasegawa Yu, Nakagawa Takashi, Uekawa Ken, Ma Mingjie, Lin Bowen, Kusaka Hiroaki, Katayama Tetsuji, Sueta Daisuke, Toyama Kensuke, Koibuchi Nobutaka, Kim-Mitsuyama Shokei
Department of Pharmacology and Molecular Therapeutics, Graduate School of Medical Sciences, Kumamoto University, 1-1-1, Honjo, Chuo-ku, Kumamoto-shi, Kumamoto-ken, 8608556, Japan.
Transl Stroke Res. 2016 Feb;7(1):79-87. doi: 10.1007/s12975-014-0383-5. Epub 2014 Dec 23.
Although calcium channel blockers, angiotensin II receptor blockers, and combination therapy are effective for hypertensive patients, the significant differences among them against stroke onset are undetermined. In this study, we investigated the significant beneficial effects of the combination therapy using amlodipine and irbesartan against stroke onset in hypertensive rats. The animals were fed an 8% sodium diet and assigned to (1) vehicle, (2) amlodipine (2 mg/kg/day), (3) irbesartan (20 mg/kg/day), and (4) amlodipine + irbesartan groups. The drugs were given orally until 35 days, and incidences of stroke-related signs and mortality and blood pressure (BP) were monitored. Cerebral blood flow (CBF), brain water content, weight of the brain and left ventricle, and histological evaluations were conducted for the treated groups at 42 days after the start of the high-salt diet. Amlodipine and the combination therapy significantly reduced BP compared with the vehicle. Although the rates of stroke-related signs and mortality were high in the vehicle group, the rats in the treatment groups were mostly healthy until 35 days. After all drugs were discontinued, stroke onset was frequently seen in the monotherapy groups until 42 days, but no signs were observed in the combination therapy group. Although there were no significant differences in CBF or brain edema, the combination therapy reduced blood-brain barrier disruption, white matter injury, and reactive astrocytes compared with irbesartan, and the combination also inhibited left ventricular hypertrophy and preserved brain-derived neurotrophic factor (BDNF) expression on cerebral vessels compared to the monotherapies. These data suggest that the combination therapy had a persistent preventive effect on stroke onset in hypertensive rats, and the effects might be associated with BDNF preservation on cerebral vessels.
虽然钙通道阻滞剂、血管紧张素II受体阻滞剂及联合治疗对高血压患者有效，但它们在预防中风发作方面的显著差异尚未确定。在本研究中，我们调查了氨氯地平和厄贝沙坦联合治疗对高血压大鼠中风发作的显著有益作用。给动物喂食8%的高盐饮食，并将其分为（1）溶剂对照组、（2）氨氯地平组（2毫克/千克/天）、（3）厄贝沙坦组（20毫克/千克/天）和（4）氨氯地平+厄贝沙坦联合治疗组。口服给药持续35天，监测中风相关体征、死亡率和血压（BP）。在高盐饮食开始42天后，对治疗组进行脑血流量（CBF）、脑含水量、脑和左心室重量以及组织学评估。与溶剂对照组相比，氨氯地平和联合治疗组显著降低了血压。虽然溶剂对照组中风相关体征和死亡率较高，但治疗组的大鼠在35天前大多健康。在所有药物停用后，单药治疗组在42天前经常出现中风发作，但联合治疗组未观察到任何体征。虽然CBF或脑水肿没有显著差异，但与厄贝沙坦相比，联合治疗减少了血脑屏障破坏、白质损伤和反应性星形胶质细胞，并且与单药治疗相比，联合治疗还抑制了左心室肥厚并保留了脑血管上脑源性神经营养因子（BDNF）的表达。这些数据表明，联合治疗对高血压大鼠中风发作具有持续的预防作用，其作用可能与脑血管上BDNF的保留有关。
