Kasap Metin, Canaz Huseyin, Canaz Gokhan, Tokmak Mehmet, Bingul Alper, Alatas Ibrahim
Department of Neurosurgery, Bakirkoy Dr. Sadi Konuk Training and Research Hospital, Istanbul, Turkey.
Department of Neurosurgery, Florence Nightingale Hospital, Istanbul Bilim University, Istanbul, Turkey.
Asian J Neurosurg. 2018 Apr-Jun;13(2):271-276. doi: 10.4103/1793-5482.228567.
Our aim of this study was to determine effective doses of progesterone which has a vasodilatory effect during the early stage of vasospasm. Cerebral vasospasm (CV) is a predominant cause of morbidity and mortality which develops following subarachnoidal hemorrhage (SAH). Etiopathogenesis of CV is multifactorial. Despite many previously performed studies on this issue, the mechanism by which blood and blood products in the subarachnoidal space induce CV has not been clarified yet.
In our study, we used "Rat Femoral Artery Vasospasm Model" introduced by Okada . Thanks to easy procurement and maintenance of rats. Rats were divided into four groups as: Group 1 ( = 8; control group), Group 2 ( = 8; vasospasm group), Group 3 ( = 8; vasospasm + 3 mg/kg progesterone group), and Group 4 ( = 8; vasospasm +15 mg/kg progesterone group). Progesterone which is an endogenously synthesized natural steroid was preferred in our study. Progesterone increases the production of vasodilatory epoxyeicosatrienoic acid by acting on its binding sites termed as pregnane X receptor. It decreases the intracellular influx of Ca by blocking the functioning of L-type channels in smooth muscle cells. It manifests another vasodilatory effect by decreasing expression of TxA2 receptor. In our study, at the end of the 7 day, where the most intense vasospasm is seen, 1 cm pieces were excised from the femoral arteries and histopathologically examined under light microscope.
Vascular walls of three vasospasm-induced groups were relatively thicker when compared with the control group. Drug-treated groups were not different from each other. Vascular walls of the groups treated with lower and higher doses of the drug were thinner when compared with the vasospasm group without any statistically significant difference between groups ( > 0.05). Luminal cross-sectional areas of the drug-treated groups did not differ from each other. Mean luminal cross-sectional areas of the control and the drug-treated groups were larger than that of the vasospasm group without any statistically significant intergroup difference ( > 0.05).
Based on the results of our study, progesterone did not exert protective effects on vascular wall thickness, while histopathological examination of luminal cross-sectional areas revealed its vasodilatory effects without any statistically significant difference between groups. Starting from the study results obtained, we think that its potential use as a preventive agent against the development of post-SAH CV requires conduction of multicentered, placebo-controlled, randomized, and double-blind studies.
本研究的目的是确定在血管痉挛早期具有血管舒张作用的孕酮有效剂量。脑血管痉挛（CV）是蛛网膜下腔出血（SAH）后发病和死亡的主要原因。CV的病因是多因素的。尽管此前针对此问题进行了许多研究，但蛛网膜下腔中的血液和血液制品诱发CV的机制尚未阐明。
在本研究中，我们使用了冈田介绍的“大鼠股动脉血管痉挛模型”。由于大鼠易于获取和饲养。大鼠被分为四组：第1组（n = 8；对照组）、第2组（n = 8；血管痉挛组）、第3组（n = 8；血管痉挛 + 3 mg/kg孕酮组）和第4组（n = 8；血管痉挛 + 15 mg/kg孕酮组）。本研究选用内源性合成的天然类固醇孕酮。孕酮通过作用于其称为孕烷X受体的结合位点来增加血管舒张性环氧二十碳三烯酸的产生。它通过阻断平滑肌细胞中L型通道的功能来减少细胞内钙离子内流。它通过降低血栓素A2受体的表达表现出另一种血管舒张作用。在本研究中，在第7天结束时，即观察到最强烈血管痉挛时，从股动脉切下1厘米长的片段，并在光学显微镜下进行组织病理学检查。
与对照组相比，三个血管痉挛诱导组的血管壁相对较厚。药物治疗组之间没有差异。与血管痉挛组相比，低剂量和高剂量药物治疗组的血管壁更薄，组间无统计学显著差异（P > 0.05）。药物治疗组的管腔横截面积彼此无差异。对照组和药物治疗组的平均管腔横截面积大于血管痉挛组，组间无统计学显著差异（P > 0.05）。
根据我们的研究结果，孕酮对血管壁厚度没有保护作用，而管腔横截面积的组织病理学检查显示了其血管舒张作用，组间无统计学显著差异。从获得的研究结果出发，我们认为其作为预防SAH后CV发生的潜在药物需要进行多中心、安慰剂对照、随机和双盲研究。
