多沙唑嗪光学异构体对高脂饮食家兔及老龄小鼠血脂水平和组织病理学改变的影响
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摘要
血脂代谢紊乱是心血管疾病的重要危险因素。目前,随着人们生活水平的提高,由于脂肪尤其是饱和脂肪酸的大量摄入,促进血清总胆固醇(total cholesterol, TC)和低密度脂蛋白胆固醇(low density lipoprotein cholesterol, LDL-C)增高,导致国人血脂异常的发生率急剧升高。实验证实TC和LDL-C增高是心血管疾病的重要危险因素,其中TC的升高是导致动脉粥样硬化(atherosclerosis, AS)及心脑血管疾病的重要危险因素之一。TC、甘油三脂(triglyceride, TG)、LDL-C水平增高及高密度脂蛋白胆固醇(high density lipoprotein cholesterol, HDL-C)水平下降与心血管疾病密切相关。因此,降低血TC、TG、LDL-C而升高HDL-C水平有助于阻止AS的发生和发展。
DOX(doxazosin)作为一种选择性α1受体阻断剂,不良反应少,安全性高,在国外已广泛用于治疗高血压和良性前列腺增生症,临床使用其消旋体((±)DOX)。动物实验及临床研究均证明(±)DOX可拮抗去甲肾上腺素(noradrenaline, NA)对血管平滑肌的收缩作用。但是,MacDonald等报道(±)DOX可能诱发头晕、血压过低和昏厥等不良反应。为了减轻(±)DOX的不良反应,科研人员对其光学异构体进行了研究。在DOX的分子中存在一个手性中心和一对光学异构体((+)DOX和(-)DOX)。Owens等和Niu等曾分别报道了(±)DOX的手性拆分技术。有研究发现在兔胸主动脉和颈总动脉等血管,(-)DOX拮抗NA诱发血管收缩的pA2值显著小于(+)DOX,而两者对动物膀胱排尿压的作用相同,提示(-)DOX可能成为心血管副作用较小的治疗BPH/LUTS药物。
国外文献报道,对高脂饲养的仓鼠AS模型,(±)DOX在降低血浆TC、TG和LDL-C水平的同时,尚能抑制主动脉脂质条纹形成。Swindell等则证明,每日灌服(±)DOX 5mg连续9wk,对高血脂模型兔的血脂水平无任何影响;但是,对主动脉粥样硬化损伤具有显著的保护作用。
González-Juanatey等发现,在体外培养的人原代心肌细胞、新生大鼠原代心肌细胞和小鼠心房肌HL-1细胞,(±)DOX可诱导心肌细胞凋亡,其促凋亡作用与药物的α1受体阻断效应无关。
至今,有关(±)DOX光学异构体对血脂水平的影响,对高脂饮食条件下动物血管AS形成的影响,以及对高血脂损害心脏和肾脏的影响,国内外尚未见报道。本实验采用高脂饮食家兔模型和老龄小鼠模型,观察(-)DOX、(+)DOX和(±)DOX对血脂水平及动物死亡率的影响;观察(-)DOX、(+)DOX和(±)DOX对高血脂家兔主动脉、心脏、肾脏组织病理学改变的影响;采用流式细胞分析技术,研究(-)DOX、(+)DOX和(±)DOX对高血脂家兔心肌细胞增殖和凋亡的影响。这些研究将为(±)DOX及其光学异构体的临床应用提供实验数据。
第一部分多沙唑嗪及其光学异构体对高血脂家兔血脂水平及动物死亡率的影响
除普通饮食组外,全部家兔均给予高脂饮食,饲养4wk后测定血脂,除剔总胆固醇低于10mmol·L-1的实验动物,其余家兔按照总胆固醇水平随机分为5组,每组10只:普通饮食组、高脂模型组、高脂模型+(+)DOX组、高脂模型+(+)DOX组以及高脂模型+(±)DOX组。采用高脂饮食法建立兔高脂模型,观察(-)DOX、(+)DOX和(±)DOX对高血脂家兔血脂水平及动物死亡率的影响。
1 (-)DOX、(+)DOX和(±)DOX对兔体重的影响
饲以高脂饮食前和给予(±)DOX及其光学异构体之前,各组之间相比,家兔体重无显著差别(P>0.05)。连续给药3wk、6wk和9wk时,各组之间相比,动物体重亦无显著差别(P>0.05)。
与饲以高脂饮食前相比时,普通饮食组在第4~13wk、高脂模型组第7~13wk、高脂模型+(+)DOX组第4~13wk、高脂模型+(±)DOX组第10~13wk,家兔体重显著增长(P<0.05和P<0.01);但是,AS模型+(-)DOX组动物体重无显著增长(P>0.05)。
2 (-)DOX、(+)DOX和(±)DOX对兔死亡率的影响
在13wk实验过程中,普通饮食组家兔死亡1只,死亡率为10%;高脂模型组死亡4只,死亡率为40%;各给药组的死亡率在10%~30%范围内。尽管各给药组的动物死亡率与高脂模型组相比无统计学差异(P>0.05),但是其各组的死亡率均低于高脂模型组,特别是高脂模型+(±)DOX组的死亡率与普通饮食组相同。
3 (-)DOX、(+)DOX和(±)DOX对兔血清脂质水平的影响
3.1血清TC的变化
饲以高脂饮食前,各组之间相比,家兔血清TC无明显差别(P>0.05)。与普通饮食组相比,给予(±)DOX及其光学异构体之前以及连续给药3wk、6wk和9wk时,各给药组血清TC含量明显升高(P<0.01);而高脂模型+(-)DOX组、高脂模型+(+)DOX组以及高脂模型+(±)DOX组兔血清TC含量与高脂模型组相比,无显著差别(P>0.05)。
与给予(±)DOX及其光学异构体之前相比,高脂模型组在第10~13wk、高脂模型+(-)DOX组在第7~13wk,家兔血清TC进一步显著升高(P<0.01);但是,高脂模型+(+)DOX组与高脂模型+(±)DOX组动物血清TC含量无显著差异(P>0.05)。
3.2血清TG的变化
饲以高脂饮食前,各组之间相比,家兔血清TG无明显差别(P>0.05)。与普通饮食组相比,给予(±)DOX及其光学异构体之前以及连续给药3wk、6wk和9wk时,各给药组血清TG含量明显升高(P<0.01);而各给药组兔血清TG含量与高脂模型组相比,无显著差别(P>0.05)。
与给予(±)DOX及其光学异构体之前相比,普通饮食组家兔在第7~13wk血清TG显著降低(P<0.05和P<0.01);但是,各给药组兔血清TG含量无显著变化(P>0.05)。
3.3血清HDL-C的变化
饲以高脂饮食前以及给予(±)DOX和两个光学异构体后,家兔血清HDL-C含量变化的组间比较结果与家兔血清TG变化的趋势相同。
与给予(±)DOX及其光学异构体之前相比,除(±)DOX连续给药第6wk末的血清HDL-C呈显著下降外(P<0.05),其他各组动物的血清HDL-C变化趋势与血清TG的变化相同。
3.4血清LDL-C的变化
饲以高脂饮食前以及给予(±)DOX和两个光学异构体后,动物血清LDL-C含量变化的组间比较结果与血清TG变化的趋势相同。
与给予(±)DOX及其光学异构体之前相比,普通饮食组家兔在第7~13wk血清LDL-C水平显著降低(P<0.01);高脂模型组在第7~13wk、高脂模型+(±)DOX组在第10wk血清LDL-C显著升高(P<0.05和P<0.01);但是,高脂模型+(-)DOX组以及高脂模型+(+)DOX组动物血清LDL-C含量无显著改变(P>0.05)。
第二部分多沙唑嗪及其光学异构体对高血脂家兔主动脉及肾脏组织病理学改变的影响
本实验观察了(±)DOX及其光学异构体对高血脂家兔胸、腹主动脉以及肾脏组织病理变化的影响,明确了(±)DOX光学异构体在AS中的作用及其降低高血脂家兔死亡率的可能机制。
1 (-)DOX、(+)DOX和(±)DOX对胸主动脉大体形态学变化的影响
普通饮食组家兔胸主动脉血管壁未见异常。高脂模型组标本内膜表面粗糙,可见明显的AS斑块形成,为灰白色,大小不等,并相互融合成大片状,斑块覆盖面积占总面积的百分比为75.4±17.21%,各给药组胸主动脉也均有大小不一的AS斑块形成,但各给药组斑块覆盖面积占总面积的百分比较高脂模型组明显减低(P<0.05和P<0.01);各给药组之间未见明显差异(P>0.05)。
2 (-)DOX、(+)DOX和(±)DOX对胸主动脉组织形态学变化的影响
光学显微镜下观察:普通饮食组兔胸主动脉管壁未见异常。高脂模型组6例标本中,3例家兔胸主动脉呈典型的AS病变,管壁结构不清,内膜增厚,管腔表面粗糙,内皮细胞缺失或不连续,内膜下层可见大量泡沫细胞,胞核呈椭圆形或圆形;中膜肌层内胞质嗜酸性的SMC减少,出现少量充满脂质空泡的泡沫细胞;内膜下可见弹力纤维断裂,SMC排列紊乱,并向下迁徙;2例可见少量或大量的纤维斑块;1例仅见脂质条纹。采用Ridit检验分析结果表明,(-)DOX和(+)DOX显著减少纤维斑块和粥样斑块的形成。
3 (-)DOX、(+)DOX和(±)DOX对腹主动脉组织形态学变化的影响
光学显微镜下观察:普通饮食组兔腹主动脉管壁未见异常。AS模型组1例腹主动脉呈现少量AS病变,其管壁结构不清,内膜增厚,管腔表面不光滑,内膜下层可见增生细胞;中膜肌层内胞质嗜酸性的SMC减少,出现少量充满脂质空泡的泡沫细胞;内膜下可见弹力纤维断裂,SMC排列紊乱;其余5例均可见少量纤维斑块形成。组织病理学数据分析同胸主动脉,并采用Ridit检验分析药物的作用,研究结果表明(-)DOX显著抑制重度粥样斑块的形成。
4 (-)DOX、(+)DOX和(±)DOX对肾脏组织形态学变化的影响
光学显微镜下观察:普通饮食组兔肾脏组织结构正常。高脂模型组6例均可见肾小管上皮细胞内脂质蓄积,呈颗粒及空泡变性,甚至出现嗜酸性变;肾间质可见片状甚至大量泡沫细胞聚集,纤维组织坏死;肾小球增大,系膜细胞泡沫样变,毛细血管壁增厚、僵硬,毛细血管襻间胶原纤维增多。Ridit检验分析结果表明,(±)DOX及(-)DOX显著抑制肾小球系膜细胞的泡沫样变,(±)DOX亦对肾小管上皮细胞具有显著的保护作用。
第三部分多沙唑嗪及其光学异构体对高血脂家兔心肌细胞凋亡及心脏组织病理学改变的影响
本研究以高脂饲料喂养家兔13wk,观察高脂饮食对兔心肌细胞的增殖周期以及细胞凋亡的影响,以及高脂饮食是否诱发心肌组织发生病理性变化;在此基础上,进一步研究了(±)DOX及其光学异构体对高脂饮食家兔心肌组织的作用。
1 (-)DOX、(+)DOX和(±)DOX对家兔心肌细胞增殖周期及凋亡的影响
与普通饮食组相比,高脂饲养13wk家兔(高脂模型组)的心室肌G0/G1期细胞百分率显著升高(P<0.05),而S期细胞百分率和细胞PI显著降低(P<0.05);G2/M期细胞百分率在数值上明显降低,但无统计学意义(P>0.05)。与高脂模型组相比,(-)DOX及(±)DOX干预组的G0/G1期和S期细胞百分率,以及细胞PI均恢复至普通饮食组水平(P<0.05,P<0.01);G2/M期细胞百分率与高脂模型组相比,亦显著升高(P<0.05)。但是(+)DOX干预组的心室肌细胞增殖周期和细胞PI与高脂模型组相比,未发生显著性变化(P>0.05)。高脂模型组及各给药组的心室肌凋亡百分率无显著改变(P>0.05)。
2 (-)DOX、(+)DOX和(±)DOX对兔心室肌组织形态学变化的影响
普通饮食组心肌细胞未见异常。高脂模型组可见心肌细胞胞膜不完整,心肌细胞出现空泡变、脂肪变性、局灶性心肌坏死纤维化以及局灶性淋巴细胞浸润,心肌纤维排列紊乱。Ridit检验分析结果表明,(-)DOX及(±)DOX可显著减轻高脂饮食诱发的家兔心室肌病理变化,而(+)DOX组心室肌病理变化加重。
第四部分多沙唑嗪及其光学异构体长期给药对老龄小鼠血脂水平的影响
本研究为了探索研究(±)DOX调血脂作用的新的实验动物模型,观察了(±)DOX及其光学异构体对16月龄老年小鼠血脂水平的作用。
1 (-)DOX、(+)DOX和(±)DOX对老龄小鼠体重的影响
给药前,各组之间无明显差别(P>0.05)。给药12wk后,老龄模型组小鼠的体重虽有所降低,但是统计学分析未见显著性差异(P>0.05)。与老龄模型组相比,(+)DOX 0.6mg?kg-1给药12wk后,体重显著增加(P<0.05);其他各给药组与老龄模型组相比,动物体重均无明显差异(P>0.05)。给药12wk后,与药前值相比,仅(±)DOX 0.6mg?kg-1组小鼠的体重明显下降(P<0.05)。
2 (-)DOX、(+)DOX和(±)DOX对老龄小鼠死亡率的影响
老龄模型组11只小鼠,在12wk实验过程中死亡5只,死亡率为45.4%。各给药组老年小鼠的死亡情况与老龄模型组小鼠相似,死亡率均在36.4%~54.6%范围内。各给药组的动物死亡率与老龄模型组小鼠死亡率无显著差异(P>0.05)。
3 (-)DOX、(+)DOX和(±)DOX对老龄小鼠血清脂质水平的影响
老龄(16月龄)模型组小鼠的血清TC、TG、LDL-C和VLDL-C水平的均值均高于青年(11周龄)组小鼠,而血清HDL-C水平的均值低于青年组小鼠;其中VLDL-C和HDL-C水平,两组间具有显著性差异(P<0.01)。
与老龄模型组比较,各给药组小鼠的血清TC水平均有所降低,其中(-)DOX 1.8mg?kg-1组和0.6mg?kg-1组、(+)DOX 6.0mg?kg-1和0.6mg?kg-1组的降低程度具有统计学意义(P<0.05和P<0.01)。各给药组老龄鼠的血清TG和LDL-C水平与老龄模型组相比,均有下降趋势,但无统计学意义(P>0.05)。各给药组小鼠的血清HDL-C水平均有所升高,其中(-)DOX 6.0mg?kg-1组的升高程度具有统计学意义(P<0.05)。除(±)DOX 0.6mg?kg-1组外,其他各给药组均可显著降低老龄小鼠的血清VLDL-C水平,具有明显的统计学差异(P<0.05和P < 0.01)。
结论
1 (-)DOX和(±)DOX可提高高脂饮食家兔的生存率,并对高血脂家兔的血清LDL-C紊乱具有轻度的改善作用;但是,家兔不是研究α1受体阻断药降血脂作用的理想动物模型。
2 (-)DOX和(±)DOX显著抑制胸主动脉和腹主动脉粥样硬化的形成和发展,显著抑制肾小球系膜细胞的泡沫样变,(±)DOX尚对肾小管上皮细胞具有显著的保护作用。这些作用可能在(-)DOX和(±)DOX提高高脂饮食家兔生存率方面发挥重要作用。
3高脂饮食可使家兔心脏细胞的增殖能力减退并产生明显的心肌组织病理学改变,(-)DOX长时间给药可改善高脂饮食所致的心脏损害。在高脂血症相关的心室肌病理改变和细胞增殖周期变化方面,(-)DOX和(+)DOX具有显著的光学选择性作用。
4昆明种雄性老龄小鼠血VLDL-C水平显著升高,HDL-C水平显著降低,可作为研究DOX类药物调血脂作用的实验动物模型。长期灌胃给予(-)DOX、(+)DOX和(±)DOX,显著降低血VLDL-C和TC水平,两种光学异构体对老龄小鼠的血脂调节作用无明显差异。
Lipid disorder is a major risk factor of cardiovascular disease. With improvement in living standards, large amounts of fatty acids are taken in, which promotes the increases in total serum cholesterol (TC) and low density lipoprotein cholesterol (LDL-C). Clinical evidences show that the elevated TC and LDL-C levels are closely related to the cardiovascular diseases, and the elevated TC level is one of the most important risk factors for atherosclerosis (AS) and coronary arterial diseases. Decreases in the levels of TC, TG and LDL-C and an inecrease in HDL-C level could be helpful in protecting the formation and development of AS.
Doxazosin (DOX), a long lasting selective antagonist ofα1- adrenoceptors, has been widely used in treatment of hypertension and benign prostatic hyperplasia (BPH), and its racemic form of (±)DOX has been used in clinical practice at present. Basic and clinical experiments have proved that (±)DOX is able to antagonize the contractile responses to noradrenaline in vascular smooth muscle. In the treatment of BPH, adverse effects induced by (±)DOX were reported such as dizziness, postural hypotension and syncope. It was reported that (?)doxazosin [(?)DOX] and (+)doxazosin [(+)DOX] were prepared using chiral mobile phase HPLC and high performance capillary electrophoresis. The blocking effect of (?)DOX onα1-adrenoceptor was significantly weaker than that of (±)DOX and (+)DOX in the isolated rabbit thoracic aorta, carotid artery and mesenteric artery. The effect of (?)DOX on arterial blood pressure in the anesthetized rats was also significantly weaker than that of (±)DOX and (+)DOX administered intravenously or intraduo- denally. However, the effect of decreasing urinary bladder pressure by (?)DOX in the anesthetized rats and guinea-pig was the same as that of (±)DOX. These findings suggested that the pharmacological activity of (?)DOX had chiral selective effect between the cardiovascular system and lower urinary tract system, and (?)DOX might become a potential agent for the treatment of BPH/LUTS.
It was reported that (±)DOX decreased serum TC, TG and LDL-C levels, and inhibited the aortic fatty streak formation in the hypercholesterolemic hamster model. In the rabbit fed an atherogenic diet, (±)DOX administered by oral gavage daily at 5mg for 9 wk did not affect the serum lipid levels significantly, but it was able to protect the arteries from atherosclerosis.
González-Juanatey and colleagues reported that (±)DOX induced cell apoptosis in the primary rat cardiomyocytes, primary neonatal rat atrial myocytes and HL-1 mouse cardiomyocytes, and the apoptosis induction by (±)DOX was not dependent on its effect ofα1-adrenoceptor blockade.
So far it is not clarified whether (-)DOX and (+)DOX affect the serum lipid levels and histopathological changes in arteries, heart and kidney in the rabbits fed an atherogenic diet and serum lipid levels in the aged mice. In the present study, the hyperlipidemic rabbits and aged mice were used to observe the effects of (-)DOX, (+)DOX and (±)DOX on serum lipid levels and animal mortality. Histopathological changes in arteries, heart and kidney were observed in the rabbit fed an atherogenic diet, and cell proliferation and apoptosis of the heart ventricle of the hyperlipidemic rabbits were detected by flow cytometry (FCM).
PartⅠEffect of doxazosin and its enantiomers on serum lipid levels and animal mortality in rabbits fed an atherogenic diet
Except for the rabbits in normal diet group, all the other animals were fed an atherogenic diet. Serum lipids were determined in the rabbits fed a normal or atherogenic diet for 4 wk. Then, the rabbits fed an atherogenic diet were randomly divided into 4 groups (10 rabbits per group) according to their serum TC level, except for the animals whose serum TC level less than 10 mmol?L-1. Four groups included ather- ogenic diet group, atherogenic diet with (-)DOX group, atherogenic diet with (+)DOX group and atherogenic diet with (±)DOX group. Ten rabbits fed a normal diet were taken as the normal diet group in the study at the same time. Effects of (-)DOX, (+)DOX and (±)DOX on serum lipid levels and animal mortality were observed.
1 Effects of doxazosin and its enantiomers on rabbit body weight
Body weights of the rabbits before atherogenic diet feeding and before administration of (-)DOX, (+)DOX and (±)DOX in the 5 experimental groups were not significantly different from each other (P>0.05). Body weights of the rabbits after 3wk, 6wk and 9wk of daily administration of the three agents in the 5 experimental groups were not significantly different from each other as well (P>0.05).
Body weights of the rabbits after 4~13wk of normal diet, 7~13wk of atherogenic diet, 4~13wk of atherogenic diet with (+)DOX, and 10~13wk of atherogenic diet with (±)DOX were increased significantly (P<0.05 and P<0.01) in comparison with the body weights before atherogenic diet feeding. However, rabbit body weight in the group of atherogenic diet with (-)DOX was not significantly increased during 13wk of atherogenic diet feeding (P>0.05).
2 Effects of doxazosin and its enantiomers on rabbit mortality
During the experimental period, one rabbit died in normal diet group (mortality rate, 10%), 4 rabbits died in atherogenic diet group (mortality rate, 40%), and the mortality rates were 10% to 30% in the groups treated with (-)DOX, (+)DOX and (±)DOX. Although mortality rates in the drug-treated groups did not change significantly in comparison with atherogenic diet group (P>0.05), the mortality rates in the drug-treated groups were lower than the mortality rate in atherogenic diet group. The mortality rate in the group of atherogenic diet with (±)DOX was the same as that in normal diet group.
3 Effects of doxazosin and its enantiomers on serum lipid levels of rabbits fed an atherogenic diet
3.1 Effects of doxazosin and its enantiomers on serum TC levels of rabbits fed an atherogenic diet
Serum TC levels of the rabbits before atherogenic diet feeding in the 5 experimental groups were not significantly different from each other (P>0.05). Serum TC levels of the rabbits before administration of (-)DOX, (+)DOX and (±)DOX and after 3wk, 6wk and 9wk of daily administration of the three agents (including atherogenic diet group) were significantly elevated in comparison with serum TC level of the rabbits fed a normal diet (P<0.01). However, serum TG levels of the rabbits in atherogenic diet with (-)DOX group, atherogenic diet with (+)DOX group and atherogenic diet with (±)DOX group were not significantly different from the serum TG level of the rabbits in atherogenic diet group (P>0.05).
Serum TC levels of the rabbits after 10~13wk of atherogenic diet and 7~13wk of atherogenic diet with (-)DOX were further increased significantly (P<0.01) in comparison with those of the rabbits before administration of solvent and (-)DOX, respectively. On the other hand, serum TC levels of the rabbits after 7~13wk of atherogenic diet with (+)DOX and 7~13wk of atherogenic diet with (±)DOX did not change significantly (P>0.05) in comparison with those of the rabbits before administration of (+)DOX and (±)DOX, respectively.
3.2 Effects of doxazosin and its enantiomers on serum TG levels of rabbits fed an atherogenic diet
Serum TG levels of the rabbits before atherogenic diet feeding in the 5 experimental groups were not significantly different from each other (P>0.05). Serum TG levels of the rabbits before administration of (-)DOX, (+)DOX and (±)DOX and after 3wk, 6wk and 9wk of daily administration of the three agents (including atherogenic diet group) were significantly elevated in comparison with serum TG level of the rabbits fed an normal diet (P<0.01). However, serum TG levels of the rabbits in atherogenic diet with (-)DOX group, atherogenic diet with (+)DOX group and atherogenic diet with (±)DOX group were not significantly different from the serum TG level of the rabbits in atherogenic diet group (P>0.05).
Serum TG levels of the rabbits after 7~13wk of normal diet were decreased significantly (P<0.05 and P<0.01) in comparison with serum TG level of the rabbits before administration of solvent. On the other hand, serum TC levels of the rabbits after 7~13wk of atherogenic diet, 7~13wk of atherogenic diet with (-)DOX, 7~13wk of atherogenic diet with (+)DOX and 7~13wk of atherogenic diet with (±)DOX did not change significantly (P>0.05) in comparison with those of the rabbits before administration of solvent, (-)DOX, (+)DOX and (±)DOX, respectively.
3.3 Effects of doxazosin and its enantiomers on serum HDL-C levels of rabbits fed an atherogenic diet
Results from statistical comparisons among the 5 groups of the data before atherogenic diet feeding and of the data after administration of the three agents indicate that changes in serum HDL-C levels were similar to those in serum TG levels mentioned above.
Results from the statistical comparison between the data obtained before and after administration of (-)DOX, (+)DOX, (±)DOX and solvent indicate that changes in serum HDL-C levels were similar to those in serum TG levels mentioned above except for a significant decrease in serum HDL-C level after 6wk of daily administration of (±)DOX (P<0.05).
3.4 Effects of doxazosin and its enantiomers on serum LDL-C levels of rabbits fed an atherogenic diet
Results from statistical comparisons among the 5 groups of the data before atherogenic diet feeding and of the data after administration of the three agents indicate that changes in serum LDL-C levels were similar to those in serum TG levels mentioned above.
Serum LDL-C levels of the rabbits after 7~13wk of normal diet were decreased significantly (P<0.01) in comparison with serum LDL-C level of the rabbits before administration of solvent. On the other hand, serum LDL-C levels of the rabbits after 7~13wk of atherogenic diet and 10wk of atherogenic diet with (±)DOX were increased significantly (P<0.05 and P<0.01) in comparison with those of the rabbits before administration of solvent and (±)DOX, respectively. However, serum LDL-C levels of the rabbits after 7~13wk of atherogenic diet with (-)DOX and 7~13wk of atherogenic diet with (+)DOX did not change significantly (P>0.05) in comparison with those of the rabbits before administration of (-)DOX and (+)DOX, respectively.
PartⅡEffects of doxazosin and its enantiomers on histopathological changes in aorta and kidney in rabbits fed an atherogenic diet
The effects of (±)DOX and its enantiomers on histopathological changes in thoracic and abdominal aorta and in kidney of the rabbits fed an atherogenic diet were observed, and a possible mechanism underlying the decreased mortality in hyperlipemic rabbits was investigated.
1 Effects of doxazosin and its enantiomers on morphological changes in the thoracic aorta of rabbits fed an atherogenic diet
Morphological abnormalities had not been seen in the thoracic aorta of rabbits fed a normal diet. In the rabbits fed an atherogenic diet for 13wk, the luminal surface of intima of thoracic arota became rough, and AS plague could be seen clearly in different sizes. The ratio of aortic plaque area to total intima area was examined, and the percentage of total plaque area was 75.4±17.21% in the rabbits fed an atherogenic diet for 13wk. Percentages of total plaque area in the rabbits treated with (-)DOX, (+)DOX and (±)DOX were significantly decreased in comparison with the value in the rabbits fed an atherogenic diet (P<0.05 and P<0.01). There was no significant difference in percentages of total plaque area among the three groups treated with (-)DOX, (+)DOX and (±)DOX (P>0.05).
2 Effects of doxazosin and its enantiomers on histomorphological changes in the thoracic aorta of rabbits fed an atherogenic diet
Histomorphological abnormalities had not been seen in the thoracic aorta of rabbits fed a normal diet under an ordinary optical microscope. In 6 rabbits fed an atherogenic diet for 13wk, typical atherosclerotic lesions in the thoracic aorta were found in 3 rabbits, such as arterial wall thickness, intima thickness, roughness of the luminal surface, endothelial cell damage, foam cells accumulated in the subintimal space, decrease of acidophilic cytoplasm SMCs in the tunica media and disorganized smooth muscle orientation. Fibrous plague was found in 2 rabbits, and fatty streak was found in one rabbit. Results from the statistical analysis (Ridit test) indicate that (-)DOX and (+)DOX significantly reduced the formation of fibrous plaque and atherosclerotic plaque.
3 Effects of doxazosin and its enantiomers on histomorphological changes in the abdominal aorta of rabbits fed an atherogenic diet
Histomorphological abnormalities had not been seen in the abdominal aorta of rabbits fed a normal diet under an ordinary optical microscope. In 6 rabbits fed an atherogenic diet for 13wk, atherosclerotic lesions in the abdominal aorta were found in one rabbits, such as intima thickness, roughness of the luminal surface, foam cells accumulated in the subintimal space, decrease of acidophilic cytoplasm SMCs in the tunica media and disorganized smooth muscle orientation. A few of fibrous plaques were found in 5 rabbits. Results from the statistical analysis (Ridit test) indicate that (-)DOX significantly reduced the formation of heavy atherosclerotic plaque.
4 Effects of doxazosin and its enantiomers on histomorphological changes in the kidney of rabbits fed an atherogenic diet
Histomorphological abnormalities had not been seen in the kidney of rabbits fed a normal diet under an ordinary optical microscope. In 6 rabbits fed an atherogenic diet for 13wk, lipids were accumulated in the renal tubular epithelial cells in all animals, and ranular degeneration and vacuolar degeneration of the tubular epithelial cells were observed. A large number of foam cells were found in renal interstitium accompanying with necrotic fibrous tissue. Other pathological changes included the glomeralar enlargement, foam cell formation in glomerular mesangial cells, and thickening or stiffening of capillary wall. Results from the statistical analysis (Ridit test) indicate that (-)DOX and (±)DOX significantly inhibited the foam cell formation in renal interstitium, and (±)DOX had a protective effect on renal tubular epithelial cells in the rabbits fed an atherogenic diet.
PartⅢEffects of doxazosin and its enantiomers on cell cycle and apoptosis of the ventricular heart cells and histopathological changes of heart ventricle in rabbits fed an atherogenic diet
Cell cycle and apoptosis in the ventricular heart cells detected by flow cytometry and histopathological changes in heart ventricle were investigated in the rabbits fed an atherogenic diet for 13wk. Then, the effects of (±)DOX and its enantiomers on cell cycle and apoptosis in the ventricular heart cells and on histopathological changes of heart ventricle were investigated in the rabbits fed an atherogenic diet for 13wk.
1 Effects of doxazosin and its enantiomers on cell cycle and apoptosis of the ventricular heart cells in rabbits fed an atherogenic diet
The proportion of cells in G0/G1 phase was increased significantly (P<0.05), and that in S phase and PI value were decreased significantly (P<0.05) in the rabbit fed an atherogenic diet for 13wk in comparison with those in the rabbits fed an normal diet. Although the proportion of cells in G2/M phase was decreased, there was no significant difference between the two groups (P>0.05).
The proportions of cells in G0/G1 phase and S phase and PI values of the ventricular heart cells in the rabbits after 7~13wk of atherogenic diet with (-)DOX or (±)DOX were significantly different from that in the rabbits fed an atherogenic diet (P<0.05 and P<0.01), and reached the levels in the rabbits fed a normal diet. The proportions of cells in G2/M phase of the ventricular heart cells in the rabbits after 7~13wk of atherogenic diet with (-)DOX or (±)DOX were significantly increased in comparison with that in the rabbits fed an atherogenic diet (P<0.05). There were no significant changes in cell cycle and PI value of the ventricular heart cells in the rabbits fed an atherogenic diet with (+)DOX in comparison with that in the rabbits fed an atherogenic diet (P>0.05). Cell apoptosis and apoptotic rate of the ventricular heart cells in the rabbits treated with the three agents and in the rabbits fed an atherogenic diet did not change significantly in comparison with that in the rabbits fed a normal diet (P>0.05).
2 Effects of doxazosin and its enantiomers on histomorphological changes in the heart ventricle of rabbits fed an atherogenic diet
Histomorphological abnormalities had not been seen in the heart ventricle of the rabbits fed a normal diet under an ordinary optical microscope. In 6 rabbits fed an atherogenic diet for 13wk, pathological changes, such as vacuolar degeneration, fatty degeneration, focal lymphocyte infiltration, focal myocardial necrosis, focal myocardial fibrosis and disorganized smooth muscle orientation, were observed. Results from the statistical analysis (Ridit test) indicate that (-)DOX and (±)DOX significantly reduced the pathological changes in heart ventricle of the rabbits fed an atherogenic diet, but (+)DOX worsened the pathological changes.
PartⅣEffects of doxazosin and its enantiomers on the serum lipid levels after long-term administration in aged mice
In order to establish a new animal model for further investigation of lipid regulation action by (±)DOX, we observed the changes in serum lipid levels in the male mouse at 13 mouths of age and the effects of (±)DOX and its enantiomers on serum lipid levels in aged mice.
1 Effects of doxazosin and its enantiomers on the body weight of aged mice
Before drug administration, there was no significant difference in the body weight among all groups (P>0.05). After 12wk administration of solvent, the body weight of aged mice was decreased slightly without statistical significance (P>0.05). In comparison with the aged mice without drug-treatment, the body weight of aged mice treated by (+)DOX at 0.6 mg?kg-1 for 12wk was significantly increased (P<0.05), and significant changes in the body weight were not observed in the aged mice of other groups (P>0.05). In comparison with the body weight of aged mice before drug-treatment, the body weight of aged mice treated by (±)DOX at 0.6 mg?kg-1 for 12wk was significantly decreased only (P<0.05).
2 Effects of doxazosin and its enantiomers on the survival rate of aged mice
In the group of aged mice withou drug-treatment, 5 mice died during 12wk experiments, and the mortality rate was 45.4%. The mortality rate in each of drug-treated groups was similar to that in the group of aged mice, and the mortality rates were 36.4%~54.6%. The mortality rate of aged mice treated with (-)DOX (+)DOX or (±)DOX was not significantly different from that of aged mice without drug-treatment (P>0.05).
3 Effects of doxazosin and its enantiomers on the serum lipid levels of aged mice
The levels of serum TC, TG, LDL-C and VLDL-C in aged mice without drug-treatment were higher than those in young mice, and there were significant differences in VLDL-C and HDL-C levels between the two groups (P <0.01).
In comparison with the level of serum TC of aged mice without drug-treatment, serum TC levels of aged mice in all drug-treated groups were decreased, and there were significant differences in the groups treated with (-)DOX 1.8 mg?kg-1, 0.6 mg?kg-1, (+) DOX 6.0 mg?kg-1 and 0.6 mg?kg-1 (P<0.05 and P<0.01). In comparison with the levels of serum TG and LDL-C of aged mice without drug-treatment, serum TG and LDL-C levels of aged mice in all drug-treated groups were decreased slightly without statistical significance (P>0.05). The serum HDL-C levels were increased in all drug-treated groups, but a statistical significance was only existed at (-)DOX 6.0 mg?kg-1 group (P<0.05). The serum VLDL-C levels of aged mice were significant decreased by treatments with (-)DOX (+)DOX and (±)DOX (P<0.05 and P<0.01) except for (±)DOX 0.6 mg?kg-1 group.
Conclusion
1 (-)DOX and (±)DOX increase the survival rate of rabbits fed an atherogenic diet and improve LDL-C disorder mildly. Rabbit fed an atherogenic diet is not a suitable animal model for investigating the lipid-regulating action byα1-adrenoceptor antagonists.
2 (-)DOX and (±)DOX inhibit the formation and development of athero- sclerosis in thoracic and abdominal aorta, and foam cell formation in glomerular mesangial cells obviously. Moreover, (±)DOX offers a significant protective effect on the renal tubular epithelial cells. Those effects might contribute to their action of survival rate increase of the rabbits fed an atherogenic diet.
3 Atherogenic diet is able to reduce cell proliferation of the rabbit ventricular heart cells and induce a histopathological damage in the heart ventricle. (-)DOX improves histopathological damage in the heart ventricle induced by atherogenic diet. (-)DOX and (+)DOX have chiral selective effects on cell proliferation and histopathological damage in the rabbits with hyperlipidemia.
4 The VLDL-C levels are significantly increased, and HDL-C levels are significantly decreased in aged male Kunming mice. Long-term administrations of (-)DOX, (+)DOX and (±)DOX significantly decrease serum VLDL-C and TC levels, and there is no significant difference in the effects of lipid-regulation between the two enantiomers. Therefore, the aged male Kunming mice might be a suitable animal model for investigating the lipid-regulating action byα1-adrenoceptor antagonists.
DOX(doxazosin)作为一种选择性α1受体阻断剂,不良反应少,安全性高,在国外已广泛用于治疗高血压和良性前列腺增生症,临床使用其消旋体((±)DOX)。动物实验及临床研究均证明(±)DOX可拮抗去甲肾上腺素(noradrenaline, NA)对血管平滑肌的收缩作用。但是,MacDonald等报道(±)DOX可能诱发头晕、血压过低和昏厥等不良反应。为了减轻(±)DOX的不良反应,科研人员对其光学异构体进行了研究。在DOX的分子中存在一个手性中心和一对光学异构体((+)DOX和(-)DOX)。Owens等和Niu等曾分别报道了(±)DOX的手性拆分技术。有研究发现在兔胸主动脉和颈总动脉等血管,(-)DOX拮抗NA诱发血管收缩的pA2值显著小于(+)DOX,而两者对动物膀胱排尿压的作用相同,提示(-)DOX可能成为心血管副作用较小的治疗BPH/LUTS药物。
国外文献报道,对高脂饲养的仓鼠AS模型,(±)DOX在降低血浆TC、TG和LDL-C水平的同时,尚能抑制主动脉脂质条纹形成。Swindell等则证明,每日灌服(±)DOX 5mg连续9wk,对高血脂模型兔的血脂水平无任何影响;但是,对主动脉粥样硬化损伤具有显著的保护作用。
González-Juanatey等发现,在体外培养的人原代心肌细胞、新生大鼠原代心肌细胞和小鼠心房肌HL-1细胞,(±)DOX可诱导心肌细胞凋亡,其促凋亡作用与药物的α1受体阻断效应无关。
至今,有关(±)DOX光学异构体对血脂水平的影响,对高脂饮食条件下动物血管AS形成的影响,以及对高血脂损害心脏和肾脏的影响,国内外尚未见报道。本实验采用高脂饮食家兔模型和老龄小鼠模型,观察(-)DOX、(+)DOX和(±)DOX对血脂水平及动物死亡率的影响;观察(-)DOX、(+)DOX和(±)DOX对高血脂家兔主动脉、心脏、肾脏组织病理学改变的影响;采用流式细胞分析技术,研究(-)DOX、(+)DOX和(±)DOX对高血脂家兔心肌细胞增殖和凋亡的影响。这些研究将为(±)DOX及其光学异构体的临床应用提供实验数据。
第一部分多沙唑嗪及其光学异构体对高血脂家兔血脂水平及动物死亡率的影响
除普通饮食组外,全部家兔均给予高脂饮食,饲养4wk后测定血脂,除剔总胆固醇低于10mmol·L-1的实验动物,其余家兔按照总胆固醇水平随机分为5组,每组10只:普通饮食组、高脂模型组、高脂模型+(+)DOX组、高脂模型+(+)DOX组以及高脂模型+(±)DOX组。采用高脂饮食法建立兔高脂模型,观察(-)DOX、(+)DOX和(±)DOX对高血脂家兔血脂水平及动物死亡率的影响。
1 (-)DOX、(+)DOX和(±)DOX对兔体重的影响
饲以高脂饮食前和给予(±)DOX及其光学异构体之前,各组之间相比,家兔体重无显著差别(P>0.05)。连续给药3wk、6wk和9wk时,各组之间相比,动物体重亦无显著差别(P>0.05)。
与饲以高脂饮食前相比时,普通饮食组在第4~13wk、高脂模型组第7~13wk、高脂模型+(+)DOX组第4~13wk、高脂模型+(±)DOX组第10~13wk,家兔体重显著增长(P<0.05和P<0.01);但是,AS模型+(-)DOX组动物体重无显著增长(P>0.05)。
2 (-)DOX、(+)DOX和(±)DOX对兔死亡率的影响
在13wk实验过程中,普通饮食组家兔死亡1只,死亡率为10%;高脂模型组死亡4只,死亡率为40%;各给药组的死亡率在10%~30%范围内。尽管各给药组的动物死亡率与高脂模型组相比无统计学差异(P>0.05),但是其各组的死亡率均低于高脂模型组,特别是高脂模型+(±)DOX组的死亡率与普通饮食组相同。
3 (-)DOX、(+)DOX和(±)DOX对兔血清脂质水平的影响
3.1血清TC的变化
饲以高脂饮食前,各组之间相比,家兔血清TC无明显差别(P>0.05)。与普通饮食组相比,给予(±)DOX及其光学异构体之前以及连续给药3wk、6wk和9wk时,各给药组血清TC含量明显升高(P<0.01);而高脂模型+(-)DOX组、高脂模型+(+)DOX组以及高脂模型+(±)DOX组兔血清TC含量与高脂模型组相比,无显著差别(P>0.05)。
与给予(±)DOX及其光学异构体之前相比,高脂模型组在第10~13wk、高脂模型+(-)DOX组在第7~13wk,家兔血清TC进一步显著升高(P<0.01);但是,高脂模型+(+)DOX组与高脂模型+(±)DOX组动物血清TC含量无显著差异(P>0.05)。
3.2血清TG的变化
饲以高脂饮食前,各组之间相比,家兔血清TG无明显差别(P>0.05)。与普通饮食组相比,给予(±)DOX及其光学异构体之前以及连续给药3wk、6wk和9wk时,各给药组血清TG含量明显升高(P<0.01);而各给药组兔血清TG含量与高脂模型组相比,无显著差别(P>0.05)。
与给予(±)DOX及其光学异构体之前相比,普通饮食组家兔在第7~13wk血清TG显著降低(P<0.05和P<0.01);但是,各给药组兔血清TG含量无显著变化(P>0.05)。
3.3血清HDL-C的变化
饲以高脂饮食前以及给予(±)DOX和两个光学异构体后,家兔血清HDL-C含量变化的组间比较结果与家兔血清TG变化的趋势相同。
与给予(±)DOX及其光学异构体之前相比,除(±)DOX连续给药第6wk末的血清HDL-C呈显著下降外(P<0.05),其他各组动物的血清HDL-C变化趋势与血清TG的变化相同。
3.4血清LDL-C的变化
饲以高脂饮食前以及给予(±)DOX和两个光学异构体后,动物血清LDL-C含量变化的组间比较结果与血清TG变化的趋势相同。
与给予(±)DOX及其光学异构体之前相比,普通饮食组家兔在第7~13wk血清LDL-C水平显著降低(P<0.01);高脂模型组在第7~13wk、高脂模型+(±)DOX组在第10wk血清LDL-C显著升高(P<0.05和P<0.01);但是,高脂模型+(-)DOX组以及高脂模型+(+)DOX组动物血清LDL-C含量无显著改变(P>0.05)。
第二部分多沙唑嗪及其光学异构体对高血脂家兔主动脉及肾脏组织病理学改变的影响
本实验观察了(±)DOX及其光学异构体对高血脂家兔胸、腹主动脉以及肾脏组织病理变化的影响,明确了(±)DOX光学异构体在AS中的作用及其降低高血脂家兔死亡率的可能机制。
1 (-)DOX、(+)DOX和(±)DOX对胸主动脉大体形态学变化的影响
普通饮食组家兔胸主动脉血管壁未见异常。高脂模型组标本内膜表面粗糙,可见明显的AS斑块形成,为灰白色,大小不等,并相互融合成大片状,斑块覆盖面积占总面积的百分比为75.4±17.21%,各给药组胸主动脉也均有大小不一的AS斑块形成,但各给药组斑块覆盖面积占总面积的百分比较高脂模型组明显减低(P<0.05和P<0.01);各给药组之间未见明显差异(P>0.05)。
2 (-)DOX、(+)DOX和(±)DOX对胸主动脉组织形态学变化的影响
光学显微镜下观察:普通饮食组兔胸主动脉管壁未见异常。高脂模型组6例标本中,3例家兔胸主动脉呈典型的AS病变,管壁结构不清,内膜增厚,管腔表面粗糙,内皮细胞缺失或不连续,内膜下层可见大量泡沫细胞,胞核呈椭圆形或圆形;中膜肌层内胞质嗜酸性的SMC减少,出现少量充满脂质空泡的泡沫细胞;内膜下可见弹力纤维断裂,SMC排列紊乱,并向下迁徙;2例可见少量或大量的纤维斑块;1例仅见脂质条纹。采用Ridit检验分析结果表明,(-)DOX和(+)DOX显著减少纤维斑块和粥样斑块的形成。
3 (-)DOX、(+)DOX和(±)DOX对腹主动脉组织形态学变化的影响
光学显微镜下观察:普通饮食组兔腹主动脉管壁未见异常。AS模型组1例腹主动脉呈现少量AS病变,其管壁结构不清,内膜增厚,管腔表面不光滑,内膜下层可见增生细胞;中膜肌层内胞质嗜酸性的SMC减少,出现少量充满脂质空泡的泡沫细胞;内膜下可见弹力纤维断裂,SMC排列紊乱;其余5例均可见少量纤维斑块形成。组织病理学数据分析同胸主动脉,并采用Ridit检验分析药物的作用,研究结果表明(-)DOX显著抑制重度粥样斑块的形成。
4 (-)DOX、(+)DOX和(±)DOX对肾脏组织形态学变化的影响
光学显微镜下观察:普通饮食组兔肾脏组织结构正常。高脂模型组6例均可见肾小管上皮细胞内脂质蓄积,呈颗粒及空泡变性,甚至出现嗜酸性变;肾间质可见片状甚至大量泡沫细胞聚集,纤维组织坏死;肾小球增大,系膜细胞泡沫样变,毛细血管壁增厚、僵硬,毛细血管襻间胶原纤维增多。Ridit检验分析结果表明,(±)DOX及(-)DOX显著抑制肾小球系膜细胞的泡沫样变,(±)DOX亦对肾小管上皮细胞具有显著的保护作用。
第三部分多沙唑嗪及其光学异构体对高血脂家兔心肌细胞凋亡及心脏组织病理学改变的影响
本研究以高脂饲料喂养家兔13wk,观察高脂饮食对兔心肌细胞的增殖周期以及细胞凋亡的影响,以及高脂饮食是否诱发心肌组织发生病理性变化;在此基础上,进一步研究了(±)DOX及其光学异构体对高脂饮食家兔心肌组织的作用。
1 (-)DOX、(+)DOX和(±)DOX对家兔心肌细胞增殖周期及凋亡的影响
与普通饮食组相比,高脂饲养13wk家兔(高脂模型组)的心室肌G0/G1期细胞百分率显著升高(P<0.05),而S期细胞百分率和细胞PI显著降低(P<0.05);G2/M期细胞百分率在数值上明显降低,但无统计学意义(P>0.05)。与高脂模型组相比,(-)DOX及(±)DOX干预组的G0/G1期和S期细胞百分率,以及细胞PI均恢复至普通饮食组水平(P<0.05,P<0.01);G2/M期细胞百分率与高脂模型组相比,亦显著升高(P<0.05)。但是(+)DOX干预组的心室肌细胞增殖周期和细胞PI与高脂模型组相比,未发生显著性变化(P>0.05)。高脂模型组及各给药组的心室肌凋亡百分率无显著改变(P>0.05)。
2 (-)DOX、(+)DOX和(±)DOX对兔心室肌组织形态学变化的影响
普通饮食组心肌细胞未见异常。高脂模型组可见心肌细胞胞膜不完整,心肌细胞出现空泡变、脂肪变性、局灶性心肌坏死纤维化以及局灶性淋巴细胞浸润,心肌纤维排列紊乱。Ridit检验分析结果表明,(-)DOX及(±)DOX可显著减轻高脂饮食诱发的家兔心室肌病理变化,而(+)DOX组心室肌病理变化加重。
第四部分多沙唑嗪及其光学异构体长期给药对老龄小鼠血脂水平的影响
本研究为了探索研究(±)DOX调血脂作用的新的实验动物模型,观察了(±)DOX及其光学异构体对16月龄老年小鼠血脂水平的作用。
1 (-)DOX、(+)DOX和(±)DOX对老龄小鼠体重的影响
给药前,各组之间无明显差别(P>0.05)。给药12wk后,老龄模型组小鼠的体重虽有所降低,但是统计学分析未见显著性差异(P>0.05)。与老龄模型组相比,(+)DOX 0.6mg?kg-1给药12wk后,体重显著增加(P<0.05);其他各给药组与老龄模型组相比,动物体重均无明显差异(P>0.05)。给药12wk后,与药前值相比,仅(±)DOX 0.6mg?kg-1组小鼠的体重明显下降(P<0.05)。
2 (-)DOX、(+)DOX和(±)DOX对老龄小鼠死亡率的影响
老龄模型组11只小鼠,在12wk实验过程中死亡5只,死亡率为45.4%。各给药组老年小鼠的死亡情况与老龄模型组小鼠相似,死亡率均在36.4%~54.6%范围内。各给药组的动物死亡率与老龄模型组小鼠死亡率无显著差异(P>0.05)。
3 (-)DOX、(+)DOX和(±)DOX对老龄小鼠血清脂质水平的影响
老龄(16月龄)模型组小鼠的血清TC、TG、LDL-C和VLDL-C水平的均值均高于青年(11周龄)组小鼠,而血清HDL-C水平的均值低于青年组小鼠;其中VLDL-C和HDL-C水平,两组间具有显著性差异(P<0.01)。
与老龄模型组比较,各给药组小鼠的血清TC水平均有所降低,其中(-)DOX 1.8mg?kg-1组和0.6mg?kg-1组、(+)DOX 6.0mg?kg-1和0.6mg?kg-1组的降低程度具有统计学意义(P<0.05和P<0.01)。各给药组老龄鼠的血清TG和LDL-C水平与老龄模型组相比,均有下降趋势,但无统计学意义(P>0.05)。各给药组小鼠的血清HDL-C水平均有所升高,其中(-)DOX 6.0mg?kg-1组的升高程度具有统计学意义(P<0.05)。除(±)DOX 0.6mg?kg-1组外,其他各给药组均可显著降低老龄小鼠的血清VLDL-C水平,具有明显的统计学差异(P<0.05和P < 0.01)。
结论
1 (-)DOX和(±)DOX可提高高脂饮食家兔的生存率,并对高血脂家兔的血清LDL-C紊乱具有轻度的改善作用;但是,家兔不是研究α1受体阻断药降血脂作用的理想动物模型。
2 (-)DOX和(±)DOX显著抑制胸主动脉和腹主动脉粥样硬化的形成和发展,显著抑制肾小球系膜细胞的泡沫样变,(±)DOX尚对肾小管上皮细胞具有显著的保护作用。这些作用可能在(-)DOX和(±)DOX提高高脂饮食家兔生存率方面发挥重要作用。
3高脂饮食可使家兔心脏细胞的增殖能力减退并产生明显的心肌组织病理学改变,(-)DOX长时间给药可改善高脂饮食所致的心脏损害。在高脂血症相关的心室肌病理改变和细胞增殖周期变化方面,(-)DOX和(+)DOX具有显著的光学选择性作用。
4昆明种雄性老龄小鼠血VLDL-C水平显著升高,HDL-C水平显著降低,可作为研究DOX类药物调血脂作用的实验动物模型。长期灌胃给予(-)DOX、(+)DOX和(±)DOX,显著降低血VLDL-C和TC水平,两种光学异构体对老龄小鼠的血脂调节作用无明显差异。
Lipid disorder is a major risk factor of cardiovascular disease. With improvement in living standards, large amounts of fatty acids are taken in, which promotes the increases in total serum cholesterol (TC) and low density lipoprotein cholesterol (LDL-C). Clinical evidences show that the elevated TC and LDL-C levels are closely related to the cardiovascular diseases, and the elevated TC level is one of the most important risk factors for atherosclerosis (AS) and coronary arterial diseases. Decreases in the levels of TC, TG and LDL-C and an inecrease in HDL-C level could be helpful in protecting the formation and development of AS.
Doxazosin (DOX), a long lasting selective antagonist ofα1- adrenoceptors, has been widely used in treatment of hypertension and benign prostatic hyperplasia (BPH), and its racemic form of (±)DOX has been used in clinical practice at present. Basic and clinical experiments have proved that (±)DOX is able to antagonize the contractile responses to noradrenaline in vascular smooth muscle. In the treatment of BPH, adverse effects induced by (±)DOX were reported such as dizziness, postural hypotension and syncope. It was reported that (?)doxazosin [(?)DOX] and (+)doxazosin [(+)DOX] were prepared using chiral mobile phase HPLC and high performance capillary electrophoresis. The blocking effect of (?)DOX onα1-adrenoceptor was significantly weaker than that of (±)DOX and (+)DOX in the isolated rabbit thoracic aorta, carotid artery and mesenteric artery. The effect of (?)DOX on arterial blood pressure in the anesthetized rats was also significantly weaker than that of (±)DOX and (+)DOX administered intravenously or intraduo- denally. However, the effect of decreasing urinary bladder pressure by (?)DOX in the anesthetized rats and guinea-pig was the same as that of (±)DOX. These findings suggested that the pharmacological activity of (?)DOX had chiral selective effect between the cardiovascular system and lower urinary tract system, and (?)DOX might become a potential agent for the treatment of BPH/LUTS.
It was reported that (±)DOX decreased serum TC, TG and LDL-C levels, and inhibited the aortic fatty streak formation in the hypercholesterolemic hamster model. In the rabbit fed an atherogenic diet, (±)DOX administered by oral gavage daily at 5mg for 9 wk did not affect the serum lipid levels significantly, but it was able to protect the arteries from atherosclerosis.
González-Juanatey and colleagues reported that (±)DOX induced cell apoptosis in the primary rat cardiomyocytes, primary neonatal rat atrial myocytes and HL-1 mouse cardiomyocytes, and the apoptosis induction by (±)DOX was not dependent on its effect ofα1-adrenoceptor blockade.
So far it is not clarified whether (-)DOX and (+)DOX affect the serum lipid levels and histopathological changes in arteries, heart and kidney in the rabbits fed an atherogenic diet and serum lipid levels in the aged mice. In the present study, the hyperlipidemic rabbits and aged mice were used to observe the effects of (-)DOX, (+)DOX and (±)DOX on serum lipid levels and animal mortality. Histopathological changes in arteries, heart and kidney were observed in the rabbit fed an atherogenic diet, and cell proliferation and apoptosis of the heart ventricle of the hyperlipidemic rabbits were detected by flow cytometry (FCM).
PartⅠEffect of doxazosin and its enantiomers on serum lipid levels and animal mortality in rabbits fed an atherogenic diet
Except for the rabbits in normal diet group, all the other animals were fed an atherogenic diet. Serum lipids were determined in the rabbits fed a normal or atherogenic diet for 4 wk. Then, the rabbits fed an atherogenic diet were randomly divided into 4 groups (10 rabbits per group) according to their serum TC level, except for the animals whose serum TC level less than 10 mmol?L-1. Four groups included ather- ogenic diet group, atherogenic diet with (-)DOX group, atherogenic diet with (+)DOX group and atherogenic diet with (±)DOX group. Ten rabbits fed a normal diet were taken as the normal diet group in the study at the same time. Effects of (-)DOX, (+)DOX and (±)DOX on serum lipid levels and animal mortality were observed.
1 Effects of doxazosin and its enantiomers on rabbit body weight
Body weights of the rabbits before atherogenic diet feeding and before administration of (-)DOX, (+)DOX and (±)DOX in the 5 experimental groups were not significantly different from each other (P>0.05). Body weights of the rabbits after 3wk, 6wk and 9wk of daily administration of the three agents in the 5 experimental groups were not significantly different from each other as well (P>0.05).
Body weights of the rabbits after 4~13wk of normal diet, 7~13wk of atherogenic diet, 4~13wk of atherogenic diet with (+)DOX, and 10~13wk of atherogenic diet with (±)DOX were increased significantly (P<0.05 and P<0.01) in comparison with the body weights before atherogenic diet feeding. However, rabbit body weight in the group of atherogenic diet with (-)DOX was not significantly increased during 13wk of atherogenic diet feeding (P>0.05).
2 Effects of doxazosin and its enantiomers on rabbit mortality
During the experimental period, one rabbit died in normal diet group (mortality rate, 10%), 4 rabbits died in atherogenic diet group (mortality rate, 40%), and the mortality rates were 10% to 30% in the groups treated with (-)DOX, (+)DOX and (±)DOX. Although mortality rates in the drug-treated groups did not change significantly in comparison with atherogenic diet group (P>0.05), the mortality rates in the drug-treated groups were lower than the mortality rate in atherogenic diet group. The mortality rate in the group of atherogenic diet with (±)DOX was the same as that in normal diet group.
3 Effects of doxazosin and its enantiomers on serum lipid levels of rabbits fed an atherogenic diet
3.1 Effects of doxazosin and its enantiomers on serum TC levels of rabbits fed an atherogenic diet
Serum TC levels of the rabbits before atherogenic diet feeding in the 5 experimental groups were not significantly different from each other (P>0.05). Serum TC levels of the rabbits before administration of (-)DOX, (+)DOX and (±)DOX and after 3wk, 6wk and 9wk of daily administration of the three agents (including atherogenic diet group) were significantly elevated in comparison with serum TC level of the rabbits fed a normal diet (P<0.01). However, serum TG levels of the rabbits in atherogenic diet with (-)DOX group, atherogenic diet with (+)DOX group and atherogenic diet with (±)DOX group were not significantly different from the serum TG level of the rabbits in atherogenic diet group (P>0.05).
Serum TC levels of the rabbits after 10~13wk of atherogenic diet and 7~13wk of atherogenic diet with (-)DOX were further increased significantly (P<0.01) in comparison with those of the rabbits before administration of solvent and (-)DOX, respectively. On the other hand, serum TC levels of the rabbits after 7~13wk of atherogenic diet with (+)DOX and 7~13wk of atherogenic diet with (±)DOX did not change significantly (P>0.05) in comparison with those of the rabbits before administration of (+)DOX and (±)DOX, respectively.
3.2 Effects of doxazosin and its enantiomers on serum TG levels of rabbits fed an atherogenic diet
Serum TG levels of the rabbits before atherogenic diet feeding in the 5 experimental groups were not significantly different from each other (P>0.05). Serum TG levels of the rabbits before administration of (-)DOX, (+)DOX and (±)DOX and after 3wk, 6wk and 9wk of daily administration of the three agents (including atherogenic diet group) were significantly elevated in comparison with serum TG level of the rabbits fed an normal diet (P<0.01). However, serum TG levels of the rabbits in atherogenic diet with (-)DOX group, atherogenic diet with (+)DOX group and atherogenic diet with (±)DOX group were not significantly different from the serum TG level of the rabbits in atherogenic diet group (P>0.05).
Serum TG levels of the rabbits after 7~13wk of normal diet were decreased significantly (P<0.05 and P<0.01) in comparison with serum TG level of the rabbits before administration of solvent. On the other hand, serum TC levels of the rabbits after 7~13wk of atherogenic diet, 7~13wk of atherogenic diet with (-)DOX, 7~13wk of atherogenic diet with (+)DOX and 7~13wk of atherogenic diet with (±)DOX did not change significantly (P>0.05) in comparison with those of the rabbits before administration of solvent, (-)DOX, (+)DOX and (±)DOX, respectively.
3.3 Effects of doxazosin and its enantiomers on serum HDL-C levels of rabbits fed an atherogenic diet
Results from statistical comparisons among the 5 groups of the data before atherogenic diet feeding and of the data after administration of the three agents indicate that changes in serum HDL-C levels were similar to those in serum TG levels mentioned above.
Results from the statistical comparison between the data obtained before and after administration of (-)DOX, (+)DOX, (±)DOX and solvent indicate that changes in serum HDL-C levels were similar to those in serum TG levels mentioned above except for a significant decrease in serum HDL-C level after 6wk of daily administration of (±)DOX (P<0.05).
3.4 Effects of doxazosin and its enantiomers on serum LDL-C levels of rabbits fed an atherogenic diet
Results from statistical comparisons among the 5 groups of the data before atherogenic diet feeding and of the data after administration of the three agents indicate that changes in serum LDL-C levels were similar to those in serum TG levels mentioned above.
Serum LDL-C levels of the rabbits after 7~13wk of normal diet were decreased significantly (P<0.01) in comparison with serum LDL-C level of the rabbits before administration of solvent. On the other hand, serum LDL-C levels of the rabbits after 7~13wk of atherogenic diet and 10wk of atherogenic diet with (±)DOX were increased significantly (P<0.05 and P<0.01) in comparison with those of the rabbits before administration of solvent and (±)DOX, respectively. However, serum LDL-C levels of the rabbits after 7~13wk of atherogenic diet with (-)DOX and 7~13wk of atherogenic diet with (+)DOX did not change significantly (P>0.05) in comparison with those of the rabbits before administration of (-)DOX and (+)DOX, respectively.
PartⅡEffects of doxazosin and its enantiomers on histopathological changes in aorta and kidney in rabbits fed an atherogenic diet
The effects of (±)DOX and its enantiomers on histopathological changes in thoracic and abdominal aorta and in kidney of the rabbits fed an atherogenic diet were observed, and a possible mechanism underlying the decreased mortality in hyperlipemic rabbits was investigated.
1 Effects of doxazosin and its enantiomers on morphological changes in the thoracic aorta of rabbits fed an atherogenic diet
Morphological abnormalities had not been seen in the thoracic aorta of rabbits fed a normal diet. In the rabbits fed an atherogenic diet for 13wk, the luminal surface of intima of thoracic arota became rough, and AS plague could be seen clearly in different sizes. The ratio of aortic plaque area to total intima area was examined, and the percentage of total plaque area was 75.4±17.21% in the rabbits fed an atherogenic diet for 13wk. Percentages of total plaque area in the rabbits treated with (-)DOX, (+)DOX and (±)DOX were significantly decreased in comparison with the value in the rabbits fed an atherogenic diet (P<0.05 and P<0.01). There was no significant difference in percentages of total plaque area among the three groups treated with (-)DOX, (+)DOX and (±)DOX (P>0.05).
2 Effects of doxazosin and its enantiomers on histomorphological changes in the thoracic aorta of rabbits fed an atherogenic diet
Histomorphological abnormalities had not been seen in the thoracic aorta of rabbits fed a normal diet under an ordinary optical microscope. In 6 rabbits fed an atherogenic diet for 13wk, typical atherosclerotic lesions in the thoracic aorta were found in 3 rabbits, such as arterial wall thickness, intima thickness, roughness of the luminal surface, endothelial cell damage, foam cells accumulated in the subintimal space, decrease of acidophilic cytoplasm SMCs in the tunica media and disorganized smooth muscle orientation. Fibrous plague was found in 2 rabbits, and fatty streak was found in one rabbit. Results from the statistical analysis (Ridit test) indicate that (-)DOX and (+)DOX significantly reduced the formation of fibrous plaque and atherosclerotic plaque.
3 Effects of doxazosin and its enantiomers on histomorphological changes in the abdominal aorta of rabbits fed an atherogenic diet
Histomorphological abnormalities had not been seen in the abdominal aorta of rabbits fed a normal diet under an ordinary optical microscope. In 6 rabbits fed an atherogenic diet for 13wk, atherosclerotic lesions in the abdominal aorta were found in one rabbits, such as intima thickness, roughness of the luminal surface, foam cells accumulated in the subintimal space, decrease of acidophilic cytoplasm SMCs in the tunica media and disorganized smooth muscle orientation. A few of fibrous plaques were found in 5 rabbits. Results from the statistical analysis (Ridit test) indicate that (-)DOX significantly reduced the formation of heavy atherosclerotic plaque.
4 Effects of doxazosin and its enantiomers on histomorphological changes in the kidney of rabbits fed an atherogenic diet
Histomorphological abnormalities had not been seen in the kidney of rabbits fed a normal diet under an ordinary optical microscope. In 6 rabbits fed an atherogenic diet for 13wk, lipids were accumulated in the renal tubular epithelial cells in all animals, and ranular degeneration and vacuolar degeneration of the tubular epithelial cells were observed. A large number of foam cells were found in renal interstitium accompanying with necrotic fibrous tissue. Other pathological changes included the glomeralar enlargement, foam cell formation in glomerular mesangial cells, and thickening or stiffening of capillary wall. Results from the statistical analysis (Ridit test) indicate that (-)DOX and (±)DOX significantly inhibited the foam cell formation in renal interstitium, and (±)DOX had a protective effect on renal tubular epithelial cells in the rabbits fed an atherogenic diet.
PartⅢEffects of doxazosin and its enantiomers on cell cycle and apoptosis of the ventricular heart cells and histopathological changes of heart ventricle in rabbits fed an atherogenic diet
Cell cycle and apoptosis in the ventricular heart cells detected by flow cytometry and histopathological changes in heart ventricle were investigated in the rabbits fed an atherogenic diet for 13wk. Then, the effects of (±)DOX and its enantiomers on cell cycle and apoptosis in the ventricular heart cells and on histopathological changes of heart ventricle were investigated in the rabbits fed an atherogenic diet for 13wk.
1 Effects of doxazosin and its enantiomers on cell cycle and apoptosis of the ventricular heart cells in rabbits fed an atherogenic diet
The proportion of cells in G0/G1 phase was increased significantly (P<0.05), and that in S phase and PI value were decreased significantly (P<0.05) in the rabbit fed an atherogenic diet for 13wk in comparison with those in the rabbits fed an normal diet. Although the proportion of cells in G2/M phase was decreased, there was no significant difference between the two groups (P>0.05).
The proportions of cells in G0/G1 phase and S phase and PI values of the ventricular heart cells in the rabbits after 7~13wk of atherogenic diet with (-)DOX or (±)DOX were significantly different from that in the rabbits fed an atherogenic diet (P<0.05 and P<0.01), and reached the levels in the rabbits fed a normal diet. The proportions of cells in G2/M phase of the ventricular heart cells in the rabbits after 7~13wk of atherogenic diet with (-)DOX or (±)DOX were significantly increased in comparison with that in the rabbits fed an atherogenic diet (P<0.05). There were no significant changes in cell cycle and PI value of the ventricular heart cells in the rabbits fed an atherogenic diet with (+)DOX in comparison with that in the rabbits fed an atherogenic diet (P>0.05). Cell apoptosis and apoptotic rate of the ventricular heart cells in the rabbits treated with the three agents and in the rabbits fed an atherogenic diet did not change significantly in comparison with that in the rabbits fed a normal diet (P>0.05).
2 Effects of doxazosin and its enantiomers on histomorphological changes in the heart ventricle of rabbits fed an atherogenic diet
Histomorphological abnormalities had not been seen in the heart ventricle of the rabbits fed a normal diet under an ordinary optical microscope. In 6 rabbits fed an atherogenic diet for 13wk, pathological changes, such as vacuolar degeneration, fatty degeneration, focal lymphocyte infiltration, focal myocardial necrosis, focal myocardial fibrosis and disorganized smooth muscle orientation, were observed. Results from the statistical analysis (Ridit test) indicate that (-)DOX and (±)DOX significantly reduced the pathological changes in heart ventricle of the rabbits fed an atherogenic diet, but (+)DOX worsened the pathological changes.
PartⅣEffects of doxazosin and its enantiomers on the serum lipid levels after long-term administration in aged mice
In order to establish a new animal model for further investigation of lipid regulation action by (±)DOX, we observed the changes in serum lipid levels in the male mouse at 13 mouths of age and the effects of (±)DOX and its enantiomers on serum lipid levels in aged mice.
1 Effects of doxazosin and its enantiomers on the body weight of aged mice
Before drug administration, there was no significant difference in the body weight among all groups (P>0.05). After 12wk administration of solvent, the body weight of aged mice was decreased slightly without statistical significance (P>0.05). In comparison with the aged mice without drug-treatment, the body weight of aged mice treated by (+)DOX at 0.6 mg?kg-1 for 12wk was significantly increased (P<0.05), and significant changes in the body weight were not observed in the aged mice of other groups (P>0.05). In comparison with the body weight of aged mice before drug-treatment, the body weight of aged mice treated by (±)DOX at 0.6 mg?kg-1 for 12wk was significantly decreased only (P<0.05).
2 Effects of doxazosin and its enantiomers on the survival rate of aged mice
In the group of aged mice withou drug-treatment, 5 mice died during 12wk experiments, and the mortality rate was 45.4%. The mortality rate in each of drug-treated groups was similar to that in the group of aged mice, and the mortality rates were 36.4%~54.6%. The mortality rate of aged mice treated with (-)DOX (+)DOX or (±)DOX was not significantly different from that of aged mice without drug-treatment (P>0.05).
3 Effects of doxazosin and its enantiomers on the serum lipid levels of aged mice
The levels of serum TC, TG, LDL-C and VLDL-C in aged mice without drug-treatment were higher than those in young mice, and there were significant differences in VLDL-C and HDL-C levels between the two groups (P <0.01).
In comparison with the level of serum TC of aged mice without drug-treatment, serum TC levels of aged mice in all drug-treated groups were decreased, and there were significant differences in the groups treated with (-)DOX 1.8 mg?kg-1, 0.6 mg?kg-1, (+) DOX 6.0 mg?kg-1 and 0.6 mg?kg-1 (P<0.05 and P<0.01). In comparison with the levels of serum TG and LDL-C of aged mice without drug-treatment, serum TG and LDL-C levels of aged mice in all drug-treated groups were decreased slightly without statistical significance (P>0.05). The serum HDL-C levels were increased in all drug-treated groups, but a statistical significance was only existed at (-)DOX 6.0 mg?kg-1 group (P<0.05). The serum VLDL-C levels of aged mice were significant decreased by treatments with (-)DOX (+)DOX and (±)DOX (P<0.05 and P<0.01) except for (±)DOX 0.6 mg?kg-1 group.
Conclusion
1 (-)DOX and (±)DOX increase the survival rate of rabbits fed an atherogenic diet and improve LDL-C disorder mildly. Rabbit fed an atherogenic diet is not a suitable animal model for investigating the lipid-regulating action byα1-adrenoceptor antagonists.
2 (-)DOX and (±)DOX inhibit the formation and development of athero- sclerosis in thoracic and abdominal aorta, and foam cell formation in glomerular mesangial cells obviously. Moreover, (±)DOX offers a significant protective effect on the renal tubular epithelial cells. Those effects might contribute to their action of survival rate increase of the rabbits fed an atherogenic diet.
3 Atherogenic diet is able to reduce cell proliferation of the rabbit ventricular heart cells and induce a histopathological damage in the heart ventricle. (-)DOX improves histopathological damage in the heart ventricle induced by atherogenic diet. (-)DOX and (+)DOX have chiral selective effects on cell proliferation and histopathological damage in the rabbits with hyperlipidemia.
4 The VLDL-C levels are significantly increased, and HDL-C levels are significantly decreased in aged male Kunming mice. Long-term administrations of (-)DOX, (+)DOX and (±)DOX significantly decrease serum VLDL-C and TC levels, and there is no significant difference in the effects of lipid-regulation between the two enantiomers. Therefore, the aged male Kunming mice might be a suitable animal model for investigating the lipid-regulating action byα1-adrenoceptor antagonists.
引文
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