AGEs裂解剂对DM大鼠心血管系统保护作用研究
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摘要
老龄人口的迅速增加以及糖尿病发病率的迅速攀升使老龄及糖尿病并发症的防治成为亟待解决问题。心血管系统功能紊乱是老龄人与糖尿病患者最为突出的并发症,是导致老龄人口死亡、糖尿病患者生存质量下降的最主要原因。因此发展具有针对性的治疗措施具有重要意义。
晚期糖基化终产物(Advanced glycation endproducts, AGEs)是由葡萄糖及其它还原糖与蛋白质经过一系列非酶促反应形成的巨型交联物。AGEs交联结构在心血管组织的长命蛋白上的形成与积聚与老年和糖尿病患者心血管系统硬化,心血管组织对生物活性分子与外源性调节分子的敏感性下降密切相关。裂解AGEs交联结构是一种新型的、基于逆转心血管硬化的治疗策略。临床前和临床研究表明,AGEs裂解剂明确改善老年和糖尿病的心血管系统功能紊乱。
然而,作为一种发展中的具有完全创新性思路和全新机制的药物,AGEs裂解剂的新作用、作用机制以及新型AGEs裂解药物还有待进一步研究。
本研究的目的有两个,其一,对自主研发的新型AGEs裂解剂C36体内水解主要产物C36D2进行逆转糖尿病大鼠心血管系统硬化的作用及机制进行研究,确证C36D2是C36的体内活性形式,为C36体内的有效性提供实验依据。其二,探讨AGEs裂解剂通过改善心血管系统功能是否能够改善降压药物的敏感性以及可能的机制。
第一部分工作主要以C36为对照,用经典AGEs裂解剂的评价方法对C36D2进行了实验研究。首先通过体外制备牛血清白蛋白(BSA)-AGEs-胶原的交联结构,结合酶联免疫吸附测定(ELISA)方法以及裂解糖尿病大鼠红细胞表面IgG(RBC-IgG)交联实验,对C36D2进行了体外裂解体内、外形成的AGEs的评价;其后,给予STZ诱导3个月病程的糖尿病大鼠3个剂量(9、18、36 mg/kg)的C36D2 4周,采用超声多普勒结合血流动力学检测技术,对大鼠收缩压、舒张压、心率、左室内压峰值及左室舒张末期压进行了测定,并计算心输出量、总外周阻力、系统顺应性及左室内压最大变化速率;同时,采用荧光检测法测定了主动脉、左心室心肌以及肾脏组织上AGEs含量,采用酸性条件下限制性胃蛋白酶消化实验测定尾胶原、左心室心肌胶原溶解性。结果表明,C36D2能够在体外裂解体内、外形成的AGEs交联结构,在体内显著提高糖尿病大鼠系统顺应性(7.92±1.11 vs. 5.55±0.94 10-3ml/mmHg),降低总外周阻力(77.0±19.6 vs. 109.87±19.0 103.dyne.sec/cm5),增加心输出量(84.9±13.6 vs. 60.3±7.9 ml/min);显著增加糖尿病大鼠左心室内压峰值( 170.65±8.94 vs. 153.49±20.05mmHg )和左室内压最大变化速率(12201.2±1872.2 vs. 9410.2±1294.2mmHg/s)(7762.8±1320.2 vs. 6684.2±1400.7 mmHg/s),降低左室舒张末期压(5.73±1.44 vs. 8.16±3.05mmHg),改善左室功能;并增加糖尿病大鼠尾胶原、左心室心肌胶原溶解性;显著减少糖尿病大鼠主动脉、左心室心肌以及肾脏的AGEs荧光含量。其药效强度均与阳性药ALT-711和C36相当,且作用机制与ALT-711和C36相同。因此,C36D2能够改善糖尿病大鼠心血管功能紊乱,其机制与裂解体内过度形成的AGEs交联结构相关;C36D2是新型AGEs裂解剂C36在体内的主要要的活性形式,也是一个新型的AGEs裂解剂。
第二部分工作,首先采用慢性给予STZ诱导糖尿病大鼠1%NaCl饮水的方法,复制和建立了一种新型的糖尿病-高血压大鼠模型;在此模型建立的基础上,预灌胃给予AGEs裂解剂4周,采用乌氯合剂麻醉大鼠,颈总动脉插管监测血压,股静脉插管,从低至高浓度梯度给予硝苯地平,观察AGEs裂解剂对作用在血管平滑肌上的降压药的降压作用的影响。同时,对循环血液及肾组织中与高血压相关的一些生物活性因子的含量及基因表达进行了测定,并采用免疫组织化学的方法对肾脏中ET-1的表达进行了分析;此外,采用离体动脉环试验对AGEs裂解剂对血管及内皮细胞功能的影响进行评价。实验结果表明,给予AGEs裂解剂治疗的糖尿病-高血压大鼠对硝苯地平的降压反应明显强于对照组的糖尿病-高血压大鼠(ALT-711最大升高降压幅度达108%,C36D2达83.74%),并且其血浆NO含量明显升高(8.45±1.85,7.72±1.61 vs. 3.53±1.32μmol/L);主动脉前内皮素原基因的表达和肾脏血管紧张素原的基因表达显著降低,肾脏ET-1蛋白表达显著降低,但血浆中的AngⅡ、ET-1未表现出明显变化。此外,给予AGEs裂解剂的糖尿病大鼠胸主动脉环对ACh诱导的内皮依赖性血管舒张反应明显增强。表明,STZ致糖尿病大鼠慢性饮用1%NaCl可成功诱导出与AGEs相关的糖尿病基础上的高血压大鼠。该模型大鼠血压稳定升高,并伴有缩血管活性物质的ET-1以及肾脏AngⅡ分泌的增加;AGEs裂解剂在糖尿病高血压大鼠模型上,对硝苯地平的降压作用具有增敏效应,其机制主要与改善糖尿病诱导的血管内皮细胞功能紊乱相关。此外,AGEs裂解剂对肾脏局部RAS的影响可能也参与了此作用。
综上所述,自主研发的AGEs裂解剂C36及其水解产物C36D2作为治疗糖尿病和老年心血管系统并发症的候选药物具有进一步发展的价值;AGEs裂解剂在治疗糖尿病与老年心血管并发症的联合用药上具有广阔的应用前景。
It is urgent to treat complications induced by old age and diabetes mellitus because of rapidly increase of the elder people and morbidities of diabetes. Dysfunctions of the cardiovascular system that mainly cause the death of aged people and declining life quality of diabetic patients is the most prominent complication caused by aging and diabetes mellitus. Accordingly, the development of targeted treatment is of great significance.
Glucose and other reducing sugars react with proteins by a series of reactions to form a class of heterogeneous, nonenzymatic sugar-amino adducts that are called advanced glycation endproducts (AGEs). Formations and accumulations of AGEs crosslinks in longevity proteins of cardiovascular were closely related to cardiovascular stiffness and the decrease of cardiovascular tissues’sensitivity to bioactive molecules of aging people and diabetic patients. Breaking AGEs crosslinks is a novel therapeutic strategy based on reversing cardiovascular stiffness. Preclinical and clinical studies both indicated that AGEs breakers could explicitly improve cardiovascular system dysfunction associated with ageing and diabetes mellitus. However, AGEs breakers are developing drug with innovative ideas and mechanisms. Novel compounds with higher AGEs breaking activity still need to be further studied.
The aims of this study include two parts: In partⅠ, to research the effectiveness and mechanisms of C36D2, the main hydrolysate of the novel AGEs breaker C36, on reversing cardiovascular system stiffness in experimental diabetic rats, and to confirm whether it is the active form of C36 in vivo, and to provide experimental evidences for in vivo efficacy of C36. In partⅡ, to explore whether AGEs breakers can improve sensitivity of diabetic-hypertensive rats to antihypertensive agents and its possible mechanism.
In the first part, with C36 as the control, C36D2 was studied by classical method which was used to evaluate AGEs breakers. First of all, the specific enzyme labeled immunosorbent assay (ELISA) method was used to evaluate the ability of C36D2 to break formed crosslinks of glycated bovine serum albumin (AGEs-BSA) to the collagen in vitro, and the experiment of breaking immunoglobulin G crosslinked to diabetic rats’red blood cell surface (RBC-IgG) was used to evaluate the ability of C36D2 to break established AGEs crosslinks in vivo. And then, STZ-induced DM rats (course of DM for 3 monthes) treated with C36D2 (9 mg/kg, 18mg/kg, and 36mg/kg, respectively) for 4 weeks were studied by hemodynamic study with Doppler technique. In the measurement of cardiovascular system, systolic and diastolic blood pressure, cardiac output, and heart rate were measured. Total peripheral resistance (TPR) was determined as the quotient of mean arterial blood pressure and cardiac output. Stroke volume was calculated as the quotient of cardiac output and heart rate. Systemic arterial compliance (SAC) was calculated as the quotient of stroke volume and pulse pressure. In the measurement of left ventricle, the left ventricular systolic pressure and the left ventricular diastolic end pressure were measured and the maximal rate of left ventricular pressure rise (pos dp/dtmax) and pressure fall (neg dp/dtmax) were calculated from the digitized left ventricular pressure recording. Meanwhile, AGE contents in aorta, left ventricular myocardium, and kidney were determined by fluorescence detection. And solubility of tail-tendon collagen and ventricular myocardium were investigated by limited pepsin digestion under acidic conditions. Experimental results indicated that C36D2 could break AGEs crosslinks in vitro, and could significantly increase systemic arterial compliance, reduce total peripheral resistance and increase cardiac output in experimental diabetic rats. Moreover, the compound had the abilities to increase the left ventricular systolic pressure, the maximal rate of left ventricular pressure change and to reduce the left ventricular diastolic end pressure, and finally restored left ventricular functions in experimental diabetic rats. In addition, treatment with C36D2 resulted in an increase of solubility of tail tendon collagen and left ventricular myocardial collagen and a reduction of AGEs fluorescence in aorta, left ventricular and kidney. In conclusion, the effects of C36D2 almost resembled all those of ALT-711 and C36, and the mechanism was also similar to that of ALT-711 and C36. For the reason that C36D2 can restore cardiovascular system disorder in DM rats through the mechanism relating to breaking AGEs crosslinks over-accumulated in vivo, C36D2 should be the active form of C36, and a novel AGEs breaker.
In the second part, at the very beginning, A novel experimental diabetic-hypertensive model wad established by treating STZ-diabetic rats with 1% NaCl-drinking chronically. And then, after AGEs breakers treatment for 4 weeks, diabetic-hypertensive rats were anesthetized with urethane- chloralosane-combination. A fluid-filled catheter was introduced through the right carotid artery for blood pressure monitoring. Another catheter was introduced into femoral vein for injecting Nifedipine of gradient concentration. The influence of AGEs breakers on effect of lowering blood pressure of antihypertensive which acts on vascular smooth muscle were observed. Meanwhile, contents and gene expressions of some bioactive factors in circulation system and kidney were measured as well. Immunohistochemical method was used to assay ET-1 expression in the kidney. In addition, aorta rings experiment was applied to evaluate effects of the compound on vascular systems. The results indicated that Nifedipine had significantly better anti-hypertensive effects on diabetic-hypertensive rats with AGEs breakers treatment than those vehicle treated control . Moreover, in AGEs breakers treatment diabetic-hypertensive rats, plasma NO contents were significantly increased while expressions of preproendothelin gene in aorta and Angiotensinogen gene in renal were significantly decreased. But there was no remarkable change on plasma AngⅡor ET-1. In addition, the relaxation of thoracic aorta rings from AGEs breakers treated diabetic-hypertensive rats induced by ACh significantly exceeded those from non-treated rats. Those studies demonstrated that STZ-diabetic rats that underwent chronic 1% salt loading showed a stable elevation in blood pressure, accompanying with increases in vasoconstriction substance ET-1 and renal AngⅡ. AGEs breakers could significantly augment anti-hypertensive effects of Nifedipine in diabetic-hypertensive rats. Its mechanisms may relate to improving functions of vascular endothelial cells which had been disordered by diabetes. Besides, effects of AGEs on local renal RAS may participate in these mechanisms as well.
In conclusion, as candidates of treating diabetic and aging cardiovascular complications, C36, an noevl AGEs breaker, and its hydrolysate C36D2 have great values of further development.
晚期糖基化终产物(Advanced glycation endproducts, AGEs)是由葡萄糖及其它还原糖与蛋白质经过一系列非酶促反应形成的巨型交联物。AGEs交联结构在心血管组织的长命蛋白上的形成与积聚与老年和糖尿病患者心血管系统硬化,心血管组织对生物活性分子与外源性调节分子的敏感性下降密切相关。裂解AGEs交联结构是一种新型的、基于逆转心血管硬化的治疗策略。临床前和临床研究表明,AGEs裂解剂明确改善老年和糖尿病的心血管系统功能紊乱。
然而,作为一种发展中的具有完全创新性思路和全新机制的药物,AGEs裂解剂的新作用、作用机制以及新型AGEs裂解药物还有待进一步研究。
本研究的目的有两个,其一,对自主研发的新型AGEs裂解剂C36体内水解主要产物C36D2进行逆转糖尿病大鼠心血管系统硬化的作用及机制进行研究,确证C36D2是C36的体内活性形式,为C36体内的有效性提供实验依据。其二,探讨AGEs裂解剂通过改善心血管系统功能是否能够改善降压药物的敏感性以及可能的机制。
第一部分工作主要以C36为对照,用经典AGEs裂解剂的评价方法对C36D2进行了实验研究。首先通过体外制备牛血清白蛋白(BSA)-AGEs-胶原的交联结构,结合酶联免疫吸附测定(ELISA)方法以及裂解糖尿病大鼠红细胞表面IgG(RBC-IgG)交联实验,对C36D2进行了体外裂解体内、外形成的AGEs的评价;其后,给予STZ诱导3个月病程的糖尿病大鼠3个剂量(9、18、36 mg/kg)的C36D2 4周,采用超声多普勒结合血流动力学检测技术,对大鼠收缩压、舒张压、心率、左室内压峰值及左室舒张末期压进行了测定,并计算心输出量、总外周阻力、系统顺应性及左室内压最大变化速率;同时,采用荧光检测法测定了主动脉、左心室心肌以及肾脏组织上AGEs含量,采用酸性条件下限制性胃蛋白酶消化实验测定尾胶原、左心室心肌胶原溶解性。结果表明,C36D2能够在体外裂解体内、外形成的AGEs交联结构,在体内显著提高糖尿病大鼠系统顺应性(7.92±1.11 vs. 5.55±0.94 10-3ml/mmHg),降低总外周阻力(77.0±19.6 vs. 109.87±19.0 103.dyne.sec/cm5),增加心输出量(84.9±13.6 vs. 60.3±7.9 ml/min);显著增加糖尿病大鼠左心室内压峰值( 170.65±8.94 vs. 153.49±20.05mmHg )和左室内压最大变化速率(12201.2±1872.2 vs. 9410.2±1294.2mmHg/s)(7762.8±1320.2 vs. 6684.2±1400.7 mmHg/s),降低左室舒张末期压(5.73±1.44 vs. 8.16±3.05mmHg),改善左室功能;并增加糖尿病大鼠尾胶原、左心室心肌胶原溶解性;显著减少糖尿病大鼠主动脉、左心室心肌以及肾脏的AGEs荧光含量。其药效强度均与阳性药ALT-711和C36相当,且作用机制与ALT-711和C36相同。因此,C36D2能够改善糖尿病大鼠心血管功能紊乱,其机制与裂解体内过度形成的AGEs交联结构相关;C36D2是新型AGEs裂解剂C36在体内的主要要的活性形式,也是一个新型的AGEs裂解剂。
第二部分工作,首先采用慢性给予STZ诱导糖尿病大鼠1%NaCl饮水的方法,复制和建立了一种新型的糖尿病-高血压大鼠模型;在此模型建立的基础上,预灌胃给予AGEs裂解剂4周,采用乌氯合剂麻醉大鼠,颈总动脉插管监测血压,股静脉插管,从低至高浓度梯度给予硝苯地平,观察AGEs裂解剂对作用在血管平滑肌上的降压药的降压作用的影响。同时,对循环血液及肾组织中与高血压相关的一些生物活性因子的含量及基因表达进行了测定,并采用免疫组织化学的方法对肾脏中ET-1的表达进行了分析;此外,采用离体动脉环试验对AGEs裂解剂对血管及内皮细胞功能的影响进行评价。实验结果表明,给予AGEs裂解剂治疗的糖尿病-高血压大鼠对硝苯地平的降压反应明显强于对照组的糖尿病-高血压大鼠(ALT-711最大升高降压幅度达108%,C36D2达83.74%),并且其血浆NO含量明显升高(8.45±1.85,7.72±1.61 vs. 3.53±1.32μmol/L);主动脉前内皮素原基因的表达和肾脏血管紧张素原的基因表达显著降低,肾脏ET-1蛋白表达显著降低,但血浆中的AngⅡ、ET-1未表现出明显变化。此外,给予AGEs裂解剂的糖尿病大鼠胸主动脉环对ACh诱导的内皮依赖性血管舒张反应明显增强。表明,STZ致糖尿病大鼠慢性饮用1%NaCl可成功诱导出与AGEs相关的糖尿病基础上的高血压大鼠。该模型大鼠血压稳定升高,并伴有缩血管活性物质的ET-1以及肾脏AngⅡ分泌的增加;AGEs裂解剂在糖尿病高血压大鼠模型上,对硝苯地平的降压作用具有增敏效应,其机制主要与改善糖尿病诱导的血管内皮细胞功能紊乱相关。此外,AGEs裂解剂对肾脏局部RAS的影响可能也参与了此作用。
综上所述,自主研发的AGEs裂解剂C36及其水解产物C36D2作为治疗糖尿病和老年心血管系统并发症的候选药物具有进一步发展的价值;AGEs裂解剂在治疗糖尿病与老年心血管并发症的联合用药上具有广阔的应用前景。
It is urgent to treat complications induced by old age and diabetes mellitus because of rapidly increase of the elder people and morbidities of diabetes. Dysfunctions of the cardiovascular system that mainly cause the death of aged people and declining life quality of diabetic patients is the most prominent complication caused by aging and diabetes mellitus. Accordingly, the development of targeted treatment is of great significance.
Glucose and other reducing sugars react with proteins by a series of reactions to form a class of heterogeneous, nonenzymatic sugar-amino adducts that are called advanced glycation endproducts (AGEs). Formations and accumulations of AGEs crosslinks in longevity proteins of cardiovascular were closely related to cardiovascular stiffness and the decrease of cardiovascular tissues’sensitivity to bioactive molecules of aging people and diabetic patients. Breaking AGEs crosslinks is a novel therapeutic strategy based on reversing cardiovascular stiffness. Preclinical and clinical studies both indicated that AGEs breakers could explicitly improve cardiovascular system dysfunction associated with ageing and diabetes mellitus. However, AGEs breakers are developing drug with innovative ideas and mechanisms. Novel compounds with higher AGEs breaking activity still need to be further studied.
The aims of this study include two parts: In partⅠ, to research the effectiveness and mechanisms of C36D2, the main hydrolysate of the novel AGEs breaker C36, on reversing cardiovascular system stiffness in experimental diabetic rats, and to confirm whether it is the active form of C36 in vivo, and to provide experimental evidences for in vivo efficacy of C36. In partⅡ, to explore whether AGEs breakers can improve sensitivity of diabetic-hypertensive rats to antihypertensive agents and its possible mechanism.
In the first part, with C36 as the control, C36D2 was studied by classical method which was used to evaluate AGEs breakers. First of all, the specific enzyme labeled immunosorbent assay (ELISA) method was used to evaluate the ability of C36D2 to break formed crosslinks of glycated bovine serum albumin (AGEs-BSA) to the collagen in vitro, and the experiment of breaking immunoglobulin G crosslinked to diabetic rats’red blood cell surface (RBC-IgG) was used to evaluate the ability of C36D2 to break established AGEs crosslinks in vivo. And then, STZ-induced DM rats (course of DM for 3 monthes) treated with C36D2 (9 mg/kg, 18mg/kg, and 36mg/kg, respectively) for 4 weeks were studied by hemodynamic study with Doppler technique. In the measurement of cardiovascular system, systolic and diastolic blood pressure, cardiac output, and heart rate were measured. Total peripheral resistance (TPR) was determined as the quotient of mean arterial blood pressure and cardiac output. Stroke volume was calculated as the quotient of cardiac output and heart rate. Systemic arterial compliance (SAC) was calculated as the quotient of stroke volume and pulse pressure. In the measurement of left ventricle, the left ventricular systolic pressure and the left ventricular diastolic end pressure were measured and the maximal rate of left ventricular pressure rise (pos dp/dtmax) and pressure fall (neg dp/dtmax) were calculated from the digitized left ventricular pressure recording. Meanwhile, AGE contents in aorta, left ventricular myocardium, and kidney were determined by fluorescence detection. And solubility of tail-tendon collagen and ventricular myocardium were investigated by limited pepsin digestion under acidic conditions. Experimental results indicated that C36D2 could break AGEs crosslinks in vitro, and could significantly increase systemic arterial compliance, reduce total peripheral resistance and increase cardiac output in experimental diabetic rats. Moreover, the compound had the abilities to increase the left ventricular systolic pressure, the maximal rate of left ventricular pressure change and to reduce the left ventricular diastolic end pressure, and finally restored left ventricular functions in experimental diabetic rats. In addition, treatment with C36D2 resulted in an increase of solubility of tail tendon collagen and left ventricular myocardial collagen and a reduction of AGEs fluorescence in aorta, left ventricular and kidney. In conclusion, the effects of C36D2 almost resembled all those of ALT-711 and C36, and the mechanism was also similar to that of ALT-711 and C36. For the reason that C36D2 can restore cardiovascular system disorder in DM rats through the mechanism relating to breaking AGEs crosslinks over-accumulated in vivo, C36D2 should be the active form of C36, and a novel AGEs breaker.
In the second part, at the very beginning, A novel experimental diabetic-hypertensive model wad established by treating STZ-diabetic rats with 1% NaCl-drinking chronically. And then, after AGEs breakers treatment for 4 weeks, diabetic-hypertensive rats were anesthetized with urethane- chloralosane-combination. A fluid-filled catheter was introduced through the right carotid artery for blood pressure monitoring. Another catheter was introduced into femoral vein for injecting Nifedipine of gradient concentration. The influence of AGEs breakers on effect of lowering blood pressure of antihypertensive which acts on vascular smooth muscle were observed. Meanwhile, contents and gene expressions of some bioactive factors in circulation system and kidney were measured as well. Immunohistochemical method was used to assay ET-1 expression in the kidney. In addition, aorta rings experiment was applied to evaluate effects of the compound on vascular systems. The results indicated that Nifedipine had significantly better anti-hypertensive effects on diabetic-hypertensive rats with AGEs breakers treatment than those vehicle treated control . Moreover, in AGEs breakers treatment diabetic-hypertensive rats, plasma NO contents were significantly increased while expressions of preproendothelin gene in aorta and Angiotensinogen gene in renal were significantly decreased. But there was no remarkable change on plasma AngⅡor ET-1. In addition, the relaxation of thoracic aorta rings from AGEs breakers treated diabetic-hypertensive rats induced by ACh significantly exceeded those from non-treated rats. Those studies demonstrated that STZ-diabetic rats that underwent chronic 1% salt loading showed a stable elevation in blood pressure, accompanying with increases in vasoconstriction substance ET-1 and renal AngⅡ. AGEs breakers could significantly augment anti-hypertensive effects of Nifedipine in diabetic-hypertensive rats. Its mechanisms may relate to improving functions of vascular endothelial cells which had been disordered by diabetes. Besides, effects of AGEs on local renal RAS may participate in these mechanisms as well.
In conclusion, as candidates of treating diabetic and aging cardiovascular complications, C36, an noevl AGEs breaker, and its hydrolysate C36D2 have great values of further development.
引文
[1] S.Vasan, P.Foiles, H.Founds. Therapeutic potential of breakers of advanced glycation end product-protein crosslinks, Arch.Biochem.Biophys., 419, (2003) 89-96.
[2] A.M.Schmidt, O.Hori, J.X.Chen, J.F.Li, J.Crandall, J.Zhang, R.Cao, S.D.Yan, J.Brett, D.Stern. Advanced glycation endproducts interacting with their endothelial receptor induce expression of vascular cell adhesion molecule-1 (VCAM-1) in cultured human endothelial cells and in mice. A potential mechanism for the accelerated vasculopathy of diabetes, J.Clin.Invest, 96, (1995) 1395-1403.
[3] H.P.Hammes, A.Weiss, S.Hess, N.Araki, S.Horiuchi, M.Brownlee, K.T.Preissner. Modification of vitronectin by advanced glycation alters functional properties in vitro and in the diabetic retina, Lab Invest, 75, (1996) 325-338.
[4] S.F.Yan, R.Ramasamy, Y.Naka, A.M.Schmidt. Glycation, inflammation, and RAGE: a scaffold for the macrovascular complications of diabetes and beyond, Circ.Res., 93, (2003) 1159-1169.
[5] S.Schiekofer, M.Andrassy, J.Chen, G.Rudofsky, J.Schneider, T.Wendt, N.Stefan, P.Humpert, A.Fritsche, M.Stumvoll, E.Schleicher, H.U.Haring, P.P.Nawroth, A.Bierhaus. Acute hyperglycemia causes intracellular formation of CML and activation of ras, p42/44 MAPK, and nuclear factor kappaB in PBMCs, Diabetes, 52, (2003) 621-633.
[6] G.L.Bakris, A.J.Bank, D.A.Kass, J.M.Neutel, R.A.Preston, S.Oparil. Advanced glycation end-product cross-link breakers. A novel approach to cardiovascular pathologies related to the aging process, Am.J.Hypertens., 17, (2004) 23S-30S.
[7] D.Aronson. Cross-linking of glycated collagen in the pathogenesis of arterial and myocardial stiffening of aging and diabetes, J.Hypertens., 21, (2003) 3-12.
[8] D.Susic, J.Varagic, J.Ahn, E.D.Frohlich. Cardiovascular and renal effects of a collagen cross-link breaker (ALT 711) in adult and aged spontaneously hypertensive rats, Am.J.Hypertens., 17, (2004) 328-333.
[9] P.V.Vaitkevicius, M.Lane, H.Spurgeon, D.K.Ingram, G.S.Roth, J.J.Egan, S.Vasan, D.R.Wagle, P.Ulrich, M.Brines, J.P.Wuerth, A.Cerami, E.G.Lakatta. A cross-link breaker has sustained effects on arterial and ventricular properties in older rhesus monkeys, Proc.Natl.Acad.Sci.U.S.A, 98, (2001) 1171-1175.
[10] J.Liu, M.R.Masurekar, D.E.Vatner, G.N.Jyothirmayi, T.J.Regan, S.F.Vatner, L.G.Meggs, A.Malhotra. Glycation end-product cross-linkbreaker reduces collagen and improves cardiac function in aging diabetic heart, Am.J.Physiol Heart Circ.Physiol, 285, (2003) H2587-H2591.
[11] S.Vasan, X.Zhang, X.Zhang, A.Kapurniotu, J.Bernhagen, S.Teichberg, J.Basgen, D.Wagle, D.Shih, I.Terlecky, R.Bucala, A.Cerami, J.Egan, P.Ulrich. An agent cleaving glucose-derived protein crosslinks in vitro and in vivo, Nature, 382, (1996) 275-278.
[12] B.H.Wolffenbuttel, C.M.Boulanger, F.R.Crijns, M.S.Huijberts, P.Poitevin, G.N.Swennen, S.Vasan, J.J.Egan, P.Ulrich, A.Cerami, B.I.Levy. Breakers of advanced glycation end products restore large artery properties in experimental diabetes, Proc.Natl.Acad.Sci.U.S.A, 95, (1998) 4630-4634.
[13] R.Candido, J.M.Forbes, M.C.Thomas, V.Thallas, R.G.Dean, W.C.Burns, C.Tikellis, R.H.Ritchie, S.M.Twigg, M.E.Cooper, L.M.Burrell. A breaker of advanced glycation end products attenuates diabetes-induced myocardial structural changes, Circ.Res., 92, (2003) 785-792.
[14] D.A.Kass, E.P.Shapiro, M.Kawaguchi, A.R.Capriotti, A.Scuteri, R.C.deGroof, E.G.Lakatta. Improved arterial compliance by a novel advanced glycation end-product crosslink breaker, Circulation, 104, (2001) 1464-1470.
[15] W.C.Little, M.R.Zile, D.W.Kitzman, W.G.Hundley, T.X.O'Brien, R.C.Degroof. The effect of alagebrium chloride (ALT-711), a novel glucose cross-link breaker, in the treatment of elderly patients with diastolic heart failure, J.Card Fail., 11, (2005) 191-195.
[16] S.J.Zieman, V.Melenovsky, L.Clattenburg, M.C.Corretti, A.Capriotti, G.Gerstenblith, D.A.Kass. Advanced glycation endproduct crosslink breaker (alagebrium) improves endothelial function in patients with isolated systolic hypertension, J.Hypertens., 25, (2007) 577-583.
[17] G.Cheng, L.L.Wang, W.S.Qu, L.Long, H.Cui, H.Y.Liu, Y.L.Cao, S.Li. C16, a novel advanced glycation endproduct breaker, restores cardiovascular dysfunction in experimental diabetic rats, Acta Pharmacol.Sin., 26, (2005) 1460-1466.
[18] G.Cheng, L.L.Wang, L.Long, H.Y.Liu, H.Cui, W.S.Qu, S.Li. Beneficial effects of C36, a novel breaker of advanced glycation endproducts cross-links, on the cardiovascular system of diabetic rats, Br.J.Pharmacol., 152, (2007) 1196-1206.
[19] J.R.Sowers. Hypertension in the elderly, Am.J.Med., 82, (1987) 1-8.
[20] V.Jakus, N.Rietbrock. Advanced glycation end-products and the progress of diabetic vascular complications, Physiol Res., 53, (2004) 131-142.
[21] Z.Makita, H.Vlassara, A.Cerami, R.Bucala. Immunochemical detection of advanced glycosylation end products in vivo, J.Biol.Chem., 267, (1992)5133-5138.
[22] Wang LL, Liu HY, Wang RH. Screening breaker of advanced-glycation end-product cross-links by enzyme-linked immunosorbent assay method in vitro, Chin J Pharmacol Toxicol 18. (2004) 228-32.
[23] B.H.Wolffenbuttel, C.M.Boulanger, F.R.Crijns, M.S.Huijberts, P.Poitevin, G.N.Swennen, S.Vasan, J.J.Egan, P.Ulrich, A.Cerami, B.I.Levy. Breakers of advanced glycation end products restore large artery properties in experimental diabetes, Proc.Natl.Acad.Sci.U.S.A, 95, (1998) 4630-4634.
[24] B.I.Levy, M.Duriez, M.Phillipe, P.Poitevin, J.B.Michel. Effect of chronic dihydropyridine (isradipine) on the large arterial walls of spontaneously hypertensive rats, Circulation, 90, (1994) 3024-3033.
[25] F.C.Yin, P.A.Guzman, K.P.Brin, W.L.Maughan, J.A.Brinker, T.A.Traill, J.L.Weiss, M.L.Weisfeldt. Effect of nitroprusside on hydraulic vascular loads on the right and left ventricle of patients with heart failure, Circulation, 67, (1983) 1330-1339.
[26] D.Chemla, J.L.Hebert, C.Coirault, K.Zamani, I.Suard, P.Colin, Y.Lecarpentier. Total arterial compliance estimated by stroke volume-to-aortic pulse pressure ratio in humans, Am.J.Physiol, 274, (1998) H500-H505.
[27] G.de Simone, M.J.Roman, M.J.Koren, G.A.Mensah, A.Ganau, R.B.Devereux. Stroke volume/pulse pressure ratio and cardiovascular risk in arterial hypertension, Hypertension, 33, (1999) 800-805.
[28] K.Yamamoto, T.Masuyama, Y.Sakata, N.Nishikawa, T.Mano, J.Yoshida, T.Miwa, M.Sugawara, Y.Yamaguchi, T.Ookawara, K.Suzuki, M.Hori. Myocardial stiffness is determined by ventricular fibrosis, but not by compensatory or excessive hypertrophy in hypertensive heart, Cardiovasc.Res., 55, (2002) 76-82.
[29] V.M.Monnier, V.Vishwanath, K.E.Frank, C.A.Elmets, P.Dauchot, R.R.Kohn. Relation between complications of type I diabetes mellitus and collagen-linked fluorescence, N.Engl.J.Med., 314, (1986) 403-408.
[30] R.Candido, J.M.Forbes, M.C.Thomas, V.Thallas, R.G.Dean, W.C.Burns, C.Tikellis, R.H.Ritchie, S.M.Twigg, M.E.Cooper, L.M.Burrell. A breaker of advanced glycation end products attenuates diabetes-induced myocardial structural changes, Circ.Res., 92, (2003) 785-792.
[31] T.Mitsuhashi, H.Nakayama, T.Itoh, S.Kuwajima, S.Aoki, T.Atsumi, T.Koike. Immunochemical detection of advanced glycation end products in renal cortex from STZ-induced diabetic rat, Diabetes, 42, (1993) 826-832.
[32] M.Kochakian, B.N.Manjula, J.J.Egan. Chronic dosing with aminoguanidine and novel advanced glycosylation end product-formationinhibitors ameliorates cross-linking of tail tendon collagen in STZ-induced diabetic rats, Diabetes, 45, (1996) 1694-1700.
[33] H.Stegemann, K.Stalder. Determination of hydroxyproline, Clin.Chim.Acta, 18, (1967) 267-273.
[34] R.Candido, J.M.Forbes, M.C.Thomas, V.Thallas, R.G.Dean, W.C.Burns, C.Tikellis, R.H.Ritchie, S.M.Twigg, M.E.Cooper, L.M.Burrell. A breaker of advanced glycation end products attenuates diabetes-induced myocardial structural changes, Circ.Res., 92, (2003) 785-792.
[35] M.E.Cooper, V.Thallas, J.Forbes, E.Scalbert, S.Sastra, I.Darby, T.Soulis. The cross-link breaker, N-phenacylthiazolium bromide prevents vascular advanced glycation end-product accumulation, Diabetologia, 43, (2000) 660-664.
[36] M.Brownlee, H.Vlassara, A.Kooney, P.Ulrich, A.Cerami. Aminoguanidine prevents diabetes-induced arterial wall protein cross-linking, Science, 232, (1986) 1629-1632.
[37] A.Kizu, H.Koyama, S.Tanaka, T.Maeno, M.Komatsu, S.Fukumoto, M.Emoto, T.Shoji, M.Inaba, A.Shioi, T.Miki, Y.Nishizawa. Arterial wall stiffness is associated with peripheral circulation in patients with type 2 diabetes, Atherosclerosis, 170, (2003) 87-91.
[38] J.R.Cockcroft, D.J.Webb, I.B.Wilkinson. Arterial stiffness, hypertension and diabetes mellitus, J.Hum.Hypertens., 14, (2000) 377-380.
[39] S.E.Papapietro, H.C.Coghlan, D.Zissermann, R.O.Russell, Jr., C.E.Rackley, W.J.Rogers. Impaired maximal rate of left ventricular relaxation in patients with coronary artery disease and left ventricular dysfunction, Circulation, 59, (1979) 984-991.
[40] G.F.Avendano, R.K.Agarwal, R.I.Bashey, M.M.Lyons, B.J.Soni, G.N.Jyothirmayi, T.J.Regan. Effects of glucose intolerance on myocardial function and collagen-linked glycation, Diabetes, 48, (1999) 1443-1447.
[41] J.Lambert, R.A.Smulders, M.Aarsen, A.J.Donker, C.D.Stehouwer. Carotid artery stiffness is increased in microalbuminuric IDDM patients, Diabetes Care, 21, (1998) 99-103.
[42] D.D.Waters, P.Da Luz, H.L.Wyatt, H.J.Swan, J.S.Forrester. Early changes in regional and global left ventricular function induced by graded reductions in regional coronary perfusion, Am.J.Cardiol., 39, (1977) 537-543.
[43] K.E.Airaksinen, P.I.Salmela, M.K.Linnaluoto, M.J.Ikaheimo, K.Ahola, L.J.Ryhanen. Diminished arterial elasticity in diabetes: association with fluorescent advanced glycosylation end products in collagen, Cardiovasc.Res., 27, (1993) 942-945.
[44] F.R.Buhler. Age and pathophysiology-oriented antihypertensive response to calcium antagonists, J.Cardiovasc.Pharmacol., 12 Suppl 8, (1988) S156-S166.
[45] R.W.Piepho, K.J.Fendler. Antihypertensive therapy in the aged patient. Clinical pharmacokinetic considerations, Drugs Aging, 1, (1991) 194-211.
[46] P.Ulrich, A.Cerami. Protein glycation, diabetes, and aging, Recent Prog.Horm.Res., 56, (2001) 1-21.
[47] M.Asif, J.Egan, S.Vasan, G.N.Jyothirmayi, M.R.Masurekar, S.Lopez, C.Williams, R.L.Torres, D.Wagle, P.Ulrich, A.Cerami, M.Brines, T.J.Regan. An advanced glycation endproduct cross-link breaker can reverse age-related increases in myocardial stiffness, Proc.Natl.Acad.Sci.U.S.A, 97, (2000) 2809-2813.
[48] Donald E , Kohen MD. Endothelin in normal and diseased kidney, Am J Kidney Dis., 29, (2002) 2 - 26.
[49] T.Nabika, Z.Cui, J.Masuda. The stroke-prone spontaneously hypertensive rat: how good is it as a model for cerebrovascular diseases?, Cell Mol.Neurobiol., 24, (2004) 639-646.
[50] M.E.Cooper, T.J.Allen, G.Jerums, A.E.Doyle. Accelerated progression of diabetic nephropathy in the spontaneously hypertensive streptozotocin diabetic rat, Clin.Exp.Pharmacol.Physiol, 13, (1986) 655-662.
[51] A.J.Pijl, A.C.van der Wal, M.J.Mathy, K.L.Kam, M.G.Hendriks, M.Pfaffendorf, P.A.van Zwieten. Streptozotocin-induced diabetes mellitus in spontaneously hypertensive rats: a pathophysiological model for the combined effects of hypertension and diabetes, J.Pharmacol.Toxicol.Methods, 32, (1994) 225-233.
[52] S.Taddei, A.Virdis, L.Ghiadoni, A.Salvetti. Vascular effects of endothelin-1 in essential hypertension: relationship with cyclooxygenase-derived endothelium-dependent contracting factors and nitric oxide, J.Cardiovasc.Pharmacol., 35, (2000) S37-S40.
[53] M.J.Mulvany. Mechanical and other factors involved in vascular injury related to hypertension, Blood Press Suppl, 1, (1994) 11-17.
[54] R.Kikkawa, E.Kitamura, Y.Fujiwara, M.Haneda, Y.Shigeta. Biphasic alteration of renin-angiotensin-aldosterone system in streptozotocin-diabetic rats, Ren Physiol, 9, (1986) 187-192.
[55] Ritz, S.F.Yan, A.M.Schmidt. Hypertension and vascular disease as complications of diabetes. In: Laragh JH, Brenner BM. Eds. Arteriosclerosis, New York: Raven Press., (1990) 1703~1715.
[56] R.C.Turner. The U.K. Prospective Diabetes Study. A review, Diabetes Care, 21 Suppl 3, (1998) C35-C38.
[57] W.A.Hsueh, P.W.Anderson. Hypertension, the endothelial cell, and the vascular complications of diabetes mellitus, Hypertension, 20, (1992) 253-263.
[58] M.E.Todd. Hypertensive structural changes in blood vessels: do endothelial cells hold the key?, Can.J.Physiol Pharmacol., 70, (1992) 536-551.
[59] L. Deming, Z. Yinong. Chinese journal of anatomy, 6, (1996) 517-521.
[60] M.Yanagisawa, H.Kurihara, S.Kimura, Y.Tomobe, M.Kobayashi, Y.Mitsui, Y.Yazaki, K.Goto, T.Masaki. A novel potent vasoconstrictor peptide produced by vascular endothelial cells, Nature, 332, (1988) 411-415.
[61] K.C.Tan, W.S.Chow, V.H.Ai, C.Metz, R.Bucala, K.S.Lam. Advanced glycation end products and endothelial dysfunction in type 2 diabetes, Diabetes Care, 25, (2002) 1055-1059.
[2] A.M.Schmidt, O.Hori, J.X.Chen, J.F.Li, J.Crandall, J.Zhang, R.Cao, S.D.Yan, J.Brett, D.Stern. Advanced glycation endproducts interacting with their endothelial receptor induce expression of vascular cell adhesion molecule-1 (VCAM-1) in cultured human endothelial cells and in mice. A potential mechanism for the accelerated vasculopathy of diabetes, J.Clin.Invest, 96, (1995) 1395-1403.
[3] H.P.Hammes, A.Weiss, S.Hess, N.Araki, S.Horiuchi, M.Brownlee, K.T.Preissner. Modification of vitronectin by advanced glycation alters functional properties in vitro and in the diabetic retina, Lab Invest, 75, (1996) 325-338.
[4] S.F.Yan, R.Ramasamy, Y.Naka, A.M.Schmidt. Glycation, inflammation, and RAGE: a scaffold for the macrovascular complications of diabetes and beyond, Circ.Res., 93, (2003) 1159-1169.
[5] S.Schiekofer, M.Andrassy, J.Chen, G.Rudofsky, J.Schneider, T.Wendt, N.Stefan, P.Humpert, A.Fritsche, M.Stumvoll, E.Schleicher, H.U.Haring, P.P.Nawroth, A.Bierhaus. Acute hyperglycemia causes intracellular formation of CML and activation of ras, p42/44 MAPK, and nuclear factor kappaB in PBMCs, Diabetes, 52, (2003) 621-633.
[6] G.L.Bakris, A.J.Bank, D.A.Kass, J.M.Neutel, R.A.Preston, S.Oparil. Advanced glycation end-product cross-link breakers. A novel approach to cardiovascular pathologies related to the aging process, Am.J.Hypertens., 17, (2004) 23S-30S.
[7] D.Aronson. Cross-linking of glycated collagen in the pathogenesis of arterial and myocardial stiffening of aging and diabetes, J.Hypertens., 21, (2003) 3-12.
[8] D.Susic, J.Varagic, J.Ahn, E.D.Frohlich. Cardiovascular and renal effects of a collagen cross-link breaker (ALT 711) in adult and aged spontaneously hypertensive rats, Am.J.Hypertens., 17, (2004) 328-333.
[9] P.V.Vaitkevicius, M.Lane, H.Spurgeon, D.K.Ingram, G.S.Roth, J.J.Egan, S.Vasan, D.R.Wagle, P.Ulrich, M.Brines, J.P.Wuerth, A.Cerami, E.G.Lakatta. A cross-link breaker has sustained effects on arterial and ventricular properties in older rhesus monkeys, Proc.Natl.Acad.Sci.U.S.A, 98, (2001) 1171-1175.
[10] J.Liu, M.R.Masurekar, D.E.Vatner, G.N.Jyothirmayi, T.J.Regan, S.F.Vatner, L.G.Meggs, A.Malhotra. Glycation end-product cross-linkbreaker reduces collagen and improves cardiac function in aging diabetic heart, Am.J.Physiol Heart Circ.Physiol, 285, (2003) H2587-H2591.
[11] S.Vasan, X.Zhang, X.Zhang, A.Kapurniotu, J.Bernhagen, S.Teichberg, J.Basgen, D.Wagle, D.Shih, I.Terlecky, R.Bucala, A.Cerami, J.Egan, P.Ulrich. An agent cleaving glucose-derived protein crosslinks in vitro and in vivo, Nature, 382, (1996) 275-278.
[12] B.H.Wolffenbuttel, C.M.Boulanger, F.R.Crijns, M.S.Huijberts, P.Poitevin, G.N.Swennen, S.Vasan, J.J.Egan, P.Ulrich, A.Cerami, B.I.Levy. Breakers of advanced glycation end products restore large artery properties in experimental diabetes, Proc.Natl.Acad.Sci.U.S.A, 95, (1998) 4630-4634.
[13] R.Candido, J.M.Forbes, M.C.Thomas, V.Thallas, R.G.Dean, W.C.Burns, C.Tikellis, R.H.Ritchie, S.M.Twigg, M.E.Cooper, L.M.Burrell. A breaker of advanced glycation end products attenuates diabetes-induced myocardial structural changes, Circ.Res., 92, (2003) 785-792.
[14] D.A.Kass, E.P.Shapiro, M.Kawaguchi, A.R.Capriotti, A.Scuteri, R.C.deGroof, E.G.Lakatta. Improved arterial compliance by a novel advanced glycation end-product crosslink breaker, Circulation, 104, (2001) 1464-1470.
[15] W.C.Little, M.R.Zile, D.W.Kitzman, W.G.Hundley, T.X.O'Brien, R.C.Degroof. The effect of alagebrium chloride (ALT-711), a novel glucose cross-link breaker, in the treatment of elderly patients with diastolic heart failure, J.Card Fail., 11, (2005) 191-195.
[16] S.J.Zieman, V.Melenovsky, L.Clattenburg, M.C.Corretti, A.Capriotti, G.Gerstenblith, D.A.Kass. Advanced glycation endproduct crosslink breaker (alagebrium) improves endothelial function in patients with isolated systolic hypertension, J.Hypertens., 25, (2007) 577-583.
[17] G.Cheng, L.L.Wang, W.S.Qu, L.Long, H.Cui, H.Y.Liu, Y.L.Cao, S.Li. C16, a novel advanced glycation endproduct breaker, restores cardiovascular dysfunction in experimental diabetic rats, Acta Pharmacol.Sin., 26, (2005) 1460-1466.
[18] G.Cheng, L.L.Wang, L.Long, H.Y.Liu, H.Cui, W.S.Qu, S.Li. Beneficial effects of C36, a novel breaker of advanced glycation endproducts cross-links, on the cardiovascular system of diabetic rats, Br.J.Pharmacol., 152, (2007) 1196-1206.
[19] J.R.Sowers. Hypertension in the elderly, Am.J.Med., 82, (1987) 1-8.
[20] V.Jakus, N.Rietbrock. Advanced glycation end-products and the progress of diabetic vascular complications, Physiol Res., 53, (2004) 131-142.
[21] Z.Makita, H.Vlassara, A.Cerami, R.Bucala. Immunochemical detection of advanced glycosylation end products in vivo, J.Biol.Chem., 267, (1992)5133-5138.
[22] Wang LL, Liu HY, Wang RH. Screening breaker of advanced-glycation end-product cross-links by enzyme-linked immunosorbent assay method in vitro, Chin J Pharmacol Toxicol 18. (2004) 228-32.
[23] B.H.Wolffenbuttel, C.M.Boulanger, F.R.Crijns, M.S.Huijberts, P.Poitevin, G.N.Swennen, S.Vasan, J.J.Egan, P.Ulrich, A.Cerami, B.I.Levy. Breakers of advanced glycation end products restore large artery properties in experimental diabetes, Proc.Natl.Acad.Sci.U.S.A, 95, (1998) 4630-4634.
[24] B.I.Levy, M.Duriez, M.Phillipe, P.Poitevin, J.B.Michel. Effect of chronic dihydropyridine (isradipine) on the large arterial walls of spontaneously hypertensive rats, Circulation, 90, (1994) 3024-3033.
[25] F.C.Yin, P.A.Guzman, K.P.Brin, W.L.Maughan, J.A.Brinker, T.A.Traill, J.L.Weiss, M.L.Weisfeldt. Effect of nitroprusside on hydraulic vascular loads on the right and left ventricle of patients with heart failure, Circulation, 67, (1983) 1330-1339.
[26] D.Chemla, J.L.Hebert, C.Coirault, K.Zamani, I.Suard, P.Colin, Y.Lecarpentier. Total arterial compliance estimated by stroke volume-to-aortic pulse pressure ratio in humans, Am.J.Physiol, 274, (1998) H500-H505.
[27] G.de Simone, M.J.Roman, M.J.Koren, G.A.Mensah, A.Ganau, R.B.Devereux. Stroke volume/pulse pressure ratio and cardiovascular risk in arterial hypertension, Hypertension, 33, (1999) 800-805.
[28] K.Yamamoto, T.Masuyama, Y.Sakata, N.Nishikawa, T.Mano, J.Yoshida, T.Miwa, M.Sugawara, Y.Yamaguchi, T.Ookawara, K.Suzuki, M.Hori. Myocardial stiffness is determined by ventricular fibrosis, but not by compensatory or excessive hypertrophy in hypertensive heart, Cardiovasc.Res., 55, (2002) 76-82.
[29] V.M.Monnier, V.Vishwanath, K.E.Frank, C.A.Elmets, P.Dauchot, R.R.Kohn. Relation between complications of type I diabetes mellitus and collagen-linked fluorescence, N.Engl.J.Med., 314, (1986) 403-408.
[30] R.Candido, J.M.Forbes, M.C.Thomas, V.Thallas, R.G.Dean, W.C.Burns, C.Tikellis, R.H.Ritchie, S.M.Twigg, M.E.Cooper, L.M.Burrell. A breaker of advanced glycation end products attenuates diabetes-induced myocardial structural changes, Circ.Res., 92, (2003) 785-792.
[31] T.Mitsuhashi, H.Nakayama, T.Itoh, S.Kuwajima, S.Aoki, T.Atsumi, T.Koike. Immunochemical detection of advanced glycation end products in renal cortex from STZ-induced diabetic rat, Diabetes, 42, (1993) 826-832.
[32] M.Kochakian, B.N.Manjula, J.J.Egan. Chronic dosing with aminoguanidine and novel advanced glycosylation end product-formationinhibitors ameliorates cross-linking of tail tendon collagen in STZ-induced diabetic rats, Diabetes, 45, (1996) 1694-1700.
[33] H.Stegemann, K.Stalder. Determination of hydroxyproline, Clin.Chim.Acta, 18, (1967) 267-273.
[34] R.Candido, J.M.Forbes, M.C.Thomas, V.Thallas, R.G.Dean, W.C.Burns, C.Tikellis, R.H.Ritchie, S.M.Twigg, M.E.Cooper, L.M.Burrell. A breaker of advanced glycation end products attenuates diabetes-induced myocardial structural changes, Circ.Res., 92, (2003) 785-792.
[35] M.E.Cooper, V.Thallas, J.Forbes, E.Scalbert, S.Sastra, I.Darby, T.Soulis. The cross-link breaker, N-phenacylthiazolium bromide prevents vascular advanced glycation end-product accumulation, Diabetologia, 43, (2000) 660-664.
[36] M.Brownlee, H.Vlassara, A.Kooney, P.Ulrich, A.Cerami. Aminoguanidine prevents diabetes-induced arterial wall protein cross-linking, Science, 232, (1986) 1629-1632.
[37] A.Kizu, H.Koyama, S.Tanaka, T.Maeno, M.Komatsu, S.Fukumoto, M.Emoto, T.Shoji, M.Inaba, A.Shioi, T.Miki, Y.Nishizawa. Arterial wall stiffness is associated with peripheral circulation in patients with type 2 diabetes, Atherosclerosis, 170, (2003) 87-91.
[38] J.R.Cockcroft, D.J.Webb, I.B.Wilkinson. Arterial stiffness, hypertension and diabetes mellitus, J.Hum.Hypertens., 14, (2000) 377-380.
[39] S.E.Papapietro, H.C.Coghlan, D.Zissermann, R.O.Russell, Jr., C.E.Rackley, W.J.Rogers. Impaired maximal rate of left ventricular relaxation in patients with coronary artery disease and left ventricular dysfunction, Circulation, 59, (1979) 984-991.
[40] G.F.Avendano, R.K.Agarwal, R.I.Bashey, M.M.Lyons, B.J.Soni, G.N.Jyothirmayi, T.J.Regan. Effects of glucose intolerance on myocardial function and collagen-linked glycation, Diabetes, 48, (1999) 1443-1447.
[41] J.Lambert, R.A.Smulders, M.Aarsen, A.J.Donker, C.D.Stehouwer. Carotid artery stiffness is increased in microalbuminuric IDDM patients, Diabetes Care, 21, (1998) 99-103.
[42] D.D.Waters, P.Da Luz, H.L.Wyatt, H.J.Swan, J.S.Forrester. Early changes in regional and global left ventricular function induced by graded reductions in regional coronary perfusion, Am.J.Cardiol., 39, (1977) 537-543.
[43] K.E.Airaksinen, P.I.Salmela, M.K.Linnaluoto, M.J.Ikaheimo, K.Ahola, L.J.Ryhanen. Diminished arterial elasticity in diabetes: association with fluorescent advanced glycosylation end products in collagen, Cardiovasc.Res., 27, (1993) 942-945.
[44] F.R.Buhler. Age and pathophysiology-oriented antihypertensive response to calcium antagonists, J.Cardiovasc.Pharmacol., 12 Suppl 8, (1988) S156-S166.
[45] R.W.Piepho, K.J.Fendler. Antihypertensive therapy in the aged patient. Clinical pharmacokinetic considerations, Drugs Aging, 1, (1991) 194-211.
[46] P.Ulrich, A.Cerami. Protein glycation, diabetes, and aging, Recent Prog.Horm.Res., 56, (2001) 1-21.
[47] M.Asif, J.Egan, S.Vasan, G.N.Jyothirmayi, M.R.Masurekar, S.Lopez, C.Williams, R.L.Torres, D.Wagle, P.Ulrich, A.Cerami, M.Brines, T.J.Regan. An advanced glycation endproduct cross-link breaker can reverse age-related increases in myocardial stiffness, Proc.Natl.Acad.Sci.U.S.A, 97, (2000) 2809-2813.
[48] Donald E , Kohen MD. Endothelin in normal and diseased kidney, Am J Kidney Dis., 29, (2002) 2 - 26.
[49] T.Nabika, Z.Cui, J.Masuda. The stroke-prone spontaneously hypertensive rat: how good is it as a model for cerebrovascular diseases?, Cell Mol.Neurobiol., 24, (2004) 639-646.
[50] M.E.Cooper, T.J.Allen, G.Jerums, A.E.Doyle. Accelerated progression of diabetic nephropathy in the spontaneously hypertensive streptozotocin diabetic rat, Clin.Exp.Pharmacol.Physiol, 13, (1986) 655-662.
[51] A.J.Pijl, A.C.van der Wal, M.J.Mathy, K.L.Kam, M.G.Hendriks, M.Pfaffendorf, P.A.van Zwieten. Streptozotocin-induced diabetes mellitus in spontaneously hypertensive rats: a pathophysiological model for the combined effects of hypertension and diabetes, J.Pharmacol.Toxicol.Methods, 32, (1994) 225-233.
[52] S.Taddei, A.Virdis, L.Ghiadoni, A.Salvetti. Vascular effects of endothelin-1 in essential hypertension: relationship with cyclooxygenase-derived endothelium-dependent contracting factors and nitric oxide, J.Cardiovasc.Pharmacol., 35, (2000) S37-S40.
[53] M.J.Mulvany. Mechanical and other factors involved in vascular injury related to hypertension, Blood Press Suppl, 1, (1994) 11-17.
[54] R.Kikkawa, E.Kitamura, Y.Fujiwara, M.Haneda, Y.Shigeta. Biphasic alteration of renin-angiotensin-aldosterone system in streptozotocin-diabetic rats, Ren Physiol, 9, (1986) 187-192.
[55] Ritz, S.F.Yan, A.M.Schmidt. Hypertension and vascular disease as complications of diabetes. In: Laragh JH, Brenner BM. Eds. Arteriosclerosis, New York: Raven Press., (1990) 1703~1715.
[56] R.C.Turner. The U.K. Prospective Diabetes Study. A review, Diabetes Care, 21 Suppl 3, (1998) C35-C38.
[57] W.A.Hsueh, P.W.Anderson. Hypertension, the endothelial cell, and the vascular complications of diabetes mellitus, Hypertension, 20, (1992) 253-263.
[58] M.E.Todd. Hypertensive structural changes in blood vessels: do endothelial cells hold the key?, Can.J.Physiol Pharmacol., 70, (1992) 536-551.
[59] L. Deming, Z. Yinong. Chinese journal of anatomy, 6, (1996) 517-521.
[60] M.Yanagisawa, H.Kurihara, S.Kimura, Y.Tomobe, M.Kobayashi, Y.Mitsui, Y.Yazaki, K.Goto, T.Masaki. A novel potent vasoconstrictor peptide produced by vascular endothelial cells, Nature, 332, (1988) 411-415.
[61] K.C.Tan, W.S.Chow, V.H.Ai, C.Metz, R.Bucala, K.S.Lam. Advanced glycation end products and endothelial dysfunction in type 2 diabetes, Diabetes Care, 25, (2002) 1055-1059.