Pyridoxamone能延緩STZ誘發之糖尿病鼠之動脈硬化及心室肥厚

Pyridoxamine prevents arterial stiffening and cardiac hypertrophy in streptozotocin-induced diabetes in rats

蔡佩珊(Pei-Shan Tsai)

指導教授 ： 張國柱

國立臺灣大學/醫學院/生理學研究所/碩士(2008年)

https://doi.org/10.6342/NTU.2008.00909

摘要

背景：動脈管壁中的膠原蛋白間所形成之醣化最終產物 (advanced glycation end products, AGEs)，是導致糖尿病引發血管傷害的主因之一。本篇的研究目的是釐清pyridoxamine (PM) 這項AGEs抑制劑，在streptozotocin誘發之糖尿病大鼠中，對於減緩動脈硬化及心室肥
大等病徵所扮演的角色。
方法：八週大的Wistar-Kyoto大鼠從尾部靜脈注射streptozotocin (STZ, 55 mg kg-1) 以誘發糖尿病。兩天後經檢測確定已顯現高血糖病徵，再每天餵予PM（一公克溶於一公升的飲用水) 進行為期八週的療程，
並以年齡匹配之糖尿病鼠作為對照組別。
結果：與糖尿病鼠組別相較，經由PM治療八週後的糖尿病鼠顯示，無論在心輸出量、主動脈血壓相關數據、總周邊阻力及主動脈特徵阻抗等參數上均無差異。相對的，在經PM治療後，波傳輸時間 (wave transit time, τ) 明顯增加 (20.80±0.45 v.s. 25.11±0.56 ms, P＜0.01)，且波反射係數大幅降低 (0.744±0.047 v.s. 0.485±0.028, P＜0.01)。波反射係數下降及波傳輸時間上升，顯示PM能改善糖尿病所造成左心室收縮負荷的增加。此外，心室重量以體重校正後之比值 (心室肥厚的指標) 亦可經由投予PM後減少，這顯示糖尿病所導致的心室肥厚可因PM降低左心室後負荷的作用而獲得改善。另外，醣化作用會促進主動脈管壁中膠原蛋白含量的增加，此現象亦可經由PM的治療得到改
善。
結論：經過PM長期治療後，能顯著改善糖尿病所引起之血管力學傷害，推測可能是由於PM抑制動脈管壁AGEs的形成與累積所致。

關鍵字

醣化最終產物 ； 主動脈輸入阻抗 ； STZ糖尿病鼠 ； 波反射 ； pyridoxamine

並列摘要

Objective: The formation of advanced glycation end products (AGEs) on collagen within the arterial wall is one of the major factors responsible for the development of diabetic vascular injury. This study was performed to examine the role of pyridoxamine (PM), an inhibitor of AGEs formation, in prevention of arterial stiffening and cardiac hypertrophy in
streptozocin (STZ) induced diabetes in rats.
Methods: Diabetes was induced in Wistar-Kyoto rats by a single tail vein injection with STZ (55 mg kg-1). After confirmation of development of hyperglycemia (2 days later), rats were treated for 8 weeks with PM (1 g L-1 in drinking water) and compared with the age-matched untreated
diabetic controls.
Results: After exposure to PM, the STZ-diabetic rats showed no alterations in cardiac output, aortic pressure profiles, total peripheral resistance, and aortic characteristic impedance. In contrast, treatment of this experimental diabetes with PM resulted in a significant increase in wave transit time (τ), from 20.80±0.45 to 25.11±0.56 ms (P<0.01) and a decrease in wave reflection factor (Rf), from 0.744±0.047 to 0.485±0.028 (P<0.01). The decreased Rf associated with the increased τ suggest that PM may retard the diabetes-induced augmentation in systolic load of the left ventricle coupled to its arterial system. Meanwhile, the diminished ratio of left ventricular weight to body weight suggests that prevention of the diabetes-related cardiac hypertrophy by PM may correspond to drug-induced decline in aortic stiffening. Glycation-derived modification on aortic collagen was also found to be enhanced in rats with diabetes and
the advanced glycation process was retarded by PM treatment.
Conclusions: We concluded that long-term administration of PM to the STZ-treated rats imparts significant protection against the diabetes-derived deterioration in vascular dynamics, in part through
inhibition of the accumulation of AGEs on collagen in the arterial wall.

並列關鍵字

advanced glycation end products ； aortic input impedance ； streptozotocin-diabetic rats ； pulse wave reflection ； pyridoxamine

參考文獻

Abe T, Ohga Y, Nobuoki T, Kobayashi S, Sakata S, Misawa H, Tsuyushi T, Kohzuki H, Suga H, Taniguchi S, Takaki M. Left ventricular diastolic dysfunction in type 2 diabetes mellitus model rats. Am J Phyiol Heart Circ Physiol 2002; 282: H138-H148.

Abiru T, Watanabe Y, Kamata K, Kasuy Y. Changes in endothelium-dependent relaxation and levels of cyclic nucleotides in the perfuse mesenteric arterial bed from streptozotozin-induced diabetic rats. Life Sci 1993; 53: 7-12.

Amarnath V, Amarnath K, Amarnath K, Davies S, Roberts LJ 2nd. Pyridoxamine: an extremely potent scavenger of 1, 4-dicarbonyls. Chem Res Toxicol 2004; 17: 410-415.

Ballermann B, Skorecki K, Brenner B. Reduced glomerular angiotensin II receptor density in early untreated diabetes mellitus in the rats. Rennl Fluid Electrolyte Physiol 1984; 16: F110-F116.

Basta G, Schmidt AM, De Caterina R. Advanced glycation end products and vascular inflammation: implications for accelerated atherosclerosis in diabetes. Cardiovasc Res 2004; 63: 582-592.