Aminoguanidine對第二型糖尿病之新鼠模式的治療所產生動脈力學之影響

Abstract

長存於活結締組織之非酵素進展醣化最終產物的形成 (formation of advanced glycation end products, AGEs) 可能是糖尿病導致動脈管硬化、血管窄縮以及血管壁上膠原蛋白硬化等併發症的原因之一。1998年Masiello等人發展第二型糖尿病之一新鼠模式，此實驗症候群相較於其他動物模式更接近人類第二型糖尿病之臨床特徵。本實驗之主要目的乃在檢測長期投與Aminoguanidine (AG) 可否透過抑制AGEs的形成以改善高血糖所誘發動脈血行力學（如血管壁的彈性以及波反射現象）的變化。八週大成鼠禁食40小時之後先給予腹腔注射180 mg/kg之nicotinamide (NA) 以保護胰島素β細胞，30分鐘之後再靜脈注射50 mg/kg streptozotocin (STZ) 以誘發非胰島素相依型尿糖病，並以年齡匹配之正常鼠作為對照組別。此外，每天給予STZ-NA糖尿病鼠腹腔注射50 mg/kg AG，為期四週和八週作為治療組，並與無治療之糖尿病鼠相比較。在以180 mg/kg劑量的前處理下，我們發現NA可防止老鼠因STZ所造成體重的減輕、過高的血糖以及過低的胰島素等現象。此實驗症候群呈現輕微且穩定的高血糖及出現葡萄糖耐受性不良等現象。相較於正常組，第八週而非第四週之糖尿病鼠在血壓沒有改變的情況下，心輸出量的下降可導致周邊阻力(Rp) 的增加 (54.9 ± 2.5 v.s. 65.8 ± 2.8 mmHg·s·ml-1, P＜0.05)。脈態參數方面，第八週之糖尿病鼠顯示特徵阻抗( Zc ) 增加 (從1.489 ± 0.105增至1.952 ± 0.091 mmHg·s·ml-1, P＜0.05) 且波傳輸時間 (t) 變短 (從25.8 ± 1.2減至20.6 ± 0.9 ms, P＜0.05)。增加的特徵阻抗和變短的波傳輸時間提供動脈管壁延展性 (Distensibility) 變差的指標。此外，波反射強度的增加可以從波傳輸時間變短及波反射係數增加 (Rf，0.49 ± 0.03 v.s. 0.61 ± 0.04, P＜0.05) 得知。經由八週投與AG治療後，週邊阻力下降18%，驗証了AG可以改善糖尿病阻力性血管的物理特性。此外，硬化的糖尿病主動脈也可經由AG的投與而獲得顯著的改善 (特徵阻抗減少了18.7%、波傳輸時間增加了21.8%)。波傳輸時間的增加及波反射係數的下降 (22.9%) 顯示AG可改善高血糖所導致左心室收縮負荷的增加。另外，心室重量以體重校正後之比值 (心室肥厚的指標) 亦可經由AG投與後而減少，這顯示糖尿病所導致的心室肥厚可因AG降低心室後負荷的作用而獲得改善。然而，與正常組相較，第四週之糖尿病鼠不論是彈性血管或是阻力性血管之力學特性並沒有顯著差異。本實驗之結論：在發病第八週而非第四週之第二型糖尿病鼠，其動脈血流的物理特性可因高血糖而受到傷害。AG投與8週之後，推測糖尿病鼠血流力學的改善是AG經由抑制動脈管壁AGEs的形成以改善動脈管壁的延展性。

A new experimental type 2 diabetic syndrome, which is closer to human non-insulin-dependent diabetes mellitus, has been reported in adult rats administered streptozotocin (STZ) and partially protected with a suitable dose of nicotinamide (NA). The accelerated formation of advanced glycation end products (AGEs) on long-lived connective tissue may account for some of the complications of diabetes such as stiffing of collagen, vascular narrowing, and arterial stiffing. In this study, we determined the effects of long-term treatment with aminoguanidine (AG), an inhibitor of AGEs formation, on hemodynamic parameters describing arterial wall elasticity and pulse wave reflection in STZ-NA diabetic rats. Rats at 2 months were given NA 180mg/Kg i.p., 30 mins before an intravenous injection of 50mg/Kg STZ . This STZ-NA rats before use, and compared with the untreated age-matched controls. Mean while, the STZ-NA diabetic rats were treated for 4 (STZ-NA4) and 8 weeks (STZ-NA8) with AG (daily peritoneal injections of 50 mg/kg) and compared with the untreated diabetic groups. At 180 mg/Kg, NA largely prevented STZ-induced body weight loss, hyperglycemia, and hypoinsulinemia in the rats with diabetes. In comparison with controls, the STZ-NA rats of 8 weeks but not 4 weeks after induction of diabetes showed a decrease in cardiac output in the absence of any significant changes in mean aortic pressure, having increased total peripheral resistance (Rp), at 54.9±2.5 versus 65.8±2.8mmHg•s•ml-1 (P＜0.05).The STZ-NA8 diabetes also contributed to an increase in aortic characteristic impedance (Zc), from 1.489±0.105 to 1.952±0.091 mmHg．s．ml-1 (P＜0.05) and a decrease in wave transit time (τ), from 25.8±1.2 to 20.6±0.91 ms (P＜0.05). The elevated Zc and the reduced τ suggest that STZ-NA8 diabetic rats may have a detrimental effect on aortic distensibility. Meanwhile, the heavy reflection intensity occurred in rats with STZ-NA of 8 weeks diabetes because of the diminished τ and the increased wave reflection factor (Rf) (0.49±0.03 versus 0.61±0.04, P＜0.05). After exposure to AG, the STZ-NA8 diabetic rats exhibited a significant improvement in physical properties of the resistance vessels, as evidenced by the reduction of 18.1﹪in Rp. Meanwhile, AG retarded the diabetes-induced decline in aortic distensibility, as reflected in the decrease of 18.7﹪ in Zc (P＜0.05) and the increase of 21.8﹪inτ(P＜0.05). AG also prevented the diabetes-induced augmentation in systolic loading condition for the left ventricle coupled to the arterial system, due to the increased τand the decreased Rf (-22.9﹪). Moreover, the ratio of LV weight to body weight was lowered by AG treatment, suggesting that the prevention of the diabetes-related cardiac hypertrophy may correspond to the drug-induced decline in LV systolic load. By contrast, AG exerted no effects on the mechanical properties of Winkessel vessels, as well as resistance vessels, in normal controls and STZ-NA of 4 weeks diabetes. We conclude that only rats with STZ-NA of 8 weeks diabetes produce a detrimental effect on the pulsatile nature of blood flows in arteries. Treatment with AG may impart significant protection against aortic stiffening in STZ-NA of 8 weeks diabetic rats possibly through inhibition of the AGEs-accumulation on collagen in the arterial wall.