Bhatt L K, Veeranjaneyulu A
Department of Pharmacology, School of Pharmacy and Technology Management, NMIMS University, Vile Parle (W), Mumbai, Maharashtra 400 056, India.
Exp Toxicol Pathol. 2012 Nov;64(7-8):847-53. doi: 10.1016/j.etp.2011.03.005. Epub 2011 Apr 6.
Diabetes greatly increases risk of cardiovascular dysfunction and interruptions of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) have been shown to reduce the risk by alteration in extracellular matrix. We hypothesized that minocycline induced MMP-2 and MMP-9 inhibition can be enhanced by aspirin (through its COX and tPA inhibitory action) and this combination can reduce cardiovascular dysfunction of diabetes. Four weeks after diabetes induction (streptozotocin, 55 mg/kg, i.p.), rats were treated with minocycline (50 mg/kg, p.o.), aspirin (50 mg/kg, p.o.), or minocycline (50 mg/kg, p.o.) plus aspirin (50 mg/kg, p.o.) for a period of next four weeks. At the end of eighth week arterial pressure, heart rate and left ventricular pressure were recorded. Contractile response to phenylephrine (10(-5) M) and relaxation responses to acetylcholine (10(-9)-10(-4) M) were obtained from aortic rings of diabetic rats. Gel zymography was performed to evaluate MMP-2 and MMP-9 levels. Heart rate, mean arterial pressure, dp/dt(max) and dp/dt(min) were found significantly decreased in STZ diabetic rats when compared with normoglycemic group. Treatment with combination of minocycline and aspirin significantly ameliorate these compared to vehicle treated diabetic group. Endothelium-dependent relaxation responses induced by acetylcholine were decreased in diabetic rats and significantly higher in combination treated group. Collagen, MMP-2 and MMP-9 levels were significantly decreased in combined treated group when compared with diabetic control. Present study revealed that aspirin potentate minocycline induced MMP-2 and MMP-9 inhibition to ameliorate cardiovascular dysfunction of diabetes and this combination can be an approach for the treatment.
糖尿病会大幅增加心血管功能障碍的风险，而基质金属蛋白酶-2（MMP-2）和基质金属蛋白酶-9（MMP-9）的阻断已被证明可通过改变细胞外基质来降低这种风险。我们推测米诺环素诱导的MMP-2和MMP-9抑制作用可通过阿司匹林（通过其对COX和tPA的抑制作用）得到增强，并且这种联合用药可减轻糖尿病的心血管功能障碍。在诱导糖尿病（腹腔注射链脲佐菌素，55mg/kg）四周后，大鼠接受米诺环素（口服，50mg/kg）、阿司匹林（口服，50mg/kg）或米诺环素（口服，50mg/kg）加阿司匹林（口服，50mg/kg）治疗，持续四周。在第八周结束时，记录动脉血压、心率和左心室压力。从糖尿病大鼠的主动脉环获得对去氧肾上腺素（10⁻⁵M）的收缩反应以及对乙酰胆碱（10⁻⁹ - 10⁻⁴M）的舒张反应。进行凝胶酶谱分析以评估MMP-2和MMP-9水平。与血糖正常组相比，链脲佐菌素诱导的糖尿病大鼠的心率、平均动脉压、dp/dt（max）和dp/dt（min）显著降低。与溶剂处理的糖尿病组相比，米诺环素和阿司匹林联合治疗可显著改善这些指标。糖尿病大鼠中乙酰胆碱诱导的内皮依赖性舒张反应降低，而联合治疗组显著更高。与糖尿病对照组相比，联合治疗组的胶原蛋白、MMP-2和MMP-9水平显著降低。本研究表明，阿司匹林可增强米诺环素诱导的MMP-2和MMP-9抑制作用，以改善糖尿病的心血管功能障碍，并且这种联合用药可能是一种治疗方法。
