Miatello R M, Damiani M T, Nolly H L
Laboratory of Experimental Hypertension and Vasoactive Substances, School of Medicine and National Council of Research (CONICET), Mendoza, Argentina.
J Hypertens. 1998 Sep;16(9):1273-7. doi: 10.1097/00004872-199816090-00008.
The hypertensive state is often associated with metabolic abnormalities, including glucose intolerance. Tissue kallikrein, a potent kinin-generating enzyme, is present in the vascular wall and heart tissue. High dietary fructose consumption is reported to induce hyperinsulinemia, hypertriglyceridemia and hypertension. The objective of the present study was to examine the status of kallikrein in vascular and cardiac tissue from highly fructose-fed rats and to delineate the effect of kinins and the angiotensin converting enzyme inhibitor ramipril in this animal model of glucose intolerance.
Male Wistar rats (350 g body weight) were divided into four groups of 10 rats each: (1) controls; (2) oral ramipril at 500 microg/kg per day for the last 2 study weeks; (3) fructose in drinking water as a 10% (w/v) solution for 4 weeks; and (4) fructose + ramipril, with fructose administered as in group 3 plus the administration of ramipril for the last 2 study weeks. Systolic blood pressure (tail-cuff method), glucose tolerance (2 g/kg body weight intraperitoneally) and metabolic parameters were recorded. Kallikrein activity in tail artery and heart tissue homogenates was estimated at the end of the 4th study week from measurements of kininogenase activity and kinins generated by a radioimmunoassay.
The area under the curve for the glucose tolerance test increased from 1265 +/- 103 mmol/l after 120 min in the control and 1152 +/- 36 mmol/l in the ramipril group (NS) to 2628 +/- 143 mmol/l in the fructose group (P<0.01). The administration of ramipril to fructose-treated rats in group 4 improved glucose tolerance (2160 +/- 100 mmol/l; P<0.05 versus group 3). Blood pressure increased significantly in fructose-fed rats but fell markedly in fructose-fed rats treated with ramipril (P<0.01). Kallikrein activity measured in the heart and vessels increased as a consequence of fructose administration (P<0.05), but the administration of ramipril increased this parameter to a much greater extent (P<0.01 versus control group), which correlated closely with the decrease in blood pressure and the improvement in glucose tolerance observed in the fructose + ramipril group.
The administration of fructose as a solution in the drinking water induced glucose intolerance and increased blood pressure. Treatment with the angiotensin converting enzyme inhibitor ramipril improved glucose tolerance and significantly diminished blood pressure. Cardiovascular kinin-generating capability increased in treated animals and this increase was even higher when rats were treated with ramipril, suggesting that kinins, acting as a paracrine hormonal system, can exert cardiovascular protection and contribute to the beneficial effects of angiotensin converting enzyme inhibitor.
高血压状态常与代谢异常相关，包括葡萄糖不耐受。组织激肽释放酶是一种强效的激肽生成酶，存在于血管壁和心脏组织中。据报道，高糖饮食会诱发高胰岛素血症、高甘油三酯血症和高血压。本研究的目的是检测高糖喂养大鼠血管和心脏组织中激肽释放酶的状态，并阐明激肽和血管紧张素转换酶抑制剂雷米普利在这种葡萄糖不耐受动物模型中的作用。
将雄性Wistar大鼠（体重350 g）分为四组，每组10只：（1）对照组；（2）在研究的最后2周，每天口服500 μg/kg雷米普利；（3）饮用含10%（w/v）果糖溶液4周；（4）果糖+雷米普利组，果糖给药方式同第3组，在研究的最后2周加用雷米普利。记录收缩压（尾套法）、葡萄糖耐量（腹腔注射2 g/kg体重）和代谢参数。在研究第4周结束时，通过测定激肽原酶活性和放射免疫分析法测定生成的激肽，评估尾动脉和心脏组织匀浆中的激肽释放酶活性。
葡萄糖耐量试验曲线下面积在对照组120分钟后为1265±103 mmol/l，雷米普利组为1152±36 mmol/l（无统计学差异），果糖组增加至2628±143 mmol/l（P<0.01）。第4组果糖处理大鼠给予雷米普利后葡萄糖耐量得到改善（2160±100 mmol/l；与第3组相比P<0.05）。果糖喂养大鼠血压显著升高，但雷米普利治疗的果糖喂养大鼠血压明显下降（P<0.01）。果糖给药后，心脏和血管中测得的激肽释放酶活性增加（P<0.05），但雷米普利给药使该参数增加的幅度更大（与对照组相比P<0.01），这与果糖+雷米普利组血压下降和葡萄糖耐量改善密切相关。
饮用果糖溶液可诱发葡萄糖不耐受并升高血压。血管紧张素转换酶抑制剂雷米普利治疗可改善葡萄糖耐量并显著降低血压。治疗动物的心血管激肽生成能力增加，雷米普利治疗时增加更为明显，提示激肽作为旁分泌激素系统可发挥心血管保护作用，并有助于血管紧张素转换酶抑制剂的有益作用。
