Mechanisms for Cardiovascular Control Early in Diabetes

描述(由申请人提供)：我们已经证明，如果在慢性阻止一氧化氮合成的大鼠中诱导高血糖，I型糖尿病开始时的高血糖会导致显著的高血压。高血压是通过阻断血管紧张素II或交感神经系统来预防的；但我们的数据表明，这两个系统在这种反应中是联系在一起的，可能涉及超氧化物和血栓素。血压和一氧化氮也与肾小球滤过率密切相关。这项建议中的研究将检验中心假设，即一氧化氮通过抵消交感神经和肾素-血管紧张素系统的升压作用来预防糖尿病开始时的高血压。其具体目的是：1)检验一氧化氮通过以下途径防止糖尿病发作时血管紧张素系统高血压的假设：a)慢性阻断(固定)正常水平的肾素-血管紧张素系统活性；b)阻断慢性静脉注射或肾内注射一氧化氮的大鼠的血管紧张素活性；i)雷米普利和ii)氯沙坦；c)阻断ACE基因敲除的小鼠的Angii作用；d)确定糖尿病的逐渐发作是否会引起肾素的分泌和血压的同样反应；e)确定低钠摄入是否会增加血压对一氧化氮的依赖。2)验证SNS主要通过肾脏机制参与高血压反应的假说。我们将：a)确定a和b受体在介导肾脏、肾素和血压反应中的作用：b)移除肾神经以测试肾脏在介导交感升压效应中的作用；c)确定是否需要减少Ang II来阻止肾上腺素能阻断以防止高血压；d)确定SNS效应是由于SNS活性增加，还是起到允许的作用；3)测试一氧化氮是否抵消了糖尿病发作时血管紧张素Ⅱ依赖的超氧化物和血栓素的产生以控制血压的假设。 我们将通过以下方法来确定这一点：a)在大鼠和小鼠中用超氧化物歧化酶模拟物“阻断”超氧化物歧化；b)量化血管紧张素Ⅱ决定超氧化物是否显著影响血压的程度：c)确定如果不增加超氧化物，血栓素受体阻断是否会降低血压：d)确定超氧化物歧化酶1的敲除是否会加剧高血压反应。

DESCRIPTION (provided by applicant): We have shown that hyperglycemia at the onset of Type I diabetes causes significant hypertension if it is induced in rats with chronic blockade of nitric oxide synthesis. The hypertension is prevented by blocking angiotensin II, or the sympathetic nervous system; but our data suggest the two systems are linked in this response and may involve superoxide and thromboxane. Blood pressure and nitric oxide also track closely with GFR. The studies in this proposal will test the central hypothesis that nitric oxide protects against hypertension at the onset of diabetes by counteracting pressor actions of the sympathetic and renin-angiotensin systems. The Specific Aims are: 1) to test the hypothesis that nitric oxide protects against AngII-induced hypertension at the onset of diabetes by: a) chronically clamping (fixing) renin-angiotensin system activity at normal levels;b) blocking AngII action in rats with chronic intravenous and intrarenal i) ramipril and ii) iosartan; c) blocking AngII action in mice with ACE gene knockout; d) determining if gradual onset of diabetes causes the same renin secretion and blood pressure responses; e) determining whether low sodium intake increases the dependence of blood pressure on nitric oxide. 2) to test the hypothesis that the SNS contributes to the hypertensive response primarily through renal mechanisms. We will: a) determine the roles of a versus b receptors in mediating the renal, renin, and blood pressure responses:b) remove the renal nerves to test the role of the kidney in mediating the sympathetic pressor effect; c) determine if a decrease in ANG II is required for adrenergic blockade to prevent the hypertension; d) determine if the SNS effect is due to increases in SNS activity, or whether it plays a permissive role, 3) to test the hypothesis that nitric oxide counteracts AngII-dependent superoxide and thromboxane production to control blood pressure at the onset of diabetes. We will determine this by: a) "blocking" superoxide with a superoxide dismutase mimetic in rats and gene overexpression in mice; b) quantifying the degree to which AngII determines whether superoxide significantly affects blood pressure: c) determining if thromboxane receptor blockade will decrease blood pressure if superoxide is not increased: d) determining whether knockout of superoxide dismutase 1 exacerbates the hypertensive response.