Mechanisms for Cardiovascular Control Early in Diabetes

描述（由申请人提供）：我们已经证明，如果在慢性一氧化氮合成阻断的大鼠中诱导高血糖，I型糖尿病发作时的高血糖会导致严重的高血压。 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相关的，可能涉及超氧化物和血栓素。 血压和一氧化氮也与GFR密切相关。本研究将验证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在糖尿病发病时预防高血压的中心假设。具体目标是：1）检验一氧化氮在糖尿病发作时通过以下方式防止AngII诱导的高血压的假设：a）将肾素-血管紧张素系统活性长期钳制（固定）在正常水平;B）在慢性静脉内和肾内i）雷米普利和ii）iosartan的大鼠中阻断AngII作用; c）阻断ACE基因敲除小鼠中的AngII作用; d）确定糖尿病的逐渐发作是否引起相同的肾素分泌和血压反应; e）确定低钠摄入是否增加血压对一氧化氮的依赖性。2)验证SNS主要通过肾脏机制参与高血压反应的假设。我们将：a）确定a受体与B受体在介导肾、肾素和血压反应中的作用：B）去除肾神经以测试肾在介导交感升压效应中的作用; c）确定肾上腺素能阻断是否需要ANG II的降低以预防高血压; d）确定SNS效应是否是由于SNS活动的增加，或者它是否起着允许的作用，3）检验一氧化氮抵消AngII依赖性超氧化物和血栓素产生以在糖尿病发作时控制血压的假设。 我们将通过以下方式确定：a）在大鼠中用超氧化物歧化酶模拟物“阻断”超氧化物和在小鼠中基因过表达; B）定量AngII确定超氧化物是否显著影响血压的程度; c）确定如果超氧化物不增加，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.