INTERACTION OF HYPERTENSION, HYPERTROPHY, AND ISCHEMIA

长期目标是了解为什么慢性阻塞性肺疾病患者 高血压(HTN)的发病率和死亡率在以下情况下显著增加 他们会出现左心室肥厚(LVH)，并确定是否 HTN逆转和LVH消退将减少相关的发病率 和死亡率。慢性HTN患者也有较高的发病率 冠状动脉和缺血性心脏病。我们假设左心室肥厚使 心脏对缺血的耐受性降低。因此，我们的具体目标是 使用高血压大鼠和兔子来定义高血压之间的基本相互作用 缺血性和高血压性心脏病。大鼠HTN模型的建立 单肾切除+脱氧可的松+高盐组 单侧肾动脉夹夹对侧肾切除术。研究将会 1)在诱导HTN之前，2)在HTN之后但在LVH之前，3)在 4)HTN逆转后，LVH消退前， (5)LVH消退后。HTN的逆转将由几个人完成 评价药理学分类间潜在差异的方法 探员们。我们假设，相对于正常心脏，肥厚 心脏，将具有：1)对瞬变的全局或 局部缺血。我们将测量：a)收缩和舒缩功能 短暂性脑缺血前后的功能比较 动物、离体灌流心脏和带皮心肌纤维制剂。 功能的变化将与毛细血管/心肌细胞的比例相关， 心肌糖原和胶原含量。B)心肌梗死(MI) 短暂性冠状动脉闭塞和再灌流后的大小。C)的影响 在急性心肌梗塞时降低血压。2)心肌梗死后愈合受损 修理。我们将测量a)心肌梗塞后左室破裂的发生率和 动脉瘤的形成，b)心肌梗死后瘢痕组织的力学特性，c) 心肌梗死后修复过程中的降压作用。3)受损 冠脉血管舒缩功能。我们将测量：a)心肌血流量， 心内膜/心外膜分布和最大血管扩张反应，以及b) 冠脉血流灌注压下降的临界程度 产生细胞缺氧，c)之间的机械相互关系 冠脉循环和心肌。4)HTN逆转和回归 左心室肥厚可以逆转这些左心室肥厚相关的异常。我们假定 增加或保留心肌糖原含量的抗HTN药物可能 尤其有利于提高心肌对短暂性心肌的耐受性 缺血症。

The long-term objective is to understand why patients with chronic hypertension (HTN) have a marked increase in morbidity and mortality when they develop left ventricular hypertrophy (LVH), and to determine whether reversal of HTN and regression of LVH will reduce the associated morbidity and mortality. Patients with chronic HTN also have a high incidence of coronary artery and ischemic heart disease. We hypothesize that LVH makes the heart less tolerant to ischemia. Accordingly, our specific aims are to use hypertensive rats and rabbits to define basic interactions between ischemic and hypertensive heart disease. HTN will be induced in rats by uninephrectomy + deoxycortisone (DOC) + high salt and in rabbits by unilateral renal artery clip and contralateral nephrectomy. Studies will be done 1) Prior to induction of HTN, 2) After HTN but before LVH, 3) After LVH has developed, 4) After reversal of HTN but before regression of LVH, and 5) After regression of LVH. Reversal of HTN will be done by several methods to evaluate potential differences between classes of pharmacologic agents. We hypothesize that, relative to normal hearts, hypertrophied hearts, will have: 1) a decreased tolerance to transient global or regional ischemia. We will measure: a) Contractile and diastolic function before and after transient ischemia; function will be compared in intact animals, isolated perfused hearts, and skinned cardiac fiber preparations. Changes in function will be correlated with the capillary/myocyte ratio, myocardial glycogen, and collagen content. b) Myocardial infarction (MI) size after transient coronary occlusion and reperfusion. c) The effect of lowering BP during the acute MI phase. 2) Impaired post-MI healing and repair. We will measure a) The incidence of post-MI LV rupture and aneurysm formation, b) Mechanical properties of post-MI scar tissue, c) The effect of BP lowering during post-MI healing and repair. 3) Impaired coronary vasomotor function. We will measure: a) Myocardial blood flow, endo/epicardial distribution and the maximum vasodilator response, and b) the critical degree of coronary perfusion pressure decrease required to produce cellular hypoxia, c) The mechanical interrelationship between the coronary circulation and the myocardium. 4) Reversal of HTN and regression of LVH may reverse these LVH associated abnormalities. We postulate that anti-HTN agents which increase or preserve myocardial glycogen content may be particularly beneficial in increasing myocardial tolerance to transient ischemia.