INTERACTION OF HYPERTENSION, HYPERTROPHY, AND ISCHEMIA

长期目标是了解为什么慢性病患者 高血压（HTN）发病率和死亡率显著增加， 他们发展左心室肥大（LVH），并确定是否 HTN逆转和LVH消退将降低相关发病率 and mortality. 患有慢性HTN的患者也有很高的发病率， 冠状动脉和缺血性心脏病 我们假设左室肥厚 心脏对局部缺血的耐受性降低。 因此，我们的具体目标是 使用高血压大鼠和兔子来定义 缺血性和高血压性心脏病。 HTN将在大鼠中诱导， 单侧肾切除+去氧可的松（DOC）+高盐和兔 单侧肾动脉夹闭术和对侧肾切除术。 研究将 1）在HTN诱导之前，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的恢复将由几个 评价药理学类别之间潜在差异的方法 剂. 我们假设，相对于正常心脏， 心脏，将有：1）对短暂的全球或 局部缺血 我们将测量：a）收缩和舒张功能 短暂性缺血前后;功能将在完整的 动物、离体灌注心脏和去皮心脏纤维制备物。 功能的变化将与毛细血管/肌细胞比率相关， 心肌糖原和胶原含量。 B）心肌梗死（MI） 短暂冠状动脉闭塞和再灌注后的大小。 （c）影响 在急性心肌梗死期降低血压。 2)MI后愈合受损， 修复. 我们将测量a）MI后LV破裂的发生率， 动脉瘤形成，B）MI后瘢痕组织的机械性质，c） MI后愈合和修复期间血压降低的作用。 3)受损 冠状动脉血管功能 我们将测量：a）心肌血流量， 心内膜/心外膜分布和最大血管舒张反应，和B） 需要冠状动脉灌注压下降的临界程度 产生细胞缺氧，c）机械之间的相互关系， 冠状循环和心肌。 4)HTN的恢复和回归 可能逆转这些LVH相关的异常。 我们推测 增加或保持心肌糖原含量的抗HTN剂可 特别有益于增加心肌对瞬时 缺血

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.