EFFECT OF DRUGS ON DEVELOPMENT OF CARDIAC FAILURE

高血压导致心脏不良影响的机制， 包括心力衰竭和其他严重疾病，目前尚不清楚。这个 这项提案的长期目标是确定和解释 压力超负荷心肌的电生理变化 在慢性高血压和由此导致的心肌肥厚和 充血性心力衰竭的作用机制及辨证 限制这些疾病进展和严重程度的新药和旧药 疾病。感兴趣的领域将包括逐渐发展的左翼或 右室负荷过重。就这些问题提出了四个项目 1)建立渐进性慢性阻塞性肺疾病模型 全身性高血压引起的左心室压力超负荷 CAT，并确定左心室肥厚的程度， 心力衰竭的发生率和心肌细胞的改变 超负荷带来的电生理；2)生产 猫渐进性右室高血压模型 区分离子电流、收缩特性和药物反应 对肥厚和衰竭心肌的监测；3)监测跨 心肌细胞膜钙离子通道功能及钙离子活性的变化 压力超负荷的心脏；4)确定致心律失常的特征 冠状动脉介入治疗中的活动性和药理反应评估 结扎诱导的急性心肌缺血叠加先前存在的心肌缺血 疾病，即“诱因”慢性高血压。方法论 包括肾血管性高血压和渐进性肺高压的产生 动脉缩窄；细胞内微电极、膜片和电压钳 程序；等长收缩和K+收缩测量； 药物干预；单抗的分离和特性 心肌细胞、~(45)Ca~(++)流量测定和钙离子选择性 微电极。这些技术中的每一项都有助于识别细胞 高血压导致或使心脏发生更多疾病的机制 严重疾病以及药物改善或影响的机制 心肌内异常的电和收缩行为。

The mechanisms by which hypertension leads to adverse cardiac effects, including heart failure and other serious diseases, are unclear. The long-term objectives of this proposal are to identify and explain the electrophysiologic changes which occur in pressure-overloaded myocardium during chronic hypertension and resulting cardiac hypertrophy and congestive heart failure, and to distinguish the mechanisms of action of new and old drugs which limit the progression and severity of these diseases. Areas of interest will encompass gradually-developing left or right ventricular overload. Four projects are proposed concerning these areas as follows: 1) to establish a model of gradually-developing chronic pressure overload of the left ventricle via systemic hypertension in the cat, and to determine the magnitude of left ventricular hypertrophy, the incidence of heart failure, and the alterations in myocardial cellular electrophysiology brought about by the overload; 2) to produce gradually-developing right ventricular hypertension in the cat in order to distinguish ionic currents, contractile properties and drug responsiveness of hypertrophied and failed myocardium; 3) to monitor Ca++ fluxes across the sarcolemma and to evaluate Ca++ channel function and Ca++i activity in the pressure-overloaded heart; and 4) to characterize arrhythmogenic activity and assess pharmacologic responsiveness during coronary ligation-induced acute myocardial ischemia superimposed on preexisting disease, i.e., "predisposing" chronic hypertension. The methodology includes production of renovascular hypertension and gradual pulmonary artery coarctation; intracellular microelectrode, patch and voltage clamp procedures; isometric contraction and K+ contracture measurements; pharmacologic intervention; isolation and characterization of single cardiac myocytes, 45Ca++ flux measurements and Ca++ selective microelectrodes. Each of these techniques will help identify cellular mechanisms by which hypertension leads to or predisposes the heart for more serious disease, and mechanisms whereby drugs ameliorate or influence aberrant electrical and contractile behavior in the myocardium.