EFFECT OF DRUGS ON DEVELOPMENT OF CARDIAC FAILURE

药物对心力衰竭发展的影响

• 批准号: 3335732
• 负责人: ARTHUR L BASSETT
• 金额: $ 18.25万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1979
• 资助国家: 美国
• 起止时间: 1979-04-01 至 1988-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3335732
• 关键词: antiarrhythmic agent; arrhythmia; cardiotonic agents; congestive heart failure; electrophysiology; heart Purkinje's fiber; heart contraction; heart disorder chemotherapy; heart failure; heart pharmacology; hemodynamics; hypertrophic myocardiopathy; ionophores; myocardial infarction; myocardial ischemia /hypoxia; myocardium; radiotracer; renal hypertension; sarcoplasmic reticulum

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.

高血压导致心脏不良反应的机制， 包括心力衰竭和其他严重疾病，目前还不清楚。 的 本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 在慢性高血压和导致的心脏肥大期间， 充血性心力衰竭，并区分的作用机制 新的和旧的药物，限制这些进展和严重性， 疾病 感兴趣的领域将包括逐渐发展的左翼或 右心室超负荷 为此提出了四个项目 主要包括以下几个方面：1）建立渐进式慢性 通过全身性高血压导致左心室压力超负荷， 猫，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 电生理学带来的过载; 2）产生 逐渐发展的右心室高血压， 区分离子电流、收缩特性和药物反应性 3）监测心肌细胞内Ca ~（++）通量 测定心肌细胞膜Ca ~（++）通道功能和Ca ~（++）i活性 压力超负荷心脏;和4）表征致心律失常 活性和评估冠状动脉造影期间的药理学反应性 结扎诱导的急性心肌缺血叠加先前存在的 疾病，即，“诱发性”慢性高血压。 的方法 包括肾血管性高血压的产生和逐渐的肺动脉高压， 动脉缩窄;细胞内微电极;膜片钳;电压钳 等长收缩和K+挛缩测量; 药物干预;单克隆抗体的分离和鉴定 心肌细胞，45 Ca ++通量测量和Ca++选择性 微电极 这些技术中的每一种都将有助于识别细胞 高血压导致或倾向于心脏更多的机制 严重疾病，以及药物改善或影响的机制 心肌中异常的电和收缩行为。