HYPERTENSION--TRAINING-INDUCED INCREASE IN WORK CAPACITY

左心运动后细胞内钙调节的改变 继发于肾血管性高血压的左心室肥厚 (RvHtn)。在单个起搏的左室肌细胞中，RvHtn引起 胞浆[Ca~(2+)]([Ca~(2+)]c)瞬变的幅度和速率 [CA2]c回到基础水平。这些[Ca~(2+)]c动力学变化 与心肌细胞收缩反应减弱同时发生，并减慢 心肌细胞松弛。在整个器官水平上，钙依赖型LV 收缩自动调节受到RvHtn的影响。这些内在的 整体和单个细胞功能似乎发生了功能变化 伴随着几个的表达和/或功能的改变 肌膜(SL)和肌浆网(SR)钙调节蛋白。 运动训练已被证明可以预防和/或逆转 由RvHtn产生的左心室收缩功能并诱导适应性 在几个钙调控点上的反应。本项目的主要目标 建议确定耐力训练(I)是否能恢复正常 分离的单个左室肌细胞的[CA2]c动力学和收缩功能 来自RvHtn大鼠。(Ii)将采取措施将蜂窝网络本地化 导致心肌细胞[Ca~(2+)]c动力学改变的过程 RvHtn肌细胞和(Iii)确定训练对这些细胞的影响 流程。为了实现这些目标，RvHtn和LV肥厚将 用Goldblatt，2肾-1夹在雄性Fisher 344大鼠身上产生 程序。静息状态下分离的左室心肌和单个左室肌细胞 正常血压(NSD)、训练正常血压(NTR)、静息高血压 (HSD)和训练性高血压(HTR)大鼠将被研究。形态学， NSD、NTR、HSD和HTR的收缩功能和[钙]c动力学 将使用荧光和视频显微镜对心肌细胞进行评估。在 左室肌细胞检查、起搏和灌流条件将改变为 差异性扰动细胞内钙内流和外流机制；快速 冷收缩将被用于生物测定可释放的钙的量 这是在SR中的。咖啡因紧缩的研究将被用来评估 肌浆网钙摄取和钠钙交换在心肌松弛中的相对作用 完整的肌细胞。为了解释相关性，对全球的研究 左心室收缩功能将与单个心肌细胞平行进行 实验。生化、药理和免疫化学技术 将用于评估培训和培训的单一和综合影响 RvHtn对Key SL和SR钙、钠表达和/或功能的影响 调节蛋白；心肌细胞钙和钠的调节密切相关。 更好地了解钙离子的调节变化 对培训和RvHtn的响应，以及这些变化对单项 心肌细胞和整体左心室功能可能在心肌梗死的发生发展中起作用 预防心肌功能不全相关的临床策略 高血压心脏病。

Cellular Ca2+ regulation is altered in hearts having undergone left ventricular (LV) hypertrophy secondary to renovascular hypertension (RvHtn). In single paced LV myocytes, RvHtn elicits reductions in the amplitude of the cytosolic [Ca2+] ([Ca2+]c) transient and the rate at which [Ca2+]c returns to basal levels. These alterations in [Ca2+]c dynamics occur concomitantly with a reduced myocyte contractile response and slowed myocyte relaxation. At the whole organ level, Ca2+-dependent LV contractile autoregulation is compromised by RvHtn. These intrinsic functional changes in global and single cell function appear to occur concomitantly with alterations in the expression and/or function of several sarcolemmal (SL) and sarcoplasmic reticular (SR) Ca2+ regulatory proteins. Exercise training has been shown to prevent and/or reverse decrements in LV contractile function that result from RvHtn and to elicit adaptive responses at several Ca2+ regulatory loci. PRIMARY OBJECTIVES of this proposal are to determine if endurance training (i) can restore normal [Ca2+]c dynamics and contractile function to single LV myocytes isolated from RvHtn rats. (ii) Steps will be taken to localize the cellular processes that are responsible for altered myocyte [Ca2+]c dynamics in RvHtn myocytes and (iii) to identify the influence of training on those processes. to accomplish these objectives, RvHtn and LV hypertrophy will be produced in male Fisher 344 rats using a Goldblatt, 2 kidney-1 clip procedure. LV myocardium and single LV myocytes isolated from sedentary normotensive (NSd), trained normotensive (NTr), sedentary hypertensive (HSd), and trained hypertensive (HTr) rats will be studied. Morphology, contractile function, and [Ca2+]c dynamics in NSd, NTr, HSd, and HTr myocytes will be assessed using fluorescence and video microscopy. In the LV myocyte studies, pacing and perfusion conditions will be altered to differentially perturb cellular Ca2+ influx and efflux mechanisms; rapid cooling contractures will be used to bioassay the amount of releasable Ca2+ that is in the SR. Caffeine contracture studies will be used to assess the relative roles of SR Ca2+ uptake and Na+-Ca2+ exchange in relaxation in intact myocytes. For the sake of interpretive relevance, studies of global LV contractile function will be conducted in parallel to the single myocyte experiments. Biochemical, pharmacological, and immunochemical techniques will be used to assess the singular and combined effects of training and RvHtn on the expression and/or function of key SL and SR Ca2+ and Na+ regulatory proteins; myocyte Ca2+ and Na+ regulation are intimately linked. A better understanding of the Ca2+ regulatory changes that occur in response to training and RvHtn, and the impact of these changes on single myocyte and global LV function may prove useful in the development of clinical strategies to prevent myocardial dysfunction associated with hypertensive heart disease.