HYPERTENSION--TRAINING-INDUCED INCREASE IN WORK CAPACITY

左心室心肌细胞内钙离子的调节发生改变 继发于肾血管性高血压的心室（LV）肥大 （RvHtn）。 在单次起搏的左心室肌细胞中，RvHtn可使心肌细胞内的 胞浆[Ca2 +]（[Ca2 +] c）瞬变的幅度和 [Ca2+] c恢复到基础水平。 [Ca2 +] c动态的这些改变 伴随着减少的肌细胞收缩反应发生， 肌细胞松弛 在整个器官水平，Ca 2+依赖性LV 收缩性自动调节受到RvHtn的损害。 这些内在 整体和单个细胞功能似乎发生了功能性变化 伴随着几个基因的表达和/或功能的改变， 肌膜（SL）和肌浆网（SR）Ca 2+调节蛋白。 运动训练已被证明可以防止和/或逆转 由RvHtn引起的LV收缩功能， 在几个Ca2+调节位点的反应。 这方面的主要成就 建议是确定耐力训练（i）是否可以恢复正常 [Ca2分离的单个LV肌细胞的+] c动力学和收缩功能 来自RvHtn大鼠。 (ii)我们将采取措施定位 过程，负责改变心肌细胞[Ca2 +] c动力学， RvHtn肌细胞和（iii）确定训练对那些 流程. 为了实现这些目标，RvHtn和LV肥大将 使用Goldblatt，2肾-1夹在雄性Fisher 344大鼠中产生 procedure. 左心室心肌和单个左心室心肌细胞分离自久坐 血压正常（NSd）、训练血压正常（NTr）、久坐高血压 (HSd)和训练的高血压（HTr）大鼠进行研究。 形态学， NSd、NTr、HSd和HTr的收缩功能和[Ca2 +] c动态 使用荧光和视频显微镜评估肌细胞。 在 LV肌细胞研究、起搏和灌注条件将改变， 差异干扰细胞Ca2+内流和外排机制;快速 冷却挛缩将用于生物测定可释放的Ca2+的量 咖啡因挛缩研究将用于评估 SR Ca~（2+）摄取和Na~+-Ca~（2+）交换在舒张中的相对作用 完整的肌细胞 为了解释的相关性，研究全球 LV收缩功能将与单个肌细胞平行进行 实验 生物化学、药理学和免疫化学技术 将用于评估培训的单一和综合效果， RvHtn对关键SL和SR Ca 2+和Na+的表达和/或功能的影响 调节蛋白;肌细胞Ca 2+和Na+调节密切相关。 更好地理解在细胞内发生的Ca2+调节变化， 对训练和RvHtn的反应，以及这些变化对单个 心肌细胞和整体左心室功能可能被证明是有用的发展， 临床策略，以防止心肌功能障碍相关的 高血压性心脏病

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.