ALTERED FORCE KINETICS IN NORMAL AND STRESSED HEARTS

最近，钙非依赖性增强心脏的收缩能力通过 肾上腺素能药物已有报道。α刺激增加肌动球蛋白 使用V3，而不是V1，异肌球蛋白的肌肉中的ATPase速率和力量； 作用机制(S)尚不清楚。β刺激增加力量和肌动球蛋白 有V1而不有V3、异肌球蛋白的肌肉中的ATPase速率增加 V3异肌球蛋白对大鼠肌肉跨桥循环率的影响 使用V1异肌球蛋白的肌肉中的循环速度是不确定的。这些影响可能 涉及第二信使阵营；目前尚不清楚细节。这个 阿尔法刺激对循环率的影响尚未得到测试。这些 观察发现了一种耐人寻味的可能性，即肾上腺素能药物 选择性地影响心肌肌球蛋白的不同亚型，提供 调节心脏收缩能力的微妙机制。由这些驱动 令人振奋的新可能性，这项研究的长期目标是 进一步探讨心脏收缩功能良好的机制(S) 肾上腺素能刺激对过桥自行车运动的影响 运动学。其具体目的是：1)确定β-肾上腺素能 刺激增加了肌肉的跨桥循环率 主要是肌球蛋白的V1同工酶，2)决定是否升高 细胞内环AMP，第二信使级联的一个元件 由β-肾上腺素能刺激启动，是增加 肌肉中主要含有V3同工酶的交叉桥循环速度 肌球蛋白和3)确定α肾上腺素能刺激，类似于 刺激β-肾上腺素能改变大鼠跨桥循环率 主要含有V1或V3异肌球蛋白的肌肉。小的 幅度正弦长度振荡，在50个离散的每个 频率，将应用于等长收缩的右室 乳头肌。在每个频率处，刚度将被评估为 (摆动的)力与长度的比率。过桥骑行率将为 根据刚度幅值最小的频率进行测量。 除了扩大我们对多种方式的理解外， 心脏收缩能力受到调节，这些研究可能揭示一种机制 提高cAMP的新型强心药物联吡啶的作用 并可由此调节肌球蛋白的循环相互作用的动力学 肌动蛋白--心脏中的基本力量生成器。

Recently, calcium-independent enhancement of cardiac contractility by adrenergic agents has been reported. alpha stimulation increases actomyosin ATPase rate and force in muscles with V3, but not V1, isomyosin; the mechanism(s) are unknown. Beta stimulation increases force and actomyosin ATPase rate in muscles with V1, but not V3, isomyosin, and increases crossbridge cycling rate in muscles with V3 isomyosin; the effect on cycling rate in muscles with V1 isomyosin is uncertain. These effects may involve the second messenger cAMP; details are unknown at present. The effect of alpha stimulation on cycling rate has not yet been tested. These observations raise the intriguing possibility that adrenergic agents selectively affect the different isoforms of cardiac myosin, providing a subtle mechanism for modulating cardiac contractility. Driven by these exciting new possibilities, the long term objective of this research is to further probe the mechanism (s) by which cardiac contractility is fine- tuned by the influence of adrenergic stimuli on crossbridge cycling kinetics. The specific aims are to 1) determine if beta adrenergic stimulation increases crossbridge cycling rate in muscles containing primarily the V1 isoenzyme of myosin, 2) determine if elevated intracellular cyclic AMP, an element of the second messenger cascade initiated by beta adrenergic stimulation, is factor in the increase in crossbridge cycling rate in muscle containing mostly the V3 isoenzyme of myosin and 3) determine if alpha adrenergic stimulation, analogous to the effects of beta adrenergic stimulation, alters crossbridge cycling rate in muscle containing either mostly the V1 or mostly the V3 isomyosin. Small amplitude sinusoidal length oscillations, at each of 50 discrete frequencies, will be applied to isometrically contracting right ventricular papillary muscles. At each frequency stiffness will be evaluated as the ratio of (oscillatory) force to length. Crossbridge cycling rate will be gauged from the frequency at which stiffness amplitude exhibits a minimum. In addition to expanding our understanding of the manifold ways in which cardiac contractility is regulated, these studies may uncover a mechanism of action of the newer cardiotonic bipyridine derivatives which raises cAMP and may thereby modulate the kinetics of the cyclical interaction of myosin with actin-the fundamental force generator in the heart.