REGULATION OF CARDIAC RHYTHM & CONDUCTION WITH AGING

窦性和房室结功能障碍是主要的疾病 老年人。 虽然这些疾病是自发发生的，但频繁的 老年患者的表现是心动过缓或心脏传导阻滞， 接受心脏活性药物如地高辛，钙通道阻滞剂， β-肾上腺素能阻滞剂或抗抑郁药。 在研究增加的 老年人和右心室窦房结对维拉帕米的敏感性 衰老Fischer 344大鼠的心房，显著和一致的年龄相关 在衰老和成熟的人类之间观察到心率的差异， 在不存在任何药物的情况下，衰老大鼠与成熟大鼠的组织中。 对心率变化的初步分析显示， 交感神经和副交感神经输入对正常人心率调节作用 衰老的人类 然而，在三个去神经的衰老模型中--小猎犬 在药物自主神经阻滞后，分离右心房， Langendorff灌注的Fischer 344大鼠心脏--心率降低 AV传导时间的增加也与年龄一致。 这些数据导致了一个假设，即窦的内在功能 和房室结，对它们功能的自主影响，以及对 药物的这些结构随着老化而显著改变。 我们长久以来- 长期目标是确定与年龄相关的潜在机制 心率自主调节、AV传导和 心脏结组织的代谢和受体调节活动， 了解衰老如何改变这些关键结构的敏感性， 许多药物干预经常用于治疗 老人 我们建议对人类进行研究，以调查与年龄相关的自主神经功能的变化。 通过分析术前心率变化和AV传导的影响， 在自主神经阻滞和刺激之后。 使用Fischer 344大鼠心脏， 我们建议评估肾上腺素能，胆碱能， 嘌呤能和钙受体介导的房室结传导调节 使用电生理学、心电图和生物化学的组合， 技术. Langendorff灌注模型将用于评估年龄- 与肾上腺素能，胆碱能，嘌呤能， 钙和咖啡因的刺激 放射性碘标记 间碘苄基胍（MIBG），一种用于定量测定 评估交感神经支配，脑电图将用于评估年龄- 房室结组织中去甲肾上腺素摄取和释放的相关变化 调节交感神经的药物和刺激的存在和不存在 活动 胆碱能，肾上腺素能， 嘌呤能，和钙受体密度在房室结区域将是 用定量放射自显影术评估。 使用定量 组织化学，AV切片中的肾上腺素能信号转导 通过测量cAMP积累来评估结区。 这些 实验是β-受体后改变的生物化学关联 随着年龄的增长。 糖酵解代谢酶、糖原和 糖原电生理学、脑电图和生物化学技术 应该提供重要的新的见解的机制， 心率、AV传导和对 老年人的心脏药物。

Sinus and atrioventricular (AV) node dysfunction are predominantly diseases of the elderly. Although these disorders occur spontaneously, a frequent presentation of the geriatric patient is bradycardia or heart block after receiving a cardioactive drug such as digoxin, a calcium channel blocker, beta-adrenergic blocker, or antiarrhythmic drug. In studying the increased sensitivity of the sinus node to verapamil in senescent humans and right atria from senescent Fischer 344 rats, striking and consistent age-related differences in heart rate were seen between senescent and mature humans and in tissues from senescent vs. mature rats in the absence of any drugs. Preliminary analyses of heart rate variation show decreases in both sympathetic and parasympathetic input on regulation of heart rate in intact senescent humans. However, in three denervated models of aging--beagles following pharmacologic autonomic blockade, isolated right atria and Langendorff perfused hearts from Fischer 344 rats--decreases in heart rate and increases in AV conduction time were also consistently seen with aging. These data lead to the hypothesis that the intrinsic function of the sinus and AV nodes, autonomic influences on their function, and responsiveness to these structures to drugs are significantly altered with aging. Our long- term goals are to determine the mechanisms underlying age-related differences in autonomic regulation of heart rate, AV conduction, and metabolic and receptor-regulated activities of cardiac nodal tissues to understand how aging alters the sensitivity of these critical structures to many of the pharmacologic interventions frequently used in the treatment of the elderly. We propose studies in man to investigate age-related changes in autonomic influences by analyzing heart rate variation and AV conduction before and after autonomic blockade and stimulation. Using the Fischer 344 rat heart, we propose to evaluate age-related differences in adrenergic, cholinergic, purinergic, and calcium receptor-mediated regulation of AV nodal conduction using a combination of electrophysiologic, scintigraphic, and biochemical techniques. The Langendorff perfusion model will be used to assess age- related dromotropic responses to adrenergic, cholinergic, purinergic, calcium, and caffeine stimulation. With radioiodinated metaiodobenzylguanidine (MIBG), a guanidine analogue used to quantitatively assess sympathetic innervation, scintigraphy will be used to assess age- related changes in norepinephrine uptake and release in AV nodal tissues in the absence and presence of drugs and stimuli which modulate sympathetic activity. Potential age-related changes in cholinergic, adrenergic, purinergic, and calcium receptor density in the AV nodal region will be assessed with quantitative autoradiography. Using quantitative histochemistry, adrenergic signal transduction in sections from the AV nodal region will be assessed by measurement of cAMP accumulation. These experiments are a biochemical correlate of post-beta-receptor alterations with aging. Age differences in glycolytic metabolic enzymes, glycogen, and glycogen electrophysiologic, scintigraphic, and biochemical techniques should provide important new insights into the mechanisms underlying the striking changes in heart rate, AV conduction, and sensitivity to cardioactive drugs in the elderly.