REGULATION OF CARDIAC AUTONOMIC RECEPTORS

心脏自主受体的调节

• 批准号: 3343348
• 负责人: Stephen B Baker
• 金额: $ 6.23万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-02-01 至 1988-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3343348
• 关键词: 6 hydroxydopamine; adenylate cyclase; atropine; autonomic nervous system; catecholamines; glucocorticoids; heart contraction; heart pharmacology; methacholine; thyroid function

The autonomic nervous system plays a major role in regulating cardiac activity. Thus changes in post synaptic receptors, which initiate the actions of the autonomic transmitters acetylcholine and catecholamines, may contribute to possible alterations in the ability of the autonomic nervous system to regulate cardiac activity. The long term objective of this proposal is to study the regulation of the high and low agonist affinity states of cardiac beta-adrenoreceptors and muscarinic receptors and their ability to stimulate and inhibit adenylate cyclase activity. Both intact animals (rats) and isolated atria will be used. Parameters to be determined include the total receptor concentrations (as measured with labeled antagonists), the fraction of receptors that form the high and low agonist affinity states and the affinity constants for agonists. These parameters will be determined by computer analysis of agonist competition curves (for both receptors) and by direct agonist binding to high affinity sites for the muscarinic receptor. In addition, the ability of muscarinic agonists to attenuate and beta-agonists to stimulate adenylate cyclase activity will be measured. The conditions under which these parameters will be measured include development, thyroid status and during treatment with isoproterenol, 6-hydroxydopamine, nadolol, methacholine, atropine and glucocorticoid. Irreversible beta and muscarinic antagonists will be used to define the relationship between receptor number and biochemical response (coupling efficiency) in isolated atria for cAMP accululation (beta), attenuation of cAMP production and cGMP accumulation (muscarinic). The effect of microtubule inhibitors on atrial beta and muscarinic biochemical responses will also be determined and if the altered response is associated with a change in receptor-response coupling efficiency. These studies are designed to determine further, changes that may occur under various conditions, to different agonist binding states of cardiac autonomic receptors and their ability to modulate the activity of adenylate cyclase. In addition, the use of irreversible receptor antagonists will allow a further investigation on how cellular structures such as microtubules, modulate the ability of receptors to produce a biochemical response.

自主神经系统在调节心脏运动中起着重要作用。 活动 因此，突触后受体的变化启动了 自主神经递质乙酰胆碱和儿茶酚胺的作用， 有助于自主神经功能的可能改变 调节心脏活动的系统。 这一长期目标 建议研究高和低激动剂亲和力的调节 心脏β-肾上腺素受体和毒蕈碱受体的状态及其 刺激和抑制腺苷酸环化酶活性的能力。 完好 将使用动物（大鼠）和隔离的心房。 的参数 测定的浓度包括总受体浓度（如用 标记的拮抗剂），形成高和低浓度受体的部分， 激动剂亲和状态和激动剂的亲和常数。 这些 参数将通过激动剂竞争的计算机分析来确定 曲线（对于两种受体）和直接激动剂结合高亲和力 毒蕈碱受体的位点。 此外，毒蕈碱的能力 减弱腺苷酸环化酶的激动剂和刺激腺苷酸环化酶的β-激动剂 活动将被测量。 这些参数的条件 将测量包括发育，甲状腺状态和治疗期间 与异丙肾上腺素、6-羟基多巴胺、纳多洛尔、乙酰甲胆碱、阿托品和 糖皮质激素 将使用不可逆的β和毒蕈碱拮抗剂 确定受体数量和生化反应之间的关系 （偶联效率）在离体心房中cAMP积聚（β）， 减弱cAMP产生和cGMP积累（毒蕈碱）。 的 微管抑制剂对心房β和毒蕈碱生化的影响 还将确定响应，并且如果改变的响应与 受体反应偶联效率发生变化。 这些研究 旨在进一步确定在各种情况下可能发生的变化， 条件下，心脏自主神经的不同激动剂结合状态 受体及其调节腺苷酸环化酶活性的能力。 此外，不可逆受体拮抗剂的使用将允许 进一步研究细胞结构如微管， 调节受体产生生化反应的能力。