Elucidation of the molecular requirements of the low affinity 'state' of the beta1-adrenoceptor

β-受体阻滞剂用于治疗心血管疾病，包括心力衰竭、缺血性心脏病和高血压。β-受体阻滞剂主要是通过阻断一种自然产生的化学物质去甲肾上腺素的效果来发挥作用的。β-受体阻滞剂可以用来阻止去甲肾上腺素引起的人类心脏收缩速度和力量的增加。我们发现，以CGP12177为代表的一组β-受体阻滞剂具有显著的特性，不仅能够阻断β-受体，而且还可以在较高浓度下刺激它们。因此，低浓度会阻断去甲肾上腺素的作用，但较高浓度会刺激受体。更令人费解的是，这组β-受体阻滞剂的刺激作用并不容易被阻断。为了解释这一点，我们假设人类的β受体可以以两种不同的“状态”存在。一种“状态”可被去甲肾上腺素刺激，并被低浓度的β-受体阻滞剂如普萘洛尔和CGP12177所阻断。同一受体的另一种“状态”对心得安等β-受体阻滞剂有抵抗力，但可被CGP-12177等β-受体阻滞剂刺激。该项目旨在研究β-受体的分子基础，该受体负责β-受体的刺激作用。具体地说，它探索了β-肾上腺素受体的成分，这些成分对于与兴奋剂β-受体的相互作用至关重要。这个项目是我们实验室研究计划中的一个重要增量，以增加我们对β-受体阻滞剂的影响的了解。我们的长期目标是能够开发能够阻断两种状态的β-肾上腺素受体的β-受体阻滞剂，以提供更有效的受体阻断，特别是改善心力衰竭的管理。

Beta-blockers are used for the management of cardiovascular diseases including heart failure, ischaemic heart disease and high blood pressure. Beta-blockers mostly work by blocking the effects of a naturally occuring chemical called noradrenaline. Beta-blockers can be used to prevent noradrenaline induced increases in the rate and force of human heart contraction. We have discovered that one group of beta-blockers exemplified by CGP 12177 has the remarkable property of not only being able to block beta-receptors but they can also stimulate them at higher concentrations. Thus low concentrations block the effects of noradrenaline, but higher concentrations stimulate the receptor. More puzzling is that the stimulant effects of this group of beta-blockers cannot be easily blocked. To explain this we hypothesize that human beta-receptors can exist in two different 'states'. One 'state' can be stimulated by noradrenaline and blocked by low concentrations of beta-blockers such as propranolol and CGP 12177. Another 'state' of the same receptor is resistant to blockade by beta-blockers such as propranolol but can be stimulated by beta-blockers such as CGP 12177. This project seeks to investigate the molecular basis of the beta-adrenoceptor that is responsible for stimulant effects of beta-blockers. Specifically it explores the components of the beta-adrenoceptor that are critically and uniquely important for interacting with the stimulant beta-blockers. This project is an important increment in our laboratories research program to increase our understanding of the effects of beta-blockers. Our long term goal is to be able to develop beta-blockers that can block both states of the beta-adrenoceptor to provide a more effective block of the receptor and in particular for the improved management of heart failure.