NEURAL AND HUMORAL REGULATION OF THE MICROCIRCULATION

微循环的神经和体液调节

• 批准号: 3355153
• 负责人: JAMES E FABER
• 金额: $ 10.41万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-07-01 至 1995-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3355153
• 关键词: adrenergic receptor; autoradiography; biological signal transduction; blood pressure; carbon dioxide tension; hormone regulation /control mechanism; hypertension; laboratory rat; microcirculation; microscopy; neuroendocrine system; peripheral blood vessel disorder; vascular resistance; vascular smooth muscle; vasomotion

Recent in vitro studies of large vessels and in vivo studies of whole beds indicate that vascular smooth muscle (VSM) can possess 2 types of alpha adrenergic receptors (R) that mediate contraction, designated alpha1 and alpha2. Both their relative distribution and modes of post-R signal transduction have received much attention. However it is not known if they are subject to different physiological regulation, and hence their involvement in pathology and therapeutic interventions remains poorly understood. Prior to our work, no studies had examined alpha R subtypes across the microcirculation. We have found, using intravital microscopy of skeletal muscle, that large arterioles important in control of peripheral resistance functionally have both Rs with alpha2 dominant; small terminal arterioles that regulate capillary flow and blood-tissue exchange appear to have only alpha2 Rs. The overall goal of this proposal is to determine whether this distinct R distribution is important in adrenergic control of peripheral circulation, and if alpha1 and alpha2 contraction of micro-VSM is differentially modulated by other extrinsic and intrinsic controls. This distinct R distribution itself suggest different physiological roles for the 2 Rs. We have preliminary evidence that metabolic (eg, pH, PO2, adenosine), physiochemical (eg, temperature, myogenic stretch), hormonal (eg, ANF) and neural signals interact selectively with alpha1 or alpha2 responses. The hypotheses to be examined are that (1) the heterogeneity of R distribution and sensitivity to smooth muscle controllers confers distinct regulatory features on microvascular segments, and (2) differences in post-R 2nd messenger signalling pathways ("coupling") of alpha1 and alpha2 Rs are involved in conferring selective modulation of R responses by intrinsic and extrinsic determinants of micro-VSM tone. The following Specific Aims to address these hypotheses will be examined with intravital microscopy of skeletal and intestinal microvasculatures, microfluorimetry (intracellular Ca++) of isolated microvessels, and anatomical localization of alpha adrenoceptor type and density. Aim I To determine if myogenic mechanisms interact selectively with alpha2 and alpha2 adrenoceptor contraction, and the cellular basis for this interaction. Aim II. To determine the physiological relevance of selective inhibition of alpha2 adrenoceptor contraction of micro-VSM by local metabolic feedback signals (tissue O2, pH, adenosine), and the cellular mechanism for this inhibition. Aim III. To determine if either alpha1 or alpha2 adrenoceptors are preferentially activated by neuronally released NE in the microcirculation, and whether alpha2 receptors are responsible for "escape" from sympathetic nerve stimulation. Aim IV. To determine the transmembrane signaling pathways and Ca coupling of alpha1 and alpha2 adrenoceptors n microvascular smooth muscle. Aim V. To determine how alpha1 and alpha2 receptors are anatomically distributed in the microcirculation of normotensive and hypertensive animals. The results will clarify basic mechanisms of microvascular regulation and may lead to new insights into the pathophysiology and treatment of peripheral vascular disorders.

大血管的体外研究和全床的体内研究的最新进展 表明血管平滑肌（VSM）可具有两种类型α-肌动蛋白 调节收缩的肾上腺素能受体（R），命名为α 1和 α 2。 它们的相对分布和R后信号的模式 转导受到了很多关注。 但目前尚不清楚他们是否 受到不同的生理调节，因此， 参与病理学和治疗干预仍然很差 明白 在我们的工作之前，没有研究检查过α R亚型 穿过微循环。 我们发现，使用活体显微镜， 骨骼肌，即控制外周血管重要大动脉 抗性在功能上具有两个R，α 2占优势;小末端 调节毛细血管流动和血液组织交换的小动脉似乎 只有α 2 R。 本提案的总体目标是确定 这种独特的R分布是否在肾上腺素能控制 外周循环，如果微VSM的α 1和α 2收缩 受到其他外在和内在控制的差异调节。 这种独特的R分布本身表明不同的生理作用 对于2R。 我们有初步证据表明，代谢（如pH值，PO2， 腺苷），生理化学（例如，温度，肌源性拉伸），激素 (eg ANF）和神经信号选择性地与α 1或α 2相互作用 应答 待检验的假设是：（1） R分布和对平滑肌控制器的敏感性赋予 微血管节段上不同的调节特征，和（2）差异 在后R第二信使信号通路（"耦合"）的α 1和 α 2 R参与通过以下途径赋予R应答的选择性调节 微VSM音调的内在和外在决定因素。 以下 解决这些假设的具体目标将通过活体检查 骨骼和肠微血管显微镜检查，显微荧光测定法 （细胞内Ca ++）的分离微血管，和解剖定位 α肾上腺素受体的类型和密度。 目的I确定肌生成机制是否选择性地与α 2相互作用 和α 2肾上腺素能受体收缩， 互动 Aim II. 确定选择性抑制的生理相关性 局部代谢反馈对微VSM α 2肾上腺素受体收缩的影响 信号（组织O2、pH、腺苷），以及其细胞机制 抑制作用 Aim III. 为了确定α 1或α 2肾上腺素受体是否 在微循环中优先被神经元释放的NE激活， 以及α 2受体是否负责从交感神经系统中"逃逸"， 神经刺激 目标四。 确定跨膜信号通路和钙偶联 α 1和α 2肾上腺素能受体在微血管平滑肌中的表达。 目的5.确定α 1和α 2受体在解剖学上是如何 分布于正常血压者和高血压者的微循环 动物 这些结果将阐明微血管调节的基本机制， 可能会为疾病的病理生理学和治疗带来新的见解 外周血管疾病