The human brain requires adequate cerebral blood flow to meet the high demand for nutrients and to clear waste products. With age, there is a chronic reduction in cerebral blood flow in small resistance arteries that can eventually limit proper brain function. The endothelin system is a key mediator in the regulation of cerebral blood flow, but the contributions of its constituent receptors in the endothelial and vascular smooth muscle layers of cerebral arteries have not been well defined in the context of aging. We isolated posterior cerebral arteries from young and aged Fischer 344 rats, as well as ET_B receptor knock-out rats and mounted the vessels in plexiglass pressure myograph chambers to measure myogenic tone in response to increasing pressure and targeted pharmacological treatments. We used an ET_A receptor antagonist (BQ-123), an ET_B receptor antagonist (BQ-788), endothelin-1, an endothelin-1 synthesis inhibitor (phosphoramidon), and vessel denudation to dissect the roles of each receptor in aging vasculature. Aged rats exhibited a higher myogenic tone than young rats, and the tone was sensitive to the ET_A antagonist, BQ-123, but insensitive to the ET_B antagonist, BQ-788. By contrast, the tone in the vessels from young rats was raised by BQ-788 but unaffected by BQ-123. When the endothelial layer that is normally enriched with ET_B1 receptors was removed from young vessels, myogenic tone increased. However, denudation of the endothelial layer did not influence vessels from aged animals. This indicated that endothelial ET_B1 receptors were not functional in the vessels from aged rats. There was also an increase in ET_A receptor expression with age, whereas ET_B receptor expression remained constant between young and aged animals. These results demonstrate that in young vessels, ET_B1 receptors maintain a lower myogenic tone, but in aged vessels, a loss of ET_B receptor activity allows ET_A receptors in vascular smooth muscle cells to raise myogenic tone. Our findings have potentially important clinical implications for treatments to improve cerebral perfusion in older adults with diseases characterized by reduced cerebral blood flow.

人脑需要足够的脑血流量来满足对营养的高需求并清除废物。随着年龄的增长，小阻力动脉中的脑血流量会慢性减少，最终会限制正常的大脑功能。内皮素系统是调节脑血流的关键介质，但其组成受体在脑动脉的内皮和血管平滑肌层中的作用在衰老的背景下尚未得到很好的定义。我们从年轻和老年 Fischer 344 大鼠以及 ET _B受体敲除大鼠中分离出大脑后动脉，并将血管安装在有机玻璃压力肌动描记器室中，以测量肌源性张力以响应增加的压力和靶向药物治疗。我们使用了 ET受体拮抗剂 (BQ-123)、ET _{B受体拮抗剂 ( BQ} -788)、内皮素-1、内皮素-1 合成抑制剂（磷酰胺）和血管剥脱，以剖析每种受体在衰老脉管系统中的作用。老年大鼠比年轻大鼠表现出更高的肌张力，并且张力对 ET _A拮抗剂 BQ-123 敏感，但对 ET _B拮抗剂 BQ-788 不敏感。相比之下，年轻大鼠血管中的音调被 BQ-788 提高，但不受 BQ-123 的影响。_{当通常富含 ET B1}的内皮层受体从年轻血管中移除，肌原性张力增加。然而，内皮层的剥脱并不影响老年动物的血管。这表明内皮 ET _B1受体在老年大鼠的血管中没有功能。ET _A受体表达也随着年龄的增长而增加，而 ET _B受体表达在年轻和老年动物之间保持不变。这些结果表明，在年轻血管中，ET _{B1受体维持较低的肌原性张力，但在老年血管中，ET B}受体活性的丧失使得 ET _A血管平滑肌细胞中的受体以提高肌原性张力。我们的研究结果对于改善患有以脑血流减少为特征的疾病的老年人的脑灌注的治疗具有潜在的重要临床意义。