Division of Clinical Pharmacology (Retired), University of Texas Southwestern Medical School (Retired), Bonita Springs, FL, USA.
University of Pittsburgh School of Medicine, Department of Pharmacology and Chemical Biology, 100 Technology Drive, Room 514, Pittsburgh, PA 15219, USA.
Cardiovasc Ther. 2020 Apr 29;2020:2478781. doi: 10.1155/2020/2478781. eCollection 2020.
It was indeed a Don Quixote-like pursuit of the mechanism of essential hypertension when we serendipitously discovered -adrenoceptors ( -ARs) in skin-lightening experiments in the frog. Now -ARs lurk on the horizon involving hypertension causality, renal denervation for hypertension, injury from falling in the elderly and prazosin's mechanism of action in anxiety states such as posttraumatic stress disorder (PTSD). Our goal here is to focus on this horizon and bring into clear view the role of -AR-mediated mechanisms in these seemingly unrelated conditions. Our narrative begins with an explanation of how experiments in isolated perfused kidneys led to the discovery of a sodium-retaining process, a fundamental mechanism of hypertension, mediated by -ARs. In this model system and in the setting of furosemide-induced sodium excretion, -AR activation inhibited adenylate cyclase, suppressed cAMP formation, and caused sodium retention. Further investigations led to the realization that renal -AR expression in hypertensive animals is elevated, thus supporting a key role for kidney -ARs in the pathophysiology of essential hypertension. Subsequent studies clarified the molecular pathways by which -ARs activate prohypertensive biochemical systems. While investigating the role of -adrenoceptors ( -ARs) versus -ARs in renal sympathetic neurotransmission, we noted an astonishing result: in the kidney -ARs suppress the postjunctional expression of -ARs. Here, we describe how this finding relates to a broader understanding of the role of -ARs in diverse disease states. Because of the capacity for qualitative and quantitative monitoring of -AR-induced regulatory mechanisms in the kidney, we looked to the kidney and found enlightenment.
当我们在青蛙的皮肤美白实验中偶然发现肾上腺素能受体 ( -ARs ) 时，我们确实对原发性高血压的机制进行了堂吉诃德式的探索。现在， -ARs 潜伏在涉及高血压因果关系的地平线上，涉及高血压的肾去神经支配、老年人跌倒的损伤以及特拉唑嗪在创伤后应激障碍 ( PTSD ) 等焦虑状态下的作用机制。我们的目标是关注这一领域，并清楚地了解 -AR 介导的机制在这些看似无关的情况下的作用。我们的叙述从解释在分离灌注肾脏的实验中如何发现由 -AR 介导的保留钠的过程开始，这是高血压的基本机制。在这个模型系统中，在呋塞米诱导的钠排泄的情况下， -AR 激活抑制腺苷酸环化酶，抑制 cAMP 形成，并导致钠潴留。进一步的研究导致认识到高血压动物的肾脏 -AR 表达升高，因此支持肾脏 -AR 在原发性高血压病理生理学中的关键作用。随后的研究阐明了 -AR 激活促高血压生化系统的分子途径。在研究 -AR 与 -AR 在肾交感神经传递中的作用时，我们注意到一个惊人的结果：在肾脏中， -AR 抑制 -AR 的突触后表达。在这里，我们描述了这一发现如何与对 -AR 在不同疾病状态中的作用的更广泛理解相关。由于能够定性和定量监测肾脏中 -AR 诱导的调节机制，我们关注肾脏并找到了启示。
