Pharmacy Department, Faculty of Technology and Engineering, Kalabhavan, The M. S. University of Baroda, Vadodara, Gujarat, India.
Pharm Biol. 2012 Apr;50(4):439-42. doi: 10.3109/13880209.2011.611144. Epub 2011 Dec 2.
The problem of hypertension has gained enormous proportions in the past decade. Multifactorial etiology and complex pathophysiology of the disease has rendered the treatment of the disease a hard task. Sympathetic nervous system and the renin-angiotensin-aldosterone system are primary contributors of blood pressure homeostasis.
Structural similarities were identified among AT(1) and α(1)-antagonists, initiating a speculation that α(1)-antagonists could possibly block the AT(1) receptor and vice-versa.
To corroborate this speculation, we screened prototypical α(1)-antagonists such as prazosin, doxazosin, and terazosin for antagonism of angiotensin II on rat aortic strips. We also examined the AT(1) antagonists losartan, valsartan, and olmesartan for their possible antagonistic effect, on contractions of rat aortic strips induced by phenylephrine.
To our astonishment, we found that prazosin and its analogs which have been reported to have α(1)-antagonistic activity only, were able to shift concentration response curves of angiotensin II.
Our findings suggest that the potent antihypertensive effect of prazosin-type α(1)-antagonists is not purely due to α(1)-receptor blocking activity of these compounds but also due to blockade of AT(1) receptors. This finding may lead to the development of more potent dual inhibitors which would prove to be of immense value in the control of the scourge of hypertension.
在过去的十年中，高血压问题已经变得非常严重。该疾病的多因素病因和复杂的病理生理学使得治疗该疾病成为一项艰巨的任务。交感神经系统和肾素-血管紧张素-醛固酮系统是血压稳态的主要贡献者。
在 AT(1) 和 α(1)-拮抗剂之间发现了结构相似性，这引发了一种推测，即 α(1)-拮抗剂可能会阻断 AT(1)受体，反之亦然。
为了证实这一推测，我们筛选了普萘洛尔、多沙唑嗪和特拉唑嗪等典型的 α(1)-拮抗剂，以观察它们对血管紧张素 II 对大鼠主动脉条的拮抗作用。我们还检查了 AT(1)拮抗剂洛沙坦、缬沙坦和奥美沙坦对苯肾上腺素诱导的大鼠主动脉条收缩的可能拮抗作用。
令我们惊讶的是，我们发现普萘洛尔及其类似物仅具有 α(1)-拮抗活性，能够改变血管紧张素 II 的浓度反应曲线。
我们的发现表明，普萘洛尔型 α(1)-拮抗剂的强效降压作用不仅归因于这些化合物对 α(1)受体的阻断活性，还归因于对 AT(1)受体的阻断。这一发现可能导致更有效的双重抑制剂的开发，这将在控制高血压的肆虐方面证明具有巨大的价值。
