Angiotensin II as a multifunctional hormone: a regulator of haemodynamics and metabolism with potential roles in the etiologies of hypertension and the metabolic syndrome.

摘要

Angiotensin II is well known as a potent vasoconstrictor. However, the role of angiotensin II in regulating blood pressure and flow is not limited to the direct action of angiotensin II on vascular smooth muscle. Angiotensin II causes release of catecholamines from the adrenal medulla, which results in amplification of the angiotensin II cardiovascular pressor response. Angiotensin also plays a role in regulating sodium concentration and blood volume through its action on adrenal cortex aldosterone secretion and on pituitary antidiuretic hormone (ADH) secretion. Typically, reduction of angiotensin II with angiotensin-converting enzyme (ACE) inhibitors is therapeutic in reducing hypertension. Prior to the last two decades, the therapeutic effect of ACE inhibitors was presumed to be mediated through a reduction in the direct systemic pressor and indirect blood volume expansion effects of angiotensin II receptor activity. However, starting in the early 1980s, data emerged making it clear that vascular smooth muscle contraction and aldosterone/ADHsecretion were not the only outcomes of angiotensin II receptor activation. Furthermore, as more ACE inhibitors were manufactured, studies revealed that not all ACE inhibitors were equal in their ability to reduce hypertension despite their equal efficacy in reducing circulating angiotensin II levels. Many questions were raised. For example, spontaneously hypertensive rats (SHR) maintained from weaning until sacrifice at 19 weeks of age on enalapril maleate (MK-421) did not develop the arterial remodeling typical of the strain . Was this because arterial wall thickening occurred secondarily to the hypertension and the enalapril maleate-treated SHR did not develop hypertension, or was this because angiotensin II was a stimulus for arterial smooth muscle hyperplasia/hypertrophy and MK-421 blocked this growth factor effect? Other studies showed that enalapril maleate was 11-fold more potent than captopril in lowering blood pressure in SHR, yet equally active in inhibition of plasma ACE . Did enalapril maleate havea mechanism other than plasma ACE inhibition, or were there sites of non-circulating ACE production that were blocked by enalapril but not by captopril?