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

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/ADH secretion 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 [1]. 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 [2]. Did enalapril maleate have a mechanism other than plasma ACE inhibition, or were there sites of non-circulating ACE production that were blocked by enalapril but not by captopril? The kinds of questions that emerged from the early work with ACE inhibition spawned a flurry of studies over the next decade. The close inter-relationship between the renin–angiotensin system (RAS) and sympathetic nervous system in the control of blood pressure and body fluid homeostasis [3] and the role of angiotensin II as a growth factor not only in arterial smooth muscle, but also in heart and perhaps other organs [4], were revealed. Hand-in-hand with the discoveries of alternate angiotensin II functions came the discoveries of multiple angiotensin II receptor types and of tissue RAS. By the end of the 1990s, angiotensin II was recognized not only as a classical circulating vasoactive hormone, but also as a true cytokine and as a paracrine or autocrine or intracrine hormone [5]. At least two, and possibly four or more, distinct receptors were identified on numerous tissue types including but not limited to vascular muscle, adrenal cortex and adrenal medulla, myocardium, brain [6], adipose tissue and liver [7]. The discovery of the function of angiotensin II in cell proliferation and growth and the investigations of the role of angiotensin II in the pathogenesis of hypertension, kidney disease and atherosclerosis led to the generation of ideas and data revealing an additional function of angiotensin II as a pro-inflammatory modulator [8]. By the new millennium, angiotensin II was understood to be a whole organism homeostatic regulator, and was not unlike the catecholamines, epinephrine and norepinephrine in this regard. The variety of functions that could be attributed to angiotensin II spanned acute to long-term control of mean arterial pressure, body fluid balance, immune and inflammatory responses, and cytokine activity in embryonic development and in adult tissue injury and repair. All of these functions, including muscle contraction, inflammatory cell recruitment and activation, cell growth and proliferation, require increased energy. Could angiotensin II, similar to norepinephrine, also play a role in altering organism energetics? Interestingly, evidence that angiotensin II alters insulin action was accumulating [7]. In 2000, Giacchetti et al. [9] reported that a high fructose diet is associated with development of hypertension and with up-regulation of angiotensin II type 1 receptors (AT1R) in adipose. Current work shows that elevated angiotensin II raises circulating triglycerides via stimulation of hepatic triglyceride production via angiotensin II type 2 receptor (AT2R) activation [7]. As a logical extension of this work, these investigators addressed the hypothesis that the effects of elevated angiotensin II on cholesterol levels may vary dependent on the effects of diet (high fructose versus normal fructose intake) and on the balance of AT1R versus AT2R expression. In the present issue of the journal, Hirano et al. [10] report that AT1R activity increases plasma cholesterol whereas AT2R activity decreases cholesterol levels and that high sugar diets may up-regulate AT1R, resulting in an imbalance leading to hypercholesterolemia when there is abnormally high AII production. This is an interesting idea. In addition to having a role in hypertension, elevated angiotensin II appears to play a role in dyslipidemia, hypertriglyceridemia, hypercholesterolemia and insulin resistance. The intriguing work by Hirano et al. [10] is important for understanding the complex physiological functions of angiotensin II and for understanding the mechanisms involved in the etiology of hypertension, atherosclerosis and the metabolic syndrome.