The Brain Renin-Angiotensin System Modulates Angiotensin II–Induced Hypertension and Cardiac Hypertrophy

Abstract

Abstract-The potential involvement of the brain renin-angiotensin system in the hypertension induced by subpressor doses of angiotensin II was tested by the use of newly developed transgenic rats with permanent inhibition of brain angiotensinogen synthesis [TGR(ASrAOGEN)]. Basal systolic blood pressure monitored by telemetry was significantly lower in TGR(ASrAOGEN) than in Sprague-Dawley rats (parent strain) (122.5Ϯ1.5 versus 128.9Ϯ1.9 mm Hg, respectively; PϽ0.05). The increase in systolic blood pressure induced by 7 days of chronic angiotensin II infusion was significantly attenuated in TGR(ASrAOGEN) in comparison with control rats (29.8Ϯ4.2 versus 46.3Ϯ2.5 mm Hg, respectively; PϽ0.005). Moreover, an increase in heart/body weight ratio was evident only in Sprague-Dawley (11.1%) but not in TGR(ASrAOGEN) rats (2.8%). In contrast, mRNA levels of atrial natriuretic peptide (ANP) and collagen III in the left ventricle measured by ribonuclease protection assay were similarly increased in both TGR(ASrAOGEN) (ANP, ϫ2.5; collagen III, ϫ1.8) and Sprague-Dawley rats (ANP, ϫ2.4; collagen III, ϫ2) as a consequence of angiotensin II infusion. Thus, the expression of these genes in the left ventricle seems to be directly stimulated by angiotensin II. However, the hypertensive and hypertrophic effects of subpressor angiotensin II are at least in part mediated by the brain renin-angiotensin system. Key Words: renin-angiotensin system Ⅲ collagen Ⅲ angiotensin II Ⅲ hypertrophy Ⅲ atrial natriuretic peptide T he renin-angiotensin system (RAS) is acknowledged to play an important role in the pathophysiology of hypertension and cardiovascular diseases. Since tissue RASs have been postulated, local formation of angiotensin II (Ang II) is consistently invoked to explain that RAS inhibitors can exert beneficial effects in cardiovascular diseases, even in the absence of Ang II plasma levels that directly increase blood pressure (BP). 1 The mechanisms by which increases in plasma Ang II can induce an increase in BP in these situations are still not clearly defined. One experimental animal model designed to mimic human hypertension that is often used to obtain insights regarding its pathophysiological mechanisms is attained by chronic infusion (days to weeks) of subpressor doses of Ang II. 2 Infused doses of Ang II up to 250 ng/kg per minute SC that do not produce direct vasoconstriction are described as "subpressor" or "slow pressor" and can induce a gradual increase of BP. Several studies have indicated that the central nervous system is involved in the effects of the subpressor Ang II. Arguments are based on the elimination of the hypertensive effect of Ang II by ablation of area postrema 3 or lateral parabrachial nucleus. 4 Furthermore, the hypertensive effect of subpressor doses of Ang II can be inhibited by central sympathoinhibitors, 5 ganglionic blockers, 6 nonselective ␣-blockade, 7 or renal denervation, 8 supporting a neurogenic pressor mechanism.The role of the brain RAS in the central control of cardiovascular homeostasis and p...

Stress sensitivity is increased in transgenic rats with low brain angiotensinogen

“…Following on from this, in this study, we aimed to confirm the relevancy of Ang II-dependent central mechanisms for regulating HPA activity by using TGR(ASrAOGEN) that lacked brain Ang II (Schinke et al 1999). Consistent with many other studies, a slight hypotension was observed in the TGR(ASrAOGEN), which served as the fundamental characteristic of this transgenic rat in most of the studies (Baltatu et al 2000, Wang et al 2004, Campos et al 2006.…”

The Intrarenal Renin-Angiotensin System: From Physiology to the Pathobiology of Hypertension and Kidney Disease

“…Emerging evidence suggests that local formation is of major significance in the regulation of the Ang levels in many organs and tissues. For example, there is substantial evidence that the Ang peptide levels in the brain are regulated in an autonomous manner (Baltatu et al, 2000). Although every organ system in the body has elements of the RAS, the kidney is unique in having every component of the RAS with compartmentalization in the tubular and interstitial networks as well as intracellular accumulation.…”

Kidney-specific enhancement of ANG II stimulates endogenous intrarenal angiotensinogen in gene-targeted mice

“…Emerging evidence has demonstrated the importance of the tissue RAS in the brain (1), heart (7), adrenal glands (34), vasculature (5,13,15,36), and kidneys (37). The RAS has been acknowledged as an endocrine, paracrine, autocrine, and intracrine system and thus it has been difficult to delineate the quantitative contributions of systemically delivered vs. locally formed ANG peptides to the levels existing in any given tissue (37).…”