Responses to Central Na ⁺ and Ouabain Are Attenuated in Transgenic Rats Deficient in Brain Angiotensinogen

Abstract

Abstract-Studies with angiotensin (Ang) II type 1 receptor blockers suggest that the brain renin-angiotensin system contributes to sodium-induced sympathoexcitation and hypertension. To provide more specific evidence for the involvement of Ang II, locally produced in the brain, transgenic rats were used, which express an antisense RNA against angiotensinogen mRNA specifically in the brain, reducing angiotensinogen levels in the brain by Ͼ90%. In freely moving transgenic rats and Sprague-Dawley rats as control animals, blood pressure and heart rate responses to intracerebroventricular infusion (3.8 L/min for 10 minutes) of artificial cerebrospinal fluid and Na ϩ -rich artificial cerebrospinal fluid (containing 0.2, 0.3, and 0.45 mol/L Na ϩ ) as well as intracerebroventricular injection of ouabain (0.3 and 0.6 g/2 L) were assessed. Central infusion of Na ϩ -rich artificial cerebrospinal fluid increased blood pressure and heart rate in a dose-related manner. However, the peak increases by each dose of Na ϩ were attenuated by 50% to 70% in the transgenic versus Sprague-Dawley rats. Increases in blood pressure and heart rate in response to ouabain at both doses were attenuated by 55% to 70% in the transgenic versus Sprague-Dawley rats. In the hypothalamus, Ang I level was markedly lower (31Ϯ9 versus 76Ϯ13 pg/g, PϽ0.05) and Ang II level tended to be lower in the transgenic versus Sprague-Dawley rats. These results indicate that the production of angiotensins in the brain is decreased in transgenic rats. The attenuated sympathoexcitatory and pressor responses to ouabain and Na ϩ -rich artificial cerebrospinal fluid in transgenic rats support the concept that the local brain renin-angiotensin system, that is, locally produced Ang II, plays an important role in the sympathoexcitatory effects of ouabain and sodium. Key Words: angiotensinogen Ⅲ antisense elements Ⅲ brain Ⅲ DNA Ⅲ sodium Ⅲ ouabain T here is extensive evidence supporting a major role for neural mechanisms in salt-induced hypertension in Dahl salt-sensitive (S) rats receiving high salt intake (for review, see Reference 1). 1 Dahl S rats receiving high salt intake demonstrate sympathetic hyperactivity and hypertension as well as impaired baroreflex function compared with Dahl salt-resistant (R) rats. 2,3 These central effects of high salt can be prevented by blockade of ouabainlike activity ("ouabain") 2,3 or the renin-angiotensin system (RAS) 2 in the brain. Salt-induced sympathoexcitation and hypertension in salt-sensitive rats can be mimicked in normotensive rats by central sodium loading, 4,5 which can also be prevented by blockade of "ouabain" or angiotensin (Ang) II type 1 (AT 1 ) receptors in the brain. 5 These findings support the concept that in salt-sensitive rats receiving high salt, increased sodium in the cerebrospinal fluid (CSF) activates central pathways involving "ouabain" and AT 1 -receptors, causing sympathoexcitation and hypertension. Increased responsiveness to CSF Na ϩ in Dahl S versus R rats probably is one of the mechanisms through which...

Enhanced pressor response to increased CSF sodium concentration and to central ANG I in heterozygous α2Na+-K+-ATPase knockout mice

“…Glia-specific renin overexpression in mice increases blood pressure vs. control mice, and the hypertension associated with glial renin overexpression is at least as great as that produced when renin is overexpressed in neurons (37). As well, the upregulation of angiotensinogen mRNA in glia causes hypertension, while angiotensinogen downregulation in this cell type lowers blood presssure (21,36).…”

Hypertensive effects of the iv administration of picomoles of ouabain

“…This observation is supported by reports that the sympathetic hyperactivity induced by ouabain is prevented by an AT1 receptor blocker (50)(51)(52), suggesting that the central renin-angiotensin system could be the sympathoexcitatory component involved in the hypertensinogenic effect of ouabain. In addition, the acute hypertensinogenic effect of ouabain is attenuated in transgenic rats that are deficient in brain angiotensinogen (54). Therefore, in some diseases that are accompanied by an increased level of endogenous ouabain, such as hypertension (1), heart failure (55) and diabetes (35), the increase in sympathoexcitatory activity could be due to the actions of ouabain on the central reninangiotensin system.…”

Aging and the Brain Renin–Angiotensin System: Relevance to Age-Related Decline in Cardiac Function

“…By contrast, chronic AT 1 -receptor blockers given in the cerebral ventricles [68,69], median preoptic nucleus [73] or rostral ventrolateral medulla [74] prevented sympathoexcitation and hypertension in salt-sensitive strains. Further implicating the brain in the generation of the salt sensitivity is the additional finding that the ASrAogen rats are protected from the hypertension induced by centrally administered ouabain [39]. There is a large body of evidence suggesting that salt excess activates local cardiac [75][76][77][78] and renal [63] tissue RAS as well.…”

“…To better understand the specific role of the brain RAS in the aging process with respect to metabolic and cardiovascular function, our recent studies compared SD rats with transgenic rats that have a deficiency in brain angiotensinogen (ASrAogen). The ASrAogen transgenic rats have a GFAP promoter-linked angiotensinogen antisense sequence overexpressed in brain glia [38], thereby selectively targeting the main source of angiotensinogen and reducing cerebral levels of the prohormone to less than 10% of normal [38,39]. ASrAogen-deficient rats have slightly lower values of resting arterial pressure, but otherwise exhibit similar circulating levels of leptin, insulin and glucose values in early adulthood [26].…”