Brain Renin-Angiotensin System and Ouabain-Induced Sympathetic Hyperactivity and Hypertension in Wistar Rats

Abstract

Abstract-In Dahl salt-sensitive rats on a high salt diet or normotensive rats with chronic central infusion of sodium, increased brain "ouabain" results in sympathetic hyperactivity and hypertension, possibly by activating the brain renin-angiotensin system. In the present study, we tested whether the hypertension caused by exogenous ouabain also depends on activation of brain renin-angiotensin system. In Wistar rats, ouabain (50 g/d) was infused subcutaneously for 14 days with the use of osmotic minipumps. Concomitantly, in one group, the angiotensin II type 1 receptor blocker losartan (1 mg/kg per day) was infused intracerebroventricularly. On day 15, mean arterial pressure, heart rate, central venous pressure, and renal sympathetic nerve activity were recorded in conscious rats at rest and in response to air-jet stress, intracerebroventricular injection of the ␣ 2 -agonist guanabenz (25 and 75 g) or angiotensin II (30 ng), acute volume expansion, and ramp changes of blood pressure by Ϯ50 mm Hg with phenylephrine and nitroprusside. Compared with control rats, in rats treated with ouabain, resting mean arterial pressure was significantly increased (111Ϯ4 versus 93Ϯ3 mm Hg; PϽ0.05), and increases or decreases in mean arterial pressure, heart rate, and renal sympathetic nerve activity in response to air stress or guanabenz were enhanced significantly. These effects of ouabain were prevented when losartan was given concomitantly. Maximal slopes of arterial baroreflex control of renal sympathetic nerve activity and heart rate tended to be decreased in ouabain-treated versus control rats and were significantly increased in ouabain-treated rats with versus without losartan. No differences in cardiopulmonary baroreflex function were detected. It seems that by day 14 to 15, the central effect of ouabain on baroreflex control prevails over its peripheral sensitizing effect on baroreceptors, leading to a tendency of desensitization. These results indicate that chronic administration of ouabain activates the brain renin-angiotensin system, resulting in decreased sympathoinhibition and increased sympathoexcitation, impairment of baroreflex function, and hypertension. Key Words: baroreflex Ⅲ renal nerves Ⅲ stress, air-jet Ⅲ guanabenz Ⅲ renin-angiotensin system I ncreased sympathetic activity mediates salt-sensitive hypertension in spontaneously hypertensive rats (SHR) and Dahl salt-sensitive rats. 1,2 The sympathoexcitatory and pressor effects of high salt are prevented by either chronic intracerebroventricular administration of an angiotensin II type 1 (AT 1 ) receptor antagonist 3,4 or antibody Fab fragments, 3,4 binding ouabain and endogenous ouabainlike activity ("ouabain"). 5,6 Therefore, in Dahl salt-sensitive rats and SHR on high salt, both brain angiotensin II (Ang II) and brain "ouabain" contribute to sympathetic hyperactivity and hypertension. 3,4 We postulated that brain "ouabain" exerts its effects possibly by activation of the brain renin angiotensin system (RAS), 3,4,7 since blockade of brain AT 1 receptors bl...

Ouabain-induced hypertension is accompanied by increases in endothelial vasodilator factors

“…As previously demonstrated, long-term treatment with ouabain induces the development of a time-dependent hypertension (10,21,23,26,32,45,54) as well as regional changes in the ouabain-sensitive sodium pump activity and expression of the ␣-isoforms (45). This hypertension is also associated with a reduction of phenylephrine-induced contractile activity in the thoracic aorta, but not in caudal arteries, and with an increase in the negative endothelial modulation of the actions of phenylephrine in both arteries (45).…”

“…nitric oxide; endothelial-dependent hyperpolarizing factor; phenylephrine THE PLASMA LEVELS of an endogenous circulating Na ϩ -K ϩ -ATPase inhibitor, characterized as ouabain or a closely related compound (17,36), are increased in several animal models of hypertension (19,39), as well as in human essential hypertension (20). Several studies have shown that chronic administration of ouabain induces hypertension, an effect that seems to be linked to the inhibition of the Na ϩ -K ϩ -ATPase (10,22,23,45,54), although sodium pump inhibition seems not to be the exclusive mechanism of the ouabain-hypertensive effect (26,31,32,52). This enzyme is found in most eukaryotic cells and is the main system involved in the maintenance of sodium homeostasis and the membrane potential, essential factors for controlling vascular tone and blood pressure.…”

“…It has been suggested that alterations in the activity of the sodium pump might be involved in the genesis or maintenance of hypertensive states (3,33). Additionally, the hypertension induced by ouabain treatment has been associated with actions in the central nervous system that increase sympathetic activity by activation of the central renin-angiotensin system and impair the arterial baroreceptor reflex (22,23) and associated with actions in the periphery that produce changes in responsiveness to contractile agents (10,26,45).…”

Arterial baroreflex function and cardiovascular variability: interactions and implications

“…However, neural and humoral mechanisms are closely linked. For instance, increased levels of brain ANG II, such as occurs in Dahl saltsensitive rats during high sodium intake, affect the tonic level of sympathetic activity as well as the magnitude of baroreflex-induced changes in sympathetic traffic (39,80). In humans with mild to moderate hypertension, the marked increase in plasma renin activity induced by a low-sodium diet has been shown to also be associated with a blunted baroreflex modulation of sympathetic neural drive (31).…”

Estudo dos mecanismos envolvidos no remodelamento de artérias de resistência de ratos hipertensos induzidos pelo tratamento com ouabaína.

“…Além disso, apesar do efeito pressórico não requerer a glândula adrenal para sua ocorrência e não ser sensível a sal, observa-se o aumento das concentrações plasmáticas de aldosterona (MANUNTA et al, 1994). Também neste modelo de HA, a OUA ativa tanto mecanismos centrais quanto periféricos, que agem nos diferentes territórios cardiovasculares para produzir o aumento da pressão arterial CARGNELLI et al, 2000;DI FILIPPO et al, 2003;HUANG et al, 1994;HUANG, LEENEN, 1999; ROSSONI et al, 2002a e b;WENCESLAU et al, 2011;XAVIER et al, 2004a;ZHANG et al, 2009 (BRIONES et al, 2009;CARGNELLI et al, 2000; HERNANZ et al, 2008; KIMURA et al, 2000; ROSSONI et al, 2002a b;XAVIER et al, 2004a, b e c).Entre essas, verificou-se: a redução na resposta constritora à fenilefrina, observada em anéis de aorta torácica e artéria mesentérica superior; a não alteração nas respostas contráteis mediadas por agonistas α-adrenenérgicos nas artérias caudal, basilar encefálica, coronária e mesentérica de resistência (AMR); e, por outro lado, o aumento dessa resposta contrátil em anéis de artéria renal (BRIONES et al, 2009;CARGNELLI et al, 2000; HERNANZ et al, 2008; KIMURA et al, 2000; ROSSONI et al., 2002a b;XAVIER et al, 2004a GAYTON, 1990;HALL, 1986). Essas mudanças resultam no aumento da transferência de sódio e água do lúmen tubular para o capilar peritubular, contribuindo para o aumento na pressão arterial.…”