Brain ‘Ouabain’ Mediates Sympathetic Hyperactivity in Congestive Heart Failure

Leenen, Frans H. H.; Huang, Bing; Yu, Huili; Yuan, Baoxue

doi:10.1161/01.res.77.5.993

Cited by 77 publications

(58 citation statements)

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“…In this regard, the central sympathetic drive and the peripheral RAAS appear to be locked into a feedforward relationship-blood-borne ANG II acts on AT 1 receptors in the forebrain to increase sympathetic nerve activity, which in turn acts on the kidneys to stimulate the renin release, the rate-limiting step in the production of more ANG II. Interestingly, central manipulations of AT 1 receptors, or of brain ouabain-like activity, which also contributes to augmented sympathetic drive in heart failure (92), inhibit the progression of left ventricular dysfunction after MI (93). Presuming sympathetic mediation of this effect, the detrimental effects of sympathetic stimulation on left ventricular function are well described (17).…”

Section: The Neurohumoral Milieu Of Heart Failurementioning

confidence: 99%

Heart failure and the brain: new perspectives

Felder¹,

Francis²,

Zhang³

et al. 2003

American Journal of Physiology-Regulatory, Integrative and Comp

110

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Heart failure and the brain: new perspectives. Am J Physiol Regul Integr Comp Physiol 284: R259-R276, 2003; 10.1152/ajpregu.00317.2002.-Despite recent therapeutic advances, the prognosis for patients with heart failure remains dismal. Unchecked neurohumoral excitation is a critical element in the progressive clinical deterioration associated with the heart failure syndrome, and its peripheral manifestations have become the principal targets for intervention. The link between peripheral systems activated in heart failure and the central nervous system as a source of neurohumoral drive has therefore come under close scrutiny. In this context, the forebrain and particularly the paraventricular nucleus of the hypothalamus have emerged as sites that sense humoral signals generated peripherally in response to the stresses of heart failure and contribute to the altered volume regulation and augmented sympathetic drive that characterize the heart failure syndrome. This brief review summarizes recent studies from our laboratory supporting the concept that the forebrain plays a critical role in the pathogenesis of ischemiainduced heart failure and suggesting that the forebrain contribution must be considered in designing therapeutic strategies. Forebrain signaling by neuroactive products of the renin-angiotensin system and the immune system are emphasized.angiotensin; aldosterone; cytokines; tumor necrosis factor; immune system; renin; vasopressin; sympathetic; extracellular fluid volume; baroreflex THE IMPORTANCE OF AUTONOMIC dysfunction to the progression of heart failure is firmly established (55,113,120,152). The most effective treatments for heart failure specifically target the peripheral manifestations of neurohumoral activation (86,113). Yet the understanding of the mechanisms leading to neurohumoral excitation in heart failure is still quite limited.Over the last several decades, substantial evidence has been amassed to support the concept that peripheral afferent systems innervating the heart and vascular tree are altered in heart failure. Dysfunction has been described in all components of the reflexes mediated by these cardiovascular afferent systems-the afferent fibers themselves, the central processing of the afferent signals, the efferent innervation of the end organs, and the end organs themselves. In general, the influence of low-and high-pressure baroreceptors (40,42,191) that normally restrain sympathetic drive and vasopressin release is diminished, whereas the excitatory influences of arterial chemoreceptors (161) and cardiac sympathetic afferent fibers (100) are enhanced.Central nervous system (CNS) neurons affecting cardiovascular regulation respond to humoral as well neural signals. Blood-borne neuroactive peptides, too large to readily cross the blood-brain barrier, may influence the brain by activating sensory neurons at specific sites in hindbrain and forebrain that lack a blood-brain barrier (15,18) or by inducing the release of mediators that do penetrate the barrier (135). These neuroactive s...

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Section: The Neurohumoral Milieu Of Heart Failurementioning

confidence: 99%

Heart failure and the brain: new perspectives

Felder¹,

Francis²,

Zhang³

et al. 2003

American Journal of Physiology-Regulatory, Integrative and Comp

110

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“…As in Dahl S rats on high salt, in rats post-MI, blockade of brain OLC with Fab fragments (25) or of the brain RAS (7,38,41) prevents sympathetic hyperactivity and impairment of arterial baroreflex function. In addition, blockade of brain OLC or the brain RAS markedly inhibits cardiac remodeling and cardiac dysfunction post-MI (25,32,38).…”

mentioning

confidence: 96%

“…In addition, blockade of brain OLC or the brain RAS markedly inhibits cardiac remodeling and cardiac dysfunction post-MI (25,32,38). In rats post-MI, chronic blockade of brain MR with central infusion of spironolactone prevents the increased neuronal activity of the paraventricular nucleus (PVN) in the hypothalamus and decreases sympathetic drive (12,42).…”

mentioning

confidence: 99%

Blockade of brain mineralocorticoid receptors or Na⁺ channels prevents sympathetic hyperactivity and improves cardiac function in rats post-MI

Huang¹,

Leenen²

2005

American Journal of Physiology-Heart and Circulatory Physiology

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In rats postmyocardial infarction (MI), sympathetic hyperactivity can be prevented by blockade of brain mineralocorticoid receptors (MR). Stimulatory responses to central infusion of aldosterone can be blocked by benzamil and therefore appear to be mediated via Na ϩ channels, presumably epithelial Na ϩ channels (ENaC), in the brain. To evaluate this concept of endogenous mineralocorticoids in Wistar rats post-MI, we examined effects of blockade of MR and Na ϩ channels in the brain. At 3 days after coronary artery ligation, intracerebroventricular infusions were started with spironolactone (400 ng ⅐ kg Ϫ1 ⅐ h Ϫ1 ) or its vehicle, or with benzamil (4 g ⅐ kg Ϫ1 ⅐ h Ϫ1 ) or its vehicle, using osmotic minipumps. Rats with sham ligation served as control. After 4 wk, in conscious rats, mean arterial pressure, heart rate, and renal sympathetic nerve activity were recorded at rest and in response to air-jet stress, intracerebroventricular injection of the ␣ 2-adrenoceptor agonist guanabenz, and intravenous infusion of phenylephrine and nitroprusside for baroreflex function. MI size was similar among the four groups of rats (ϳ31%). In rats treated post-MI with vehicles, cardiac function was decreased, sympathetic reactivity was enhanced, and baroreflex function was impaired. Blockade of brain Na ϩ channels or brain MR similarly prevented sympathetic hyperactivity and impairment of baroreflex function and improved cardiac function. These findings suggest that in rats post-MI, increased binding of endogenous agonists to MR increases ENaC activity in the brain and thereby leads to sympathetic hyperactivity and progressive left ventricular dysfunction. myocardial infarction; cardiac dysfunction; aldosterone RECENT STUDIES DEMONSTRATED that the central mechanisms leading to sympathetic hyperactivity in rats post-MI resemble those contributing to salt-sensitive hypertension in Dahl saltsensitive (S) rats. In Dahl S rats on high salt intake, blockade of brain ouabain-like compounds (OLC) or of the brain reninangiotensin system (RAS) prevents sympathetic hyperactivity and impairment of arterial baroreflex function and prevents salt-induced hypertension (19). Gomez-Sanchez and colleagues demonstrated that blockade of brain aldosterone biosynthesis with the 3␤-hydroxysteroid dehydrogenase inhibitor trilostane (17), of brain mineralocorticoid receptors (MR) with spironolactone (15), or of brain amiloride-sensitive Na ϩ channels with the amiloride analog benzamil (16) also prevents hypertension in Dahl S rats on high salt (15). In rats, responses to intracerebroventricular infusion of aldosterone can be blocked by intracerebroventricular infusion of a MR antagonist (14), benzamil, or antibody Fab fragments binding brain OLC (39). These findings suggest that in the brain, increased binding of aldosterone to MR increases activity of amiloride-sensitive Na ϩ channels, likely epithelial Na ϩ channels (ENaC), and thereby increases brain OLC and activity of the brain RAS (39). We proposed that in Dahl S rats on high salt, increased bindin...

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“…18 Thus, it appears that a sympathoinhibitory effect of digoxin may not only result from sensitization of baroreflex function. We postulated that the sympathoinhibitory effect of digoxin depends not only on baroreflex sensitization but also on its central actions; ie, digoxin may act as a partial agonist, and in the presence of high exogenous ouabain or endogenous "ouabain," as in salt-sensitive hypertension 1,2 and congestive heart failure, 19 it acts as an antagonist of ouabain in the brain.…”

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Digoxin Prevents Ouabain and High Salt Intake–Induced Hypertension in Rats With Sinoaortic Denervation

et al. 1999

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Abstract-Digoxin prevents ouabain-induced hypertension in rats. In the present study, we tested whether this effect of digoxin depends on its sensitizing effect on baroreflex function or is due to an antagonistic action on exogenous ouabain or endogenous ouabainlike activity ("ouabain") in the brain. In Wistar rats, resting mean arterial pressure (MAP) was significantly increased by long-term subcutaneous (SC) ouabain (75 g/d) plus high salt (8%) intake for 12 days (but not after only 5 days). In rats with chronic sinoaortic denervation (SAD), MAP was increased within 5 days of ouabain treatment to the same extent as MAP after 12 days of treatment in intact rats. The effect of ouabain and high salt was prevented when digoxin was given SC concomitantly via osmotic minipump (200 g ⅐ kg Ϫ1 ⅐ d Ϫ1 ). Resting MAP was not changed in rats treated with digoxin alone. In a second set of rats with chronic SAD or sham surgery, high salt intake was given for 14 days, with or without SC digoxin (200 g ⅐ kg Ϫ1 ⅐ d Ϫ1 ) or intracerebroventricular (ICV) antibody Fab fragments (200 g/d), which bind "ouabain" with high affinity. On day 14, MAP, central venous pressure, heart rate, and renal sympathetic nerve activity were recorded in conscious rats at rest and in response to air-jet stress, IV phenylephrine and nitroprusside, and acute volume expansion with 5% dextrose IV. In rats with SAD versus sham surgery, high salt significantly increased resting MAP as well as excitatory responses of MAP, heart rate, and renal sympathetic nerve activity to air stress. These effects of high salt in rats with SAD were prevented by digoxin or Fab fragments. Arterial baroreflex function was blunted but cardiopulmonary baroreflex function was not affected in rats with SAD. Digoxin and Fab fragments had no effects on either function. In an in vitro assay for the inhibitory effects on Na ϩ ,K ϩ -ATPase activity, 20 ng of ouabain caused 29% inhibition, but 20 ng of ouabain plus 13 or 53 ng of digoxin caused only 16% or 4% inhibition, respectively. These data indicate that the arterial baroreflex opposes sympathoexcitatory responses to ouabain and "ouabain" in the brain, thereby delaying ouabain-and preventing high salt-induced hypertension in Wistar rats. In addition to possible effects on the arterial baroreflex, digoxin appears to act centrally to prevent the sympathoexcitatory and pressor effects of increased brain "ouabain" or ouabain. Key Words: digoxin Ⅲ nerve activity, sympathetic, renal Ⅲ sodium intake Ⅲ baroreflex Ⅲ ouabain Ⅲ denervation, sinoaortic Ⅲ stress, air Ⅲ Fab H igh salt intake increases endogenous compounds with ouabainlike activity ("ouabain") in the brain of rats with salt-sensitive blood pressure (BP) and to a lesser extent in the brain of normotensive rats with salt-insensitive BP. 1,2 In saltsensitive rats, such as spontaneously hypertensive and Dahl salt-sensitive rats, the increase in brain "ouabain" appears to mediate salt-induced sympathetic hyperactivity, impairment of baroreflex function, and hypertension. [3][4][5][6]...

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Brain ‘Ouabain’ Mediates Sympathetic Hyperactivity in Congestive Heart Failure

Cited by 77 publications

References 40 publications

Heart failure and the brain: new perspectives

Heart failure and the brain: new perspectives

Blockade of brain mineralocorticoid receptors or Na⁺ channels prevents sympathetic hyperactivity and improves cardiac function in rats post-MI

Digoxin Prevents Ouabain and High Salt Intake–Induced Hypertension in Rats With Sinoaortic Denervation

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Brain ‘Ouabain’ Mediates Sympathetic Hyperactivity in Congestive Heart Failure

Cited by 77 publications

References 40 publications

Heart failure and the brain: new perspectives

Heart failure and the brain: new perspectives

Blockade of brain mineralocorticoid receptors or Na+ channels prevents sympathetic hyperactivity and improves cardiac function in rats post-MI

Digoxin Prevents Ouabain and High Salt Intake–Induced Hypertension in Rats With Sinoaortic Denervation

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Blockade of brain mineralocorticoid receptors or Na⁺ channels prevents sympathetic hyperactivity and improves cardiac function in rats post-MI