Skip to main content

The brain renin-angiotensin-aldosterone system: A major mechanism for sympathetic hyperactivity and left ventricular remodeling and dysfunction after myocardial infarction

Current Heart Failure Reports volume 6, pages 81–88 (2009)Cite this article

Abstract

Following a myocardial infarction (MI), increases in plasma angiotensin II may activate central nervous system (CNS) pathways and thereby peripheral mechanisms (eg, sympathetic activity and the circulating/cardiac renin-angiotensin-aldosterone system [RAAS]). Plasma angiotensin II may directly activate CNS pathways through the subfornical organ and chronically enhance activity by way of a neuromodulatory system. The latter involves an increase in CNS aldosterone-causing “ouabain” release (eg, from magnocellular neurons of the supraoptic and paraventricular nuclei). “Ouabain” may lower membrane potential, thereby enhancing activity of angiotensinergic pathways. The resulting increases in sympathetic activity, and circulating/cardiac RAAS contributes to progressive left ventricular remodeling and dysfunction after MI and can be largely prevented by central administration of a blocker for any of the components of this neuromodulatory system. These new insights into the crucial role of the CNS may lead to new therapeutic approaches for the prevention of heart failure after MI with minimal peripheral adverse effects.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

References and Recommended Reading

  1. Patel KP, Zhang K: Neurohumoral activation in heart failure: role of paraventricular nucleus. Clin Exp Pharmacol Physiol 1996, 23:722–726.

    PubMed  Article  CAS  Google Scholar 

  2. Vahid-Ansari F, Leenen FH: Pattern of neuronal activation in rats with CHF after myocardial infarction. Am J Physiol 1998, 275(6 Pt 2):H2140–H2146.

    PubMed  CAS  Google Scholar 

  3. Yu Y, Wei SG, Zhang ZH, et al.: Does aldosterone upregulate the brain renin-angiotensin system in rats with heart failure? Hypertension 2008, 51:727–733.

    PubMed  Article  CAS  Google Scholar 

  4. Lindley TE, Doobay MF, Sharma RV, Davisson RL: Superoxide is involved in the central nervous system activation and sympathoexcitation of myocardial infarction-induced heart failure. Circ Res 2004, 94:402–409.

    PubMed  Article  CAS  Google Scholar 

  5. Basu S, Sinha SK, Shao Q, et al.: Neuropeptide Y modulation of sympathetic activity in myocardial infarction. J Am Coll Cardiol 1996, 27:1796–1803.

    PubMed  Article  CAS  Google Scholar 

  6. Zhang ZH, Francis J, Weiss RM, Felder RB: The renin-angiotensin-aldosterone system excites hypothalamic paraventricular nucleus neurons in heart failure. Am J Physiol Heart Circ Physiol 2002, 283:H423–H433.

    PubMed  CAS  Google Scholar 

  7. Wang H, Huang BS, Ganten D, Leenen FH: Prevention of sympathetic and cardiac dysfunction after myocardial infarction in transgenic rats deficient in brain angiotensinogen. Circ Res 2004, 94:843.

    PubMed  Article  CAS  Google Scholar 

  8. Leenen FH, Skarda V, Yuan B, White R: Changes in cardiac ANG II postmyocardial infarction in rats: effects of nephrectomy and ACE inhibitors. Am J Physiol 1999, 276(1 Pt 2):H317–H325.

    PubMed  CAS  Google Scholar 

  9. Francis J, Weiss RM, Wei SG, et al.: Progression of heart failure after myocardial infarction in the rat. Am J Physiol Regul Integr Comp Physiol 2001, 281:R1734–R1745. [Published erratum appears in Am J Physiol Regul Integr Comp Physiol 2005, 288:R1078.]

    PubMed  CAS  Google Scholar 

  10. Davern PJ, Head GA: Fos-related antigen immunoreactivity after acute and chronic angiotensin II-induced hypertension in the rabbit brain. Hypertension 2007, 49:1170–1177.

    PubMed  Article  CAS  Google Scholar 

  11. Lal A, Veinot JP, Leenen FH: Critical role of CNS effects of aldosterone in cardiac remodeling post-myocardial infarction in rats. Cardiovasc Res 2004, 64:437–447.

    PubMed  Article  CAS  Google Scholar 

  12. Fraccarollo D, Galuppo P, Schraut S, et al.: Immediate mineralocorticoid receptor blockade improves myocardial infarct healing by modulation of the inflammatory response. Hypertension 2008, 51:905–914.

    PubMed  Article  CAS  Google Scholar 

  13. McEwen BS, Lambdin LT, Rainbow TC, De Nicola AF: Aldosterone effects on salt appetite in adrenalectomized rats. Neuroendocrinology 1986, 43:38–43.

    PubMed  Article  CAS  Google Scholar 

  14. Zhu GQ, Gao L, Li Y, et al.: AT1 receptor mRNA antisense normalizes enhanced cardiac sympathetic afferent reflex in rats with chronic heart failure. Am J Physiol Heart Circ Physiol 2004, 287:H1828–H1835.

    PubMed  Article  CAS  Google Scholar 

  15. Kang YM, Zhang ZH, Johnson RF, et al.: Novel effect of mineralocorticoid receptor antagonism to reduce proinflammatory cytokines and hypothalamic activation in rats with ischemia-induced heart failure. Circ Res 2006, 99:758–766.

    PubMed  Article  CAS  Google Scholar 

  16. Guggilam A, Patel KP, Haque M, et al.: Cytokine blockade attenuates sympathoexcitation in heart failure: cross-talk between nNOS, AT-1R and cytokines in the hypothalamic paraventricular nucleus. Eur J Heart Fail 2008, 10:625–634.

    PubMed  Article  CAS  Google Scholar 

  17. de Kloet ER, Van Acker SA, Sibug RM, et al.: Brain mineralocorticoid receptors and centrally regulated functions. Kidney Int 2000, 57:1329–1336.

    PubMed  Article  Google Scholar 

  18. Menard J, Gonzalez MF, Guyene TT, Bissery A: Investigation of aldosterone-synthase inhibition in rats. J Hypertens 2006, 24:1147–1155.

    PubMed  CAS  Google Scholar 

  19. Vinson GP: Glomerulosa function and aldosterone synthesis in the rat. Mol Cel Endocrinol 2004, 217:59–65.

    Article  CAS  Google Scholar 

  20. Ye P, Kenyon CJ, MacKenzie SM, et al.: Regulation of aldosterone synthase gene expression in the rat adrenal gland and central nervous system by sodium and angiotensin II. Endocrinol 2003, 144:3321–3328.

    Article  CAS  Google Scholar 

  21. Ye P, Kenyon CJ, Mackenzie SM, et al.: Effects of ACTH, dexamethasone, and adrenalectomy on 11beta-hydroxylase (CYP11B1) and aldosterone synthase (CYP11B2) gene expression in the rat central nervous system. J Endocrinol 2008, 196:305–311.

    PubMed  Article  CAS  Google Scholar 

  22. Zhang ZH, Kang YM, Yu Y, et al.: 11beta-hydrosteroid dehydrogenase type 2 activity in hypothalamic paraventricular nucleus modulates sympathetic excitation. Hypertension 2006, 48:127–133.

    PubMed  Article  CAS  Google Scholar 

  23. Geerling JC, Loewy AD: Aldosterone-sensitive neurons in the nucleus of the solitary tract: bidirectional connections with the central nucleus of the amygdala. J Comp Neurol 2006, 497:646–657.

    PubMed  Article  Google Scholar 

  24. Huang BS, White RA, Ahmad M, et al.: Central infusion of aldosterone synthase inhibitor attenuates left ventricular dysfunction and remodeling in rats after myocardial infarction. Cardiovasc Res 2009, 81:574–581.

    PubMed  Article  CAS  Google Scholar 

  25. Huang BS, White RA, Jeng AY, Leenen FH: Role of CNS aldosterone synthase and mineralocorticoid receptors in salt-induced hypertension in Dahl salt-sensitive rats. Am J Physiol 2009, 296:R994–R1000.

    CAS  Article  Google Scholar 

  26. Amin MS, Wang HW, Reza E, et al.: Distribution of epithelial sodium channels and mineralocorticoid receptors in cardiovascular regulatory centers in rat brain. Am J Physiol Regul Integr Comp Physiol 2005, 289:R1787–R1797.

    PubMed  CAS  Google Scholar 

  27. Garty H: Molecular properties of epithelial, amilorideblockable Na+ channels. FASEB J 1994, 8:522–528.

    PubMed  CAS  Google Scholar 

  28. Gomez-Sanchez EP: Intracerebroventricular infusion of aldosterone induces hypertension in rats. Endocrinology 1986, 118:819–823.

    PubMed  CAS  Article  Google Scholar 

  29. Wang H, Huang BS, Leenen FH: Brain sodium channels and ouabainlike compounds mediate central aldosterone-induced hypertension. Am J Physiol Heart Circ Physiol 2003, 285:H2516–H2523.

    PubMed  CAS  Google Scholar 

  30. Leenen FH, Huang BS, Yu H, Yuan B: Brain ‘ouabain’ mediates sympathetic hyperactivity in congestive heart failure. Circ Res 1995, 77:993–1000.

    PubMed  CAS  Google Scholar 

  31. Huang BS, Cheung WJ, Wang H, et al.: Activation of brain renin-angiotensin-aldosterone system by central sodium in Wistar rats. Am J Physiol Heart Circ Physiol 2006, 291:H1109–H1117.

    PubMed  Article  CAS  Google Scholar 

  32. Budzikowski AS, Huang BS, Leenen FH: Brain “ouabain,” a neurosteroid, mediates sympathetic hyperactivity in salt-sensitive hypertension. Clin Exp Hypertens 1998, 20:119–140.

    PubMed  Article  CAS  Google Scholar 

  33. Kala G, Kumarathasan R, Peng L, et al.: Stimulation of Na+,K+-ATPase activity, increase in potassium uptake, and enhanced production of ouabain-like compounds in ammonia-treated mouse astrocytes. Neurochem Int 2000, 36:203–211.

    PubMed  Article  CAS  Google Scholar 

  34. Murrell JR, Randall JD, Rosoff J, et al.: Endogenous ouabain: upregulation of steroidogenic genes in hypertensive hypothalamus but not adrenal. Circulation 2005, 112:1301–1308.

    PubMed  Article  CAS  Google Scholar 

  35. Huang BS, Leenen FH: Brain ouabain and central effects of dietary sodium in spontaneously hypertensive rats. Circ Res 1992, 70:430–437.

    PubMed  CAS  Google Scholar 

  36. Jones DL, Lo S: Ouabain injected into the hypothalamus elicits pressor responses in anaesthetized rats: a mapping study. Pharmacol Biochem Behav 1990, 36:979–983.

    PubMed  Article  CAS  Google Scholar 

  37. Gabor A, Leenen FH: Mechanisms in the PVN mediating local and central sodium-induced hypertension in Wistar rats. Am J Physiol 2009, 296:R618–R630.

    CAS  Google Scholar 

  38. Teruya H, Yamazato M, Muratani H, et al.: Role of ouabain-like compound in the rostral ventrolateral medulla in rats. J Clin Invest 1997, 99:2791–2798.

    PubMed  Article  CAS  Google Scholar 

  39. Huang BS, Leenen FH: Sympathoexcitatory and pressor responses to increased brain sodium and ouabain are mediated via brain ANG II. Am J Physiol 1996, 270(1 Pt 2):H275–H280.

    PubMed  CAS  Google Scholar 

  40. Zhang ZH, Yu Y, Kang YM, et al.: Aldosterone acts centrally to increase brain renin-angiotensin system activity and oxidative stress in normal rats. Am J Physiol Heart Circ Physiol 2008, 294:H1067–H1074.

    PubMed  Article  CAS  Google Scholar 

  41. Huang BS, Zheng H, Patel KP, Leenen FH: Hypertension induced by central infusion of aldosterone associated with decreased nNOS, and increased AT1R and components of NADPH oxidase in the PVN. Presented at 62nd High Blood Research Conference. Atlanta, GA; September 17–20, 2008. Hypertension 2008, 52:e59.

    Article  CAS  Google Scholar 

  42. Tan J, Wang H, Leenen FH: Increases in brain and cardiac AT1 receptor and ACE densities after myocardial infarct in rats. Am J Physiol Heart Circ Physiol 2004, 286:H1665–H1671.

    PubMed  Article  CAS  Google Scholar 

  43. Gao L, Wang W, Li YL, et al.: Superoxide mediates sympathoexcitation in heart failure: roles of angiotensin II and NAD(P)H oxidase. Circ Res 2004, 95:937–944.

    PubMed  Article  CAS  Google Scholar 

  44. Lindley TE, Infanger DW, Rishniw M, et al.: Scavenging superoxide selectively in mouse forebrain is associated with improved cardiac function and survival following myocardial infarction. Am J Physiol Regul Integr Comp Physiol 2009, 296:R1–R8.

    PubMed  CAS  Google Scholar 

  45. Zhang K, Li YF, Patel KP: Blunted nitric oxide-mediated inhibition of renal nerve discharge within PVN of rats with heart failure. Am J Physiol Heart Circ Physiol 2001, 281:H995–H1004.

    PubMed  CAS  Google Scholar 

  46. Campese VM, Ye S, Zhong H, et al.: Reactive oxygen species stimulate central and peripheral sympathetic nervous system activity. Am J Physiol Heart Circ Physiol 2004, 287:H695–H703.

    PubMed  Article  CAS  Google Scholar 

  47. Francis J, Weiss RM, Johnson AK, Felder RB: Central mineralocorticoid receptor blockade decreases plasma TNF-alpha after coronary artery ligation in rats. Am J Physiol Regul Integr Comp Physiol 2003, 284:R328–R335.

    PubMed  CAS  Google Scholar 

  48. Lal A, Veinot JP, Ganten D, Leenen FH: Prevention of cardiac remodeling after myocardial infarction in transgenic rats deficient in brain angiotensinogen. J Mol Cell Cardiol 2005, 39:521–529.

    PubMed  Article  CAS  Google Scholar 

  49. Huang BS, Leenen FH: Blockade of brain mineralocorticoid receptors or Na+ channels prevents sympathetic hyperactivity and improves cardiac function in rats post-MI. Am J Physiol Heart Circ Physiol 2005, 288:H2491–H2497.

    PubMed  Article  CAS  Google Scholar 

  50. Huang BS, Yuan B, Leenen FH: Chronic blockade of brain “ouabain” prevents sympathetic hyper-reactivity and impairment of acute baroreflex resetting in rats with congestive heart failure. Can J Physiol Pharmacol 2000, 78:45–53.

    PubMed  Article  CAS  Google Scholar 

  51. DiBona GF, Jones SY, Brooks VL: ANG II receptor blockade and arterial baroreflex regulation of renal nerve activity in cardiac failure. Am J Physiol 1995, 269(5 Pt 2):R1189–R1196.

    PubMed  CAS  Google Scholar 

  52. Zhang W, Huang BS, Leenen FH: Brain renin-angiotensin system and sympathetic hyperactivity in rats after myocardial infarction. Am J Physiol 1999, 276(5 Pt 2):H1608–H1615.

    PubMed  CAS  Google Scholar 

  53. Huang BS, Ahmad M, Tan J, Leenen FH: Sympathetic hyperactivity and cardiac dysfunction post-MI: different impact of specific CNS versus general AT1 receptor blockade. J Mol Cell Cardiol 2007, 43:479–486.

    PubMed  Article  CAS  Google Scholar 

  54. Ahmad M, White R, Tan J, et al.: Angiotensin-converting enzyme inhibitors, inhibition of brain and peripheral angiotensin-converting enzymes, and left ventricular dysfunction in rats after myocardial infarction. J Cardiovasc Pharmacol 2008, 51:565–572.

    PubMed  Article  CAS  Google Scholar 

  55. Kang YM, Ma Y, Elks C, et al.: Cross-talk between cytokines and renin-angiotensin in hypothalamic paraventricular nucleus in heart failure: role of nuclear factor-kappaB. Cardiovasc Res 2008, 79:671–678.

    PubMed  Article  CAS  Google Scholar 

  56. Leenen FH, Yuan B, Huang BS: Brain “ouabain” and angiotensin II contribute to cardiac dysfunction after myocardial infarction. Am J Physiol 1999, 277(5 Pt 2):H1786–H1792.

    PubMed  CAS  Google Scholar 

  57. Bodineau L, Frugière A, Marc Y, et al.: Orally active aminopeptidase A inhibitors reduce blood pressure: a new strategy for treating hypertension. Hypertension 2008, 51:1318–1325.

    PubMed  Article  CAS  Google Scholar 

  58. Leenen FH: Brain mechanisms contributing to sympathetic hyperactivity and heart failure. Circ Res 2007, 101:221–223.

    PubMed  Article  CAS  Google Scholar 

Download references

Author information

Affiliations

  1. University of Ottawa Heart Institute, H3238, 40 Ruskin Street, Ottawa, Ontario, K1Y 4W7, Canada

    Frans H. H. Leenen

Authors
  1. Bing S. Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Frans H. H. Leenen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Frans H. H. Leenen.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Huang, B.S., Leenen, F.H.H. The brain renin-angiotensin-aldosterone system: A major mechanism for sympathetic hyperactivity and left ventricular remodeling and dysfunction after myocardial infarction. Curr Heart Fail Rep 6, 81–88 (2009). https://doi.org/10.1007/s11897-009-0013-9

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11897-009-0013-9

Keywords

  • Aldosterone
  • Ouabain
  • Mineralocorticoid Receptor
  • Left Ventricular Remodel
  • Physiol Heart Circ