Inhibition of brain angiotensin III attenuates sympathetic hyperactivity and cardiac dysfunction in rats post-myocardial infarction

Cardiovasc Res. 2013 Mar 1;97(3):424-31. doi: 10.1093/cvr/cvs420. Epub 2012 Dec 19.

Abstract

Aims: In rats post-myocardial infarction (MI), activation of angiotensinergic pathways in the brain contributes to sympathetic hyperactivity and progressive left ventricle (LV) dysfunction. The present study examined whether angiotensin III (Ang III) is one of the main effector peptides of the brain renin-angiotensin system controlling these effects.

Methods and results: After coronary artery ligation, Wistar rats were infused intracerebroventricularly for 4 weeks via minipumps with vehicle, the aminopeptidase A (APA) inhibitor RB150 (0.3 mg/day), which blocks the formation of brain Ang III, or losartan (0.25 mg/day). Blood pressure (BP), heart rate, and renal sympathetic nerve activity in response to air stress and acute changes in BP were measured, and LV function was evaluated by echocardiography and Millar catheter. At 4 weeks post-MI, brain APA activity was increased, sympatho-excitatory and pressor responses to air stress enhanced, and arterial baroreflex function impaired. LV end-diastolic pressure (LVEDP) was increased and ejection fraction (EF) and maximal first derivative of change in pressure over time (dP/dt(max)) were decreased. Central infusion of RB150 during 4 weeks post-MI normalized brain APA activity and responses to stress and baroreflex function, and improved LVEDP, EF, and dP/dt(max). Central infusion of losartan had similar effects but was somewhat less effective, and had no effect on brain APA activity.

Conclusion: These results indicate that brain APA and Ang III appear to play a pivotal role in the sympathetic hyperactivity and LV dysfunction in rats post-MI. RB150 may be a potential candidate for central nervous system-targeted therapy post-MI.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aldosterone / metabolism
  • Angiotensin III / antagonists & inhibitors*
  • Angiotensin III / drug effects
  • Animals
  • Baroreflex / drug effects
  • Baroreflex / physiology
  • Blood Pressure / drug effects
  • Blood Pressure / physiology
  • Brain / drug effects
  • Brain / metabolism*
  • Disease Models, Animal
  • Disease Progression*
  • Disulfides / administration & dosage
  • Disulfides / pharmacology
  • Glutamyl Aminopeptidase / antagonists & inhibitors
  • Heart Rate / drug effects
  • Heart Rate / physiology
  • Infusions, Intraventricular
  • Myocardial Infarction / physiopathology*
  • Rats
  • Rats, Wistar
  • Renin-Angiotensin System / drug effects
  • Renin-Angiotensin System / physiology
  • Stroke Volume / drug effects
  • Stroke Volume / physiology
  • Sulfonic Acids / administration & dosage
  • Sulfonic Acids / pharmacology
  • Sympathetic Nervous System / drug effects
  • Sympathetic Nervous System / physiopathology*
  • Ventricular Dysfunction, Left / physiopathology*
  • Ventricular Dysfunction, Left / prevention & control*

Substances

  • Disulfides
  • Sulfonic Acids
  • Angiotensin III
  • Aldosterone
  • firibastat
  • Glutamyl Aminopeptidase