Central infusion of aldosterone synthase inhibitor attenuates left ventricular dysfunction and remodelling in rats after myocardial infarction.

Abstract

AIMS:

Blockade of mineralocorticoid receptors in the central nervous system (CNS) prevents sympathetic hyperactivity and improves left ventricle (LV) function in rats post-myocardial infarction (MI). We examined whether aldosterone produced locally in the brain may contribute to the activation of mineralocorticoid receptors in the CNS.

METHODS AND RESULTS:

Two days after coronary artery ligation, Wistar rats received an intra-cerebroventricular (icv) infusion via osmotic mini-pumps of the aldosterone synthase inhibitor FAD286 at 100 microg/kg/day or vehicle for 4 weeks. LV function was assessed by echocardiography at 2 and 4 weeks, and by Millar catheter at 4 weeks. At 4 weeks post-MI, aldosterone in the hippocampus was increased by 70% and tended to increase in the hypothalamus by 20%. These increases were prevented by FAD286. Across groups, aldosterone in the hippocampus and hypothalamus showed a high correlation. There were no differences in brain corticosterone levels. Compared to sham rats, at both 2 and 4 weeks post-MI rats treated with vehicle showed increased LV dimensions and decreased LV ejection fraction. Icv infusion of FAD286 attenuated these changes in LV dimensions and ejection fraction by approximately 30%. At 4 weeks post-MI, LV peak systolic pressure (LVPSP) and dP/dt(max/min) were decreased and LV end-diastolic pressure (LVEDP) was increased. In rats treated with icv FAD286, LVPSP and dP/dt(min) remained normal and LVEDP and dP/dt(max) were markedly improved. Post-MI increases in cardiac fibrosis and cardiomyocyte diameter were substantially attenuated by icv FAD286.

CONCLUSION:

These data suggest that aldosterone produced locally in the brain acts as the main agonist of mineralocorticoid receptors in the CNS and contributes substantially to the progressive heart failure post MI.

• Authors: Bing S Huang, Roselyn A White, Monir Ahmad, Junhui Tan, Arco Y Jeng, Frans H H Leenen
• Journal: Cardiovascular research (Cardiovasc Res) Vol. 81 Issue 3 Pg. 574-81 (Feb 15 2009) ISSN: 1755-3245 [Electronic] England
• PMID: 18689429 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Enzyme Inhibitors
• Aldosterone
• Steroid Hydroxylases
• Cyp11b3 protein, rat
• Cytochrome P-450 CYP11B2
• Corticosterone

Topics

• Aldosterone (blood, metabolism)
• Animals
• Cardiac Catheterization
• Corticosterone (metabolism)
• Cytochrome P-450 CYP11B2
• Disease Models, Animal
• Echocardiography
• Enzyme Inhibitors (administration & dosage)
• Fibrosis
• Hippocampus (drug effects, enzymology)
• Hypothalamus (drug effects, enzymology)
• Infusions, Parenteral
• Myocardial Infarction (complications, drug therapy, enzymology, physiopathology)
• Myocardium (pathology)
• Rats
• Rats, Wistar
• Steroid Hydroxylases (antagonists & inhibitors, metabolism)
• Stroke Volume (drug effects)
• Time Factors
• Ventricular Dysfunction, Left (enzymology, etiology, physiopathology, prevention & control)
• Ventricular Pressure (drug effects)
• Ventricular Remodeling (drug effects)