Abstract 5834: Brain Reactive Oxygen Species and Mitogen-Activated Protein Kinase Mediate Aldosterone-Induced Sympathetic Excitation in Rats With Heart Failure
Introduction: Aldosterone (ALDO) increases sympathetic nerve activity in heart failure (HF), but the underlying mechanism is unclear. Chronic intracerebroventricular (ICV) administration of the selective mineralocorticoid receptor (MR) antagonist RU28318 reduces the expression of reactive oxygen species (ROS) in paraventricular nucleus of hypothalamus (PVN) and activation of the sympathetic nervous system in rats with HF. Systemically infused ALDO increases the expression of mitogen-activated protein kinase (MAPK) in PVN and sympathetic drive in normal rats, effects blocked by ICV RU28318. The p44/42 MAPK inhibitor PD98059, administered centrally, reduces sympathetic activity in HF rats.
Hypothesis: Brain NADPH oxidase-derived ROS and MAPK signaling mediate ALDO-induced sympathetic-excitation in rats with HF.
Methods: Sprague-Dawley rats underwent coronary ligation to induce HF. HF rats were treated ICV for 4 weeks with RU28318 (1 μg/h, n=12), the superoxide dismutase mimetic tempol (25 μg/h, n=11), or the p44/42 MAPK inhibitor PD98059 (0.025 μg/h, n=11). Comparisons were made with previous data from vehicle-treated HF (n=12) and SHAM (n=11) rats.
Results: Previous studies showed that HF rats, compared with SHAM, have increased plasma ALDO, increased mRNA for NADPH oxidase subunits p47phox and gp91phox in hypothalamus, increased superoxide production, phosphorylated p44/42 MAPK and Fra-LI positive (excited) neurons in PVN, and increased plasma norepinephrine. In the present study in HF rats, ICV RU28318 reduced (#p<0.05, vs vehicle) phosphorylated p44/42 MAPK by 35%# and Fra-LI positive neurons in PVN by 28%#. ICV tempol reduced phosphorylated p44/42 MAPK by 31%# and Fra-LI activity of PVN neurons by 28%#. ICV tempol also decreased hypothalamic mRNA for NADPH oxidase subunit p47phox by 40%# but had no effect on gp91phox. PD98059 had no effect on NADPH oxidase subunits, but reduced Fra-LI positive neurons in a manner similar to RU28318 and tempol.
Conclusion: The data suggest that ALDO induces sympathetic excitation in HF rats by activating the p44/42 MAPK signaling pathway, which is dependent on NADPH oxidase-derived ROS.