Decreased gene expression of neuronal nitric oxide synthase in hypothalamus and brainstem of rats in heart failure.
Nitric oxide may act at autonomic sites in the brain to regulate sympathetic outflow. Our goal was to determine whether gene expression of the neuronal isoform of nitric oxide synthase (nNOS) is altered in discrete autonomic brain regions of rats in the chronic phase of heart failure compared to sham-operated control rats. Experiments were performed in rats 4 to 5 weeks after left coronary artery ligation. Histological data indicated that there was a 39% outer and a 45% inner infarct of the left ventricular myocardium in the heart failure group. The myocardium in sham-operated rats showed no observable damage. Total RNA was purified from microdissected brain tissue blocks containing hypothalamus, dorsal pons, dorsal medulla, rostral ventrolateral medulla, and caudal ventrolateral medulla. Changes in nNOS mRNA were semiquantified in each region using reverse transcription-polymerase chain reactions in which known concentrations of deletion mutant of the gene were coamplified as an internal standard. Compared with controls, significant decreases in nNOS mRNA levels were found in hypothalamus (19%), dorsal pons (43%) and dorsal medulla (34%) of rats with heart failure. There were no statistically significant differences in nNOS mRNA levels in rostral or caudal ventrolateral medulla between the control and heart failure groups. Concomitant with the changes nNOS gene expression in central sites, the plasma concentration of norepinephrine was significantly elevated in rats with heart failure compared to sham-operated control rats. Our results show that heart failure is associated with decreases in nNOS gene expression in at least three regions of the brain and with increased sympathetic outflow to the periphery. The decreased NO production that is likely associated with the decreases in nNOS gene expression may lead to the increased sympathetic drive seen in chronic heart failure.
Department of Physiology and Biophysics, University of Nebraska Medical Center, Omaha 68198, USA.
K P
KP
Patel
K
K
Zhang
I H
IH
Zucker
T L
TL
Krukoff
D000818:Animals; D001921:Brain / Q000201:enzymology / Q000473:pathology; D001933:Brain Stem / Q000503:physiopathology*; D002303:Cardiac Output, Low / Q000097:blood / Q000235:genetics*; D002395:Catecholamines / Q000097:blood; D015870:Gene Expression; D007031:Hypothalamus / Q000503:physiopathology*; D008297:Male; D009203:Myocardial Infarction / Q000473:pathology; D009474:Neurons / Q000201:enzymology*; D019001:Nitric Oxide Synthase / Q000235:genetics* / Q000378:metabolism; D016133:Polymerase Chain Reaction; D051381:Rats; D017207:Rats, Sprague-Dawley; D012016:Reference Values
D002395:Catecholamines; D019001:Nitric Oxide Synthase