DECREASED GENE-EXPRESSION OF NEURONAL NITRIC-OXIDE SYNTHASE IN HYPOTHALAMUS AND BRAIN-STEM OF RATS IN HEART-FAILURE

Nitric oxide may act at autonomic sites in the brain to regulate sympa thetic outflow. Our goal was to determine whether gene expression of t he neuronal isoform of nitric oxide synthase (nNOS) is altered in disc rete autonomic brain regions of rats in the chronic phase of heart fai lure compared to sham-operated control rats. Experiments were performe d in rats 4 to 5 weeks after left coronary artery ligation. Histologic al data indicated that there was a 39% outer and a 45% inner infarct o f the left ventricular myocardium in the heart failure group. The myoc ardium in sham-operated rats showed no observable damage. Total RNA wa s purified from microdissected brain tissue blocks containing hypothal amus, dorsal pens, 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 coa mplified as an internal standard. Compared with controls, significant decreases in nNOS mRNA levels were found in hypothalamus (19%), dorsal pens (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 c entral sites, the plasma concentration of norepinephrine was significa ntly elevated in rats with heart failure compared to sham-operated con trol rats. Our results show that heart failure is associated with decr eases in nNOS gene expression in at least three regions of the brain a nd with increased sympathetic outflow to the periphery. The decreased NO production that is likely associated with the decreases in nNOS gen e expression may lead to the increased sympathetic drive seen in chron ic heart failure.