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* To whom correspondence should be addressed. E-mail: izucker{at}unmc.edu.
Chronic congestive heart failure (CHF) is characterized by sympatho-excitation. The paraventricular nucleus (PVN) is a site of integration of autonomic and endocrine-mediated cardiovascular responses. Nitric oxide (NO) is sympatho-inhibitory and neuronal NOS (nNOS) is down regulated in the PVN in CHF. We examined the role of NO in the PVN on the control of blood pressure and heart rate in conscious sham and CHF rats by using nNOS specific antisense oligonucleotides. We hypothesized that inhibition of nNOS synthesis in the PVN would lead to a pressor response in sham rats but not in CHF rats. CHF was induced by ligation of the left main coronary artery. After six to eight weeks, the coronary ligated rats showed hemodynamic and echocardiographic signs of CHF. The depression of nNOS synthesis by nNOS antisense was confirmed by immunohistochemical staining and western blot analysis. Using radio-telemetry, mean arterial pressure (MAP) and heart rate (HR) were monitored continuously. In sham rats, we found that microinjection of sodium nitroprusside (SNP, 20 nmol, 100 nl) into the PVN induced a significant decrease in MAP from minute 4 to minute 10. SNP also induced a significant decrease in HR over the next 10 minutes. In contrast, the NOS inhibitor NG-monomethyl-L-arginine (L-NMMA, 200 pmol, 100 nl) significantly increased MAP and HR over the next 18 or 20 minutes, respectively. Mismatched oligonucleotides and vehicle did not alter MAP or HR in sham or CHF rats. After injection of nNOS antisense, MAP was significantly increased in sham rats over the next 7 hours. The peak response occurred at hour 4 and the magnitude was 27.6±4.1% above baseline pressure. However, in the CHF rats MAP was only significantly increased at hour 4. The peak magnitude was 12.9±5.4% of baseline, which was significantly attenuated compared to sham rats (p<0.01). In sham rats the pressor response was completely abolished by the 
-blocker, phentolamine. The HR was significantly increased from hour 1 to hour 7 in both sham and CHF rats. There was no difference in the magnitudes of the HR responses. The tachycardia could not be abolished by the 
1-blocker, metoprolol. However, the muscarinic receptor antagonist, atropine did not further augment the tachycardia. We conclude that NO induces a significant depressor and bradycardiac response in normal rats. Delivery of nNOS antisense into the PVN exerts a significant pressor and tachycardiac response in sham rats. The pressor response is mediated by an elevated sympathetic tone, whereas the tachycardia is mediated by withdrawal of parasympathetic tone in sham rats. The pressor response was significantly blunted in CHF rats. These data are consistent with a downregulation of nNOS within the PVN in the CHF state.
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