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Effects of nNOS antisense in the paraventricular nucleus on blood pressure and heart rate in rats with heart failure

Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, Nebraska

Submitted 25 May 2004 ; accepted in final form 24 August 2004

Using neuronal NO synthase (nNOS)-specific antisense oligonucleotides, we examined the role of nitric oxide (NO) in the paraventricular nucleus (PVN) on control of blood pressure and heart rate (HR) in conscious sham rats and rats with chronic heart failure (CHF). After 6–8 wk, rats with chronic coronary ligation showed hemodynamic and echocardiographic signs of CHF. In sham rats, we found that microinjection of sodium nitroprusside (SNP, 20 nmol, 100 nl) into the PVN induced a significant decrease in mean arterial pressure (MAP). SNP also induced a significant decrease in HR over the next 10 min. In contrast, the NOS inhibitor N^G-monomethyl-L-arginine (L-NMMA, 200 pmol, 100 nl) significantly increased MAP and HR over the next 18–20 min. After injection of nNOS antisense, MAP was significantly increased in sham rats over the next 7 h. The peak response was 27.6 ± 4.1% above baseline pressure. However, in the CHF rats, only MAP was significantly increased. The peak magnitude was 12.9 ± 5.4% of baseline, which was significantly attenuated compared with sham rats (P < 0.01). In sham rats, the pressor response was completely abolished by -receptor blockade. HR was significantly increased from hour 1 to hour 7 in sham and CHF rats. There was no difference in magnitude of 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. The pressor response is mediated by an elevated sympathetic tone, whereas the tachycardia is mediated by withdrawal of parasympathetic tone in sham rats. These data are consistent with a downregulation of nNOS within the PVN in CHF.

oligonucleotides; gene expression; sympathetic nerve activity

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