Regulation of sympathetic nerve activity in heart failure - A role for nitric oxide and angiotensin II

The mechanisms by which sympathetic function is augmented in chronic heart failure (CHF) are not well understood. A previous study from this laborator y (Circ Res. 1998;82:496-502) indicated that blockade of nitric oxide (NO) synthesis resulted in only an increase in renal sympathetic nerve activity (RSNA) when plasma angiotensin II (Ang II) levels were elevated. The presen t study was undertaken to determine if NO reduces RSNA in rabbits with CHF when Ang II receptors are blocked. Twenty-four New Zealand White rabbits we re instrumented with cardiac dimension crystals, a left ventricular pacing lead, and a pacemaker. After pacing at 360 to 380 bpm for approximately 3 w eeks, a renal sympathetic nerve electrode and arterial and venous catheters were implanted. Studies were carried out in the conscious state 3 to 7 day s after electrode implantation. The effects of a 1-hour infusion of sodium nitroprusside (SNP; 3 mu g.kg(-1).min(-1)) on RSNA and mean arterial pressu re (MAP) were determined before and after Ang II blockade with losartan (5 mg/kg) in normal and CHF rabbits. Changes in MAP were readjusted to normal with phenylephrine. Before losartan, SNP evoked a decrease in MAP and an in crease in RSNA in both groups that was baroreflex-mediated, because both MA P and RSNA returned to control when phenylephrine was administered. In the normal group, losartan plus SNP caused a reduction in MAP and an increase i n RSNA that was 152.6+/-9.8% of control. Phenylephrine returned both MAP an d RSNA back to the control levels. However, in the CHF group, losartan plus SNP evoked a smaller change in RSNA for equivalent changes in MAP (117.1+/ -4.1% of control). On returning MAP to the control level with phenylephrine , RSNA was reduced to 65.2+/-2.9% of control (P<0.0001). These data suggest that endogenous Ang II contributes to the sympathoexcitation in the CHF st ate and that blockade of Ang II receptors plus providing an exogenous sourc e of NO reduces RSNA below the elevated baseline levels. We conclude that b oth a loss of NO and an increase in Ang II are necessary for sustained incr eases in sympathetic nerve activity in the CHF state.