Central Angiotensin Type 1 Receptor Blockade Decreases Cardiac But Not Renal Sympathetic Nerve Activity in Heart Failure

Abstract

In heart failure (HF), cardiac sympathetic nerve activity (SNA; CSNA) is increased, which has detrimental effects on the heart and promotes arrhythmias and sudden death. There is evidence that the central renin-angiotensin system plays an important role in stimulating renal SNA in HF. Because SNA to individual organs is differentially controlled, we have investigated whether central angiotensin receptor blockade decreases CSNA in HF. We simultaneously recorded CSNA and renal SNA in conscious normal sheep and in sheep with HF induced by rapid ventricular pacing (ejection fraction: <40%). The effect of blockade of central angiotensin type 1 receptors by intracerebroventricular infusion of losartan (1 mg/h for 5 hours) on resting levels and baroreflex control of CSNA and renal SNA were determined. In addition, the levels of angiotensin receptors in central autonomic nuclei were determined using autoradiography. Sheep in HF had a large increase in CSNA (43±2 to 88±3 bursts per 100 heart beats; P<0.05) and heart rate, with no effect on renal SNA. In HF, central infusion of losartan for 5 hours significantly reduced the baseline levels of CSNA (to 69±5 bursts per 100 heart beats) and heart rate. Losartan had no effect in normal animals. In HF, angiotensin receptor levels were increased in the paraventricular nucleus and supraoptic nucleus but reduced in the area postrema and nucleus tractus solitarius. In summary, infusion of losartan reduced the elevated levels of CNSA in an ovine model of HF, indicating that central angiotensin receptors play a critical role in stimulating the increased sympathetic activity to the heart.