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.

Figure 1

Raw traces of arterial pressure (AP), cardiac sympathetic nerve activity (SNA) and renal SNA in a conscious sheep in HF before (panel A) and after (panel B) 5 hours ICV infusion of Losartan (1mg/hr).

Figure 2

Changes in MAP, HR, CSNA and RSNA over 5 hours ICV infusion of Losartan in conscious normal (solid line) and heart failure (dashed line) sheep. Time 0 shows resting levels before the start of the Losartan infusion. Results are mean ±SEM. † indicates significant decrease in HF animals after 5 hours Losartan. # indicates significant difference between normal and HF animals at the control time point.

Figure 3

Baroreflex relations of % CSNA (a) and % RSNA (b) (both normalised to pre-losartan values in each group) to diastolic blood pressure (dBP), and of HR to systolic blood pressure (sBP) (c). Data are from normal (left panel) and HF animals (right panel) before (solid line) and after (dashed line) ICV infusion of Losartan (1mg/hr for 5 h). Resting points before (filled circle) and after (open circle) Losartan are indicated as mean±SEM. † indicates significant decrease with Losartan, † indicates decreased range with Losartan, *indicates decreased range with HF.

Figure 4

Original x-ray images of Ang II binding in the hypothalamus and brainstem of one normal (Panel A, C) and one HF animal (Panel B, D). The binding was totally displaced after co-incubation with the AT₁R antagonist Losartan. The histogram shows the density of AT₁R binding in major central cardiovascular control nuclei in normal (open bars, n = 5) and heart failure animals (filled bars, n = 5). Receptor binding densities, determined by in vitro autoradiography, are normalized to control values. PVN, paraventricular nucleus of the hypothalamus; SON, Supraoptic nucleus; AP, area postrema; NTS, nucleus of the solitary tract. Results are expressed as means ± SE. *P < 0.05 compared with normals using Student’s t-test.