Infusion of Losartan into the 4th Ventricle Reduced Cardiac Sympathoexcitation in Heart Failure

Abstract

Background and AimsA key feature of heart failure (HF) is an increase in cardiac sympathetic nerve activity (CSNA). We have found that the area postrema (AP), a brainstem circumventricular organ, plays an important role in controlling CSNA and in determining the increase in CSNA in heart failure. We hypothesized that in sheep with HF, 4th ventricular infusions of losartan (angiotensin II type 1 receptor antagonist) will reduce CSNA to a greater extent than infusion into the cisterna magna.MethodsIn sheep (n=6), when ejection fraction (EF) had fallen to ~50%, cannulae were implanted for infusion into the 4th ventricle and cisterna magna. Blood pressure, heart rate, CSNA & renal SNA were recorded when EF had fallen to <40%. Losartan (1.0 mg/h) or artificial cerebrospinal fluid (aCSF) (1.0 mL/h) were infused into the 4th ventricle and cisterna magna for 5 h, at two days after nerve recording electrodes were surgically implanted.ResultsIn sheep with HF, there was a significant decrease in EF (from 81 ± 3 % to 37 ± 1 %, P <0.001). During 4th ventricle infusion of losartan, there was a significant decrease in CSNA (89 ± 3 to 48 ± 8 bursts/100 heartbeats, P<0.01). Infusion of losartan into the cisterna magna caused a smaller decrease in CSNA (85 ± 2 to 74 ± 4 bursts/100 heartbeats, P<0.05). Infusion of losartan into the 4th ventricle caused no significant changes in renal SNA or in other parameters. Infusion of aCSF into the 4th ventricle or cistrena magna had no effects.ConclusionsInfusion of losartan into the 4th ventricle reduced the elevated CSNA in sheep with HF. The findings suggest that angiotensin type 1 receptors in the brainstem have an important role in determining the increased CSNA in heart failure.