Abstract 5841: Effect of Candesartan on Reflex Sympatho-Neural Response to Local Adenosine Infusion in Angiotensin Converting Enzyme Inhibitor-Treated Heart Failure Patients
Background: The magnitude of sympathetic nervous system activation in a heart failure (HF) patient reflects the net interaction between inhibitory and excitatory reflex influences, one of which may be a metaboreflex stimulated by adenosine. In healthy men, adenosine stimulated afferent nerve endings in skeletal muscle, causing a reflex increase in total body norepinephrine (NE) spillover (TBS) that was abolished by angiotension AT1 receptor blockade. Whether a similar reflex is active in HF is unknown.
Objective: To determine the effect of locally infused adenosine on TBS in HF patients receiving ACE-inhibitors and β-blockers in the presence and absence of angiotensin II AT1 receptor blockade.
Methods: In this double-blind study, 12 HF patients with left ventricular ejection fraction < 40% were randomized to 2 weeks of Candesartan (32 mg/day) or placebo. Bilateral forearm blood flow was measured by venous occlusion strain gauge plethysmography. TBS was determined by infusion of tritiated NE. After saline was infused into the non-dominant brachial artery to establish baseline values, adenosine (5 μg/100 ml, then 15 μg/100 ml forearm tissue, each for 5 min), and nitroprusside (as vasodilator control), were infused in random order.
Results: Both adenosine and nitroprusside caused dose-dependent increases in ipsilateral forearm blood flow, with no impact on contra-lateral blood flow or systolic blood pressure. With increasing doses of adenosine, there was a significant reduction in TBS, from 3967 pmol/min (standard deviation [SD] 2362) to 3293 pmol/min (SD 2093) (p=0.03). This effect tended to be greater in patients on placebo, with a mean reduction in TBS of 1096 pmol/min (SD 726), compared with 253 pmol/min (SD 1094) in patients taking Candesartan (p=0.22). Nitroprusside had no effect on TBS.
Conclusions: In contrast to previous observations in healthy men, locally infused adenosine exerts a reflex sympatho-inhibitory response in HF. This may be the result of saturation or desensitization of forearm afferents by endogenous adenosine, or central adaptations to the chronically altered afferent input in HF patients. Whether increased angiotensin II attenuates this response, possibly by acting on unblocked AT2 receptors, merits further investigation.