Long-term NAD(P)H oxidase inhibition reduces adipose sympathetic activation and fat loss in cardiac cachectic rats.

Abstract Advanced heart failure is characterized by activation of the sympathetic ner¬vous system. renin-angiotensin system and oxidative stress. The develop¬ment of cachexia, including fat loss, is detrimental in heart failure patients. This study evaluated in male spontaneously hypertensive rats (SHR) the effects of long-term inhibition of NAD(P)H oxidase on white adipose tissue sympathetic turnover, expressed by interstitial norepinephrine release (NE, microdialysis techniques) and by presynaptic NE reuptake (evaluated by desipramine perfusion through microdialysis probes, 10pmollmin). Blood pressure, heart rate and body weight were periodically measured on 51 SHR from 72 weeks old until the development of overt heart failure. At 72 weeks, SHR underwent a basal microdialysis procedure which showed a higher interstitial subcutaneous NE level associated with a reduced presynaptic reuptake. During the . procedure, an adipose biopsy was taken to measure triglyceride/DNA content and adipocyte diameter. SHR were then separated: (1) untreated SHR (n=27) and (2) SHR (n=24) treated with a NAD(P)H oxidase inhibitor (2.5 mg/kg/d in drinking water, Apocynin) until death or 88 weeks of age, when the rats repeated the microdialysis procedure. Between 72 and 88 weeks of age, 33% of un¬treated SHR (9/27) showed a body weight reduction of more than 15% whereas in apocynin-treated SHR only 4 rats (16%) developed cachexia. Adipose interstitial NE was higher in cachectic than non-cachectic untreated SHR with a reduced presynaptic reuptake, TG/DNA adipose content ratio and adipocyte size in the former. Non-cachectic apocynin-treated SHR showed a reduced interstitial level of NE and improved presynaptic NE reuptake associated with higher triglyceride/DNA content and J adipocyte size, demonstrating a reduced lipolytic effect. Our results indicate that long-term inhibition of NAD(P)H' oxidase, the target of many cytokines and of angiotensin II which are increased in heart failure, could improve adipose sympathetic turnover and attenuate fat loss and cachexia development in this model of heart failure.