Sympathetic modulation by carvedilol and losartan reduces angiotensin II-mediated lipolysis in subcutaneous and visceral fat.
Advanced heart failure is characterized by increased activation of the renin-angiotensin system and the development of cachexia. Angiotensin II (Ang II) has been proposed as a lipid metabolism regulator. The effects of exogenous Ang II (osmotic minipump, 525 ng/kg/min for 12 d) on interstitial sc glycerol and norepinephrine levels, indexes of lipolysis, and sympathetic activation, respectively, were measured in Sprague Dawley rats by consecutive microdialysis performed in vivo in white adipose tissue. Higher sustained interstitial glycerol and norepinephrine levels were found after 7 and 12 d of Ang II infusion. Triglyceride to DNA content ratio and adipocyte diameter were reduced in sc and visceral (retroperitoneal and epididymal) fat tissues of Ang II-infused rats, whose body weight was lower and blood pressure higher. Losartan, an Ang II receptor 1 blocker, and carvedilol, an alpha1-nonselective-beta1,2,3-adrenergic blocker, but not doxazosin, an alpha1-selective-adrenergic blocker, lowered glycerol and norepinephrine levels, preventing lipolysis and weight loss. Our results indicate that Ang II stimulates lipolysis in sc and visceral adipocytes by sympathetic activation and beta-adrenergic-receptor stimulation. Nonselective-beta-adrenergic and Ang II-receptor1 blockade markedly attenuated the rise of norepinephrine, preventing catabolic effects. The metabolic benefits of carvedilol and losartan, in addition to recognized protective cardiovascular effects, may be relevant in cachectic patients with advanced heart failure.
Cabassi
Aderville
A
Laboratory of Clinical Physiology, Hypertension Unit, Department of Internal Medicine, Nephrology, and Health Sciences, University of Parma, Via Gramsci 14, 43100 Parma, Italy. cabassia@unipr.it
Coghi
Pietro
P
Govoni
Paolo
P
Barouhiel
Elisa
E
Speroni
Ester
E
Cavazzini
Stefania
S
Cantoni
Anna Maria
AM
Scandroglio
Renato
R
Fiaccadori
Enrico
E
D017667:Adipocytes / Q000473:pathology; D000273:Adipose Tissue / Q000378:metabolism*; D000804:Angiotensin II / Q000097:blood / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure; D001835:Body Weight; D002227:Carbazoles / Q000494:pharmacology*; D000077261:Carvedilol; D005990:Glycerol / Q000378:metabolism; D006339:Heart Rate; D008066:Lipolysis / Q000187:drug effects*; D019808:Losartan / Q000494:pharmacology*; D008297:Male; D009638:Norepinephrine / Q000378:metabolism; D011412:Propanolamines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D002787:Sterol Esterase / Q000378:metabolism; D013564:Sympathetic Nervous System / Q000187:drug effects* / Q000502:physiology; D014280:Triglycerides / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D002227:Carbazoles; D011412:Propanolamines; D014280:Triglycerides; D000077261:Carvedilol; D000804:Angiotensin II; D014446:Tyrosine 3-Monooxygenase; D002787:Sterol Esterase; D019808:Losartan; D005990:Glycerol; D009638:Norepinephrine