5.6 LONG-TERM TREATMENT WITH MELATONIN MAI IMPROVE ANTICONTRACTILE ACTIVITY OF PERIVASCULAR FAT IN OBESE MICE

Abstract

Background. The anticontractile effect of perivascular adipose tissue(PVAT) is lost in obese patients due to adipocyte hypertrophy, leading to hypoxia, inflammation, and oxidative stress(Circulation 2009; 119(12):1661–1670).We recently demonstrated that the property of PVAT, partially maintained in an animal model of genetic obesity, seems to be related to the activity of BKCA channels, since is selectively blocked by iberiotoxin. We aimed to investigate functional responses of small mesenteric arteries in an animal model of genetic obesity after chronic treatment with melatonin, an endogenous hormone with antioxidant and vasculoprotective properties. Methods. Obese mice (n = 9) (B6.V-Lep ob/OlaHsd, Harlan Laboratories S.r.l.) (ob/ob) and control lean mice (n = 8) (CLM) were treated with melatonin (MEL)100 mg/kg per day for 8 weeks (from the5th to the 13th week of age).Data were compared from untreated ob/ob (n = 15) and CLM (n = 10) animals. Mesenteric small resistance arteries were dissected and mounted on a wire myograph. Concentration-response to norepinephrine was evaluated in vessels with intact PVAT (WF) and in vessels in which PVAT was removed (NoF) under normoxic and hypoxic (30’95% N2/5%CO2) conditions. Norepinephrine concentration-response curve was repeated with iberiotoxin(30’preincubation 100 nm/L). Results. MEL significantly reduced the contractile response in NoF ob/ob and CLM vessels (ANOVA P = 0.014 and P = 0.049 respectively).The improvement after MEL was also seen in CLM NoF vessels during hypoxia(ANOVA p < 0.05) and following preincubation with iberiotoxin(P < 0.05), with no significant improvements in ob/ob. Increases in contractility following hypoxia and iberiotoxin treatment were restored byMEL in Ob/Ob WF vessels (P = 0.013 and P = 0.036 respectively),whereas MEL only rescued the effects of hypoxia(P = 0.045) in CLM WF arteries. In conclusion, MEL exerts a protective effect in small vessels with and without PVAT from both ob/ob and CLM, counteracting the adverse effect of hypoxia and iberiotoxin in vessels with PVAT and in CLM vessels whitout PVAT. However, in Ob/Ob animals MEL rescues the effects only in the presence of PVAT indicating the importance of PVAT oxidative stress in vascular dysfunction observed in Ob/Ob animals.