NITRIC OXIDE-DONATING STATINS EXERT BENEFICIAL EFFECTS ON ACUTE VASCULAR INFLAMMATION IN NORMOCHOLESTEROLEMIC RABBITS

Introduction: Evidence has emerged suggesting that polymorphonuclear leukocytes (PMN) can make important contributions to vascular inflammatory processes underlying atherogenesis, thus representing new possible targets for atheroprotection. Nitric oxide (NO)-donating statins are a new class of drugs aimed to combine the effects of statins with the atheroprotective properties of NO (PNAS 2004;101: 8497\u20138502). Aim:We investigated the effects of a short-term treatment with two NO-donating derivatives of atorvastatin, NCX 6560 (successfully investigated in early clinical development; Circulation. 2010;122:A14267) and NCX 616, as compared to atorvastatin, on PMN infiltration in rabbit carotids subjected to perivascular collar placement, a model of acute arterial inflammation related to atherogenesis. Methods: Chow-fed rabbits (n = 10/group) received a daily oral dose of vehicle or experimental compounds (equivalent to 5 mg/kg/day atorvastatin) for 6 days. Collars were implanted after the last dose of treatment. Twenty-four hours later arteries were removed, immunostained for PMN, and measured by image analysis. Results: Collared carotids from the control group had a high content of PMN. Unlike atorvastatin, which did not influence the average value of PMN-positivearea compared to control, both the NO-donating statins NCX 616 and NCX 6560, which retain the inhibitory activity of atorvastatin on HMG-CoA reductase and release bioactive NO, reduced PMN infiltration of about 40% (p < 0.05) and 35% vs. control, respectively. Conclusions: NO-donating derivatives of atorvastatin exert, in addition to the effect of statin, additional beneficial effects on vascular inflammation, thus supporting a pharmacological rationale for their clinical development