Vascular effects of candesartan and tempol in a model of metabolic syndrome

RENNA NF; GONZALEZ S; LAMA C; MIATELLO RM

Buenos Aires. Argentina

Congreso; XVIth Wold Congress of Cardiology; 2008

World Heart Federetion. Sociedad Argentina de Cardiologia, Federacion Argentina de Cardiologia

VASCULAR EFFECTS OF CANDESARTAN AND TEMPOL IN A MODEL OF METABOLIC SYNDROME Renna NF, Gonzalez ES, Lama MC, Miatello RM. Dept. Pathology. School of Medicine. National University of Cuyo. Lab. Cardiovascular Pathophysiology - IMBECU-CONICET, Mendoza, Argentina Introduction: The vascular wall is continuously exposed to hemodynamic forces such as luminal pressure and shear stress. Structural changes are initially adaptive, but subsequently become maladaptive, resulting in changes in media thickness and lumen diameter. This vascular remodeling contributes to the pathophysiology of vascular diseases, including metabolic syndrome (MS). Cellular mechanisms implicated in arterial remodeling in MS are complex; however angiotensin II (A-II) and reactive oxygen species (ROS) are among the systems shown to be essential. Objective: To examine the vascular remodeling at mesenteric level and to evaluate the participation of the renin-angiotensin system (RAS) and the oxidative stress by means of pharmacological tools such as administration of candesartan (Cn), an AT1 antagonist, and 4-OH Tempol (Tp), a superoxide dismutase mimetic, respectively, in an experimental model of MS. Methods: Male spontaneously hypertensive rats (SHR) and Wistar Kyoto rats (WKY), were distributed in 4 groups (n=18 each). Two of them received 10% fructose solution along 6 weeks (FFHR and FFR). After that, groups were again divided in 3 groups (n=6 each): I- Controls, II-Cn: oral administration (10 mg/kg/d) and III- Tp 10-3M in drinking water. At the end of the protocol the following variables were examined: systolic blood pressure (SBP-mmHg), HOMA index (H), plasma triglyceride (TG-mg/dL); basal glycemia (BG-mg/dL), HDL-col (HL-mg/dL), plasmatic lipid peroxidation by TBARS (TB-ìmol/L), aortic NAD(P)H oxidase activity (NA-cpm/mg), relative heart weight (RHW-g/mg), left ventricular myocardiocyte cross-sectional area (MCA-ì2), Lumen to media ratio (L/M) and determination of NF-kB y VCAM-1 expression by inmunohistochemistry (IHC) in mesenteric arteries and connective tissue by confocal inmunofluorescence and western blot. Data (media±sem) were processed by ANOVA and Bonferroni post-test. Symbol * indicates p<0.01 v WKY and # p<0.01 v FFHR Results:  Compared with WKY, experimental model animals developed MS: SBP: 180±4* v 130±5; BG: 140±10* v 81±5; H: 4.0±1.0* v 0.8±0.5; TG: 123±25* v 55±1; and decreased HL: 11±2.5* v 19±2. Cn administration significantly reverted SBP: 100±10# and H: 2.0±0.9#. Tp administration partially reverted H: 2.7±0.5#. ROS increased in FFHR (TB: 170±20* v 50±10; NA: 300±80* v 15±3.4) but reverted after administration of both Cn (TB: 60±12#; NA: 100±20#) and Tp (TB: 70±10#; NA: 50±7.8#). FFHR developed cardiac hypertrophy: increased RHW: 4.1±0.02* v 2.5±0.01 and MCA: 1750±29* v 830±22 and reverted by Cn (RHW: 2.55±0.1# and MCA 900±35#) and Tp (RHW 3.4±0.08# and MCA 1200±85#). L/M ratio showed a significant reduction in FFHR (L/M: 10±0.2* v 14±1), that completely reverted after administration of Cn (L/M: 15±1.1#) and partiality after Tp treatment (L/M: 12.5±0.5#). Inflammatory markers were increased in the vascular wall and mesenteric tissue in FFHR, but reverted with Cn and Tp treatments. Conclusion: The data confirm the development of the pathological experimental model and suggest that oxidative stress and the consequent activation of genes participating in the inflammatory process. In addition, this study demonstrates that RAS participate in the structural and inflammatory changes associated to the MS experimental model.