EFFECT OF SHORT-TERM TREATMENT WITH LERCANIDIPINE ON INSULIN SIGNALLING AND OXIDATIVE STRESS IN HYPERTENSIVE PATIENTS

Background: It was previously demonstrated that metabolic syndrome in humans is associated with an impairment of insulin signalling in circulating mononuclear cell (Pasini E. et al. Cardiovascular Diabetology 2010). In animal models of hypertension, ACE inhibitors and angiotensin receptor blockers may correct alterations of insuling signalling (Rizzoni D et al, J Hypertens 2008). Therefore we investigated the effects of antihypertensive treatment with two drug combinations on insulin signalling and oxidative stress. Patients and methods: Twenty essential hypertensive patients were included in the study and treated for 4 weeks with lercanidipine 20 mg per day orally. Then they were treated for 6 months with lercanidipine+enalapril (n=10) or lercanidipine+ hydrochlorothiazide (n=10). Investigations were performed in basal condition, after 4 weeks of monotherapy with lercanidipine, and at the end of the combination treatment. Insulin signalling was evaluated in mononuclear cells by Wester-Blot. Circulating levels of C-reactive protein (CRP), proinflammatory cytokines interleukin-6 and interleukin-18 (IL-18), macrophage chemotactic factor- 1 (MCP-1), soluble vascular cell adhesion molecule 1 and soluble inter-cellular adhesion molecule 1, malonyldialdehyde and lipid peroxidation were measured in plasma using a spectrophotometric assay. Results are summarized in the Table (*P<0.05, **p<0.01 vs. Basal; #p<0.05 vs. lercanipine alone). Data are normalized for tubulin expression (insulin receptor, GLUT-4) or for the expression of the non phosphorylated form (activation for p70S6K1 and mTOR, inactivation for IRS-1). No difference was observed between groups for IRS-1 or mTOR. An increased expression of insulin receptor, GLUT-4 and an increased activation of p70S6K1 were observed during treatment with lercanidipine+enalapril but not with lercanidipine+hydrochlorothiazide. Changes after treatment with lercanidipine alone were modest. A reduction in circulating levels of IL 18, CRP and MCP-1 was observed after treatment with lercanidipine alone, which persisted or further improved after treatment with lercanidipine+enalapril but not with lercanidipine+hydrochlorothiazide. Conclusion: The combination treatment lercanidipine+enalapril seems to be more effective than lercanidipine+hydrochlorothiazide in activate insulin signalling in human lympho-monocytes, possibly due to a more marked antioxidant/ antiinflammatory effect.