ABSTRACT
BACKGROUND: In the present study, nitric oxide (NO) was investigated to see if it mediated effects of nebivolol on apoptosis in the rat myocardial infarction (MI) model. METHODS AND RESULTS: Rats were divided into 3 groups: sham operated (sham-control), MI-induced (MI-control) and nebivolol treated (MI-nebivolol). The initial dose of nebivolol was administrated intravenously (iv) within 10 min of post-MI reperfusion and continued orally for 28 days. NO mediated effects of nebivolol were assessed either in the early (2(nd) day) or sub-acute (28(th) day) period of MI by histologic, hemodynamic and biologic studies. Left ventricular (LV) pressure changes were prevented with nebivolol (the increase in LV end-diastolic pressure and the decrease in maximum rise and fall rate of LV pressure (+dp/dt and -dp/dt) was significantly less in MI-nebivolol). Total and regional apoptotic indexes were significantly lower in the MI-nebivolol group (10.2 vs 7.1%, respectively on the 2(nd) day; p=0.004). Although plasma nitrite/nitrate, cyclic guanylate cyclase and peroxynitrite concentrations were high both in MI-control and MI-nebivolol groups on the 2(nd) day, these concentrations were decreased to the basal value on the 28(th) day in the MI-nebivolol group. CONCLUSION: As a result, nebivolol treatment (initially by iv within 10 min of reperfusion and continued orally) reduced the myocardial apoptosis after MI. This beneficial effect of nebivolol is mediated by NO regulation.
Subject(s)
Adrenergic beta-Antagonists/pharmacology , Apoptosis/drug effects , Benzopyrans/pharmacology , Ethanolamines/pharmacology , Myocardial Infarction/drug therapy , Myocardial Infarction/pathology , Animals , Blood Pressure/drug effects , Cyclic GMP/blood , Disease Models, Animal , Male , Microscopy, Electron, Transmission , Myocardial Infarction/blood , Myocardial Infarction/physiopathology , Myocytes, Cardiac/drug effects , Myocytes, Cardiac/pathology , Nebivolol , Rats , Rats, Sprague-Dawley , Reactive Nitrogen Species/blood , Ventricular Function, Left/drug effectsABSTRACT
PURPOSE: Asymmetric dimethylarginine (ADMA), nitric oxide (NOx), and C-reactive protein (CRP) are important risk factors for endothelial dysfunction and mortality in the end stage renal diseases population. The aim of the study was to investigate the relationship between renal replacement therapy and endothelial dysfunction. METHODS: Plasma NOx, ADMA and CRP levels were examined in randomized selected 30 patients with chronic kidney diseases (CKD), 28 patients receiving continuous ambulatory peritoneal dialysis (PD) and 30 patients receiving regular hemodialysis (HD) and age-matched 20 healthy controls. The duration of dialysis was from 4, 5 to 11, and 6 years, respectively. RESULTS: CKD patients had higher plasma ADMA (1.26+/-0.53 micromol/L) and CRP levels (1.02+/-025 mg/L) and lower NOx levels (28.6+/-5.4 micromol/L) than controls (0.45+/-0.20; 0.65+/- 0.45; 32.5+/-37 respectively, P < 0.001). Plasma NOx and CRP levels were higher in HD patients (32.9+/-5.5 micromol/L, P < 0.05 and 4.59+/-3.18 mg/L, P < 0.001) and plasma ADMA and CRP levels were higher in PD patients (1.82+/-0.98 micromol/L, P < 0.001 and 2.40+/-1.53 mg/L, P < 0.001) than in CKD patients. PD patients had higher plasma ADMA levels (P < 0.05) and lower plasma NOx and CRP levels than HD patients (P < 0.001 and P < 0.001). Plasma ADMA levels were negatively correlated with NOx levels in all patient groups (P < 0.001). Plasma CRP levels in CKD and HD patients were positively correlated with plasma urea levels (r:0,437, P < 0,001) and duration of dialysis (r:0,370, P < 0.01), respectively. CONCLUSION: CRP and ADMA may be emerging as important risk factors for atherosclerosis in dialysis patients. Reduced NO elaboration secondary to accumulation of ADMA and elevated inflammation may be important pathogenic factors for endothelial dysfunction in both dialysis treatment strategies.
