Antioxidant-nebivolol association enhances antihypotensive response through no pathway improvement

POLIZIO, AH; BERTERA, FM; SANTA CRUZ, DM; LITERIO, LM; GALEANO, M; BALESTRASSE, KB; GORZALCZANY, S; GIRONACCI, MM; TAIRA, C

Congreso; High Blood Pressure Research 2011 Scientific Sessions; 2011

Adrenergic �-receptor antagonists are standard drugs for the treatment of hypertension. Oneof these blockers, nebivolol, is a highly selective and long-acting �1-adrenoceptor blocker withdirect vasodilatory properties through the endothelial nitric oxide synthase (eNOS) stimulation.Hypertension is associated with superoxide (O2.-) production that reduces the bioavailability ofNO and forms peroxynitrite, a potent oxidant believed to be responsible for endothelialdysfunction. Taking into account the fact that eNOS is highly depend of O2.-, we hypothesizedthat administration of an antioxidant as tempol, a O2.- scavenger, could increase nebivololantihypertensive efficacy by increasing NO mediated response. Twenty -Male Sprague Dawleyrats (250-270 g) were divided into two groups; control group (C, n�10) and rats treated withtempol (172 mg/ml) in the drinking water during 7 days (T, n�10). At the seventh day, thecarotid and the femoral artery were cannulated. Carotid artery was connected to a polygraphand the mean arterial pressure (MAP) and heart rate (HR) were calculated. After recovery,nebivolol was administrated via femoral vein into the C and T animals at a concentration of 3mg/kg. Whilst nebivolol did not modify the MAP in C animals (3.97 mmHg �0.93), Nebivololadministration in the T group diminished MAP (-28.3 mmHg �3.1 p�0.05) at 10 minutes.Pretreatment with L -NAME, a NOS inhibitor, (75 mg/kg, i.v), but not glyburide (an inhibitor Kcachannels) decreased 58%�5 (-14.72mmHg) vs 5%�2 (-27 mmHg) respectively, thehypotensive response found in the T animals. With respect to the HR values, they were notsignificative differences between T and C groups. Interestingly, nebivolol increased the NObioavailability in nebivol-tempol animals, but not in C animals, measured by EPR-basedhemoglobin-NO detection, Griess reaction assay. Also, tempol treatment improved vascularreactivity mediated by nebivolol stimulation. In conclusion, chronic pretreatment with theantioxidant tempol improved nebivolol NO-depent vasodilation increasing thereby hypotensiveresponse to this third-generation beta blocker. Our results support the dual associationnebivolol-tempol as a promising therapeutic strategy for hypertension treatment.