Nebivolol reduces cardiac angiotensin II, associated oxidative stress and fibrosis but not arterial pressure in salt-loaded spontaneously hypertensive rats.
OBJECTIVE
Increased sympathetic outflow, renin-angiotensin system (RAS) activity, and oxidative stress are critical mechanisms underlying the adverse cardiovascular effects of dietary salt excess. Nebivolol is a third-generation, highly selective β1-receptor blocker with RAS-reducing effects and additional antioxidant properties. This study evaluated the hypothesis that nebivolol reduces salt-induced cardiac remodeling and dysfunction in spontaneous hypertensive rats (SHRs) by suppressing cardiac RAS and oxidative stress.


METHODS
Male SHRs (8 weeks of age) were given an 8% high salt diet (HSD; n = 22), whereas their age-matched controls (n = 10) received standard chow. In a subgroup of HSD rats (n = 11), nebivolol was given at a dose of 10 mg/kg per day by gastric gavage.


RESULTS
After 5 weeks, HSD exacerbated hypertension as well as increased left-ventricular weight and collagen deposition while impairing left-ventricular relaxation. Salt-induced cardiac remodeling and dysfunction were associated with increased plasma renin concentration (PRC), cardiac angiotensin II immunostaining, and angiotensin-converting enzyme (ACE)/ACE2 mRNA and activity ratio. HSD also increased cardiac 3-nitrotyrosine staining indicating enhanced oxidative stress. Nebivolol treatment did not alter the salt-induced increase in arterial pressure, left-ventricular weight, and cardiac dysfunction but reduced PRC, cardiac angiotensin II immunostaining, ACE/ACE2 ratio, oxidative stress, and fibrosis.


CONCLUSIONS
Our data suggest that nebivolol, in a blood pressure-independent manner, ameliorated cardiac oxidative stress and associated fibrosis in salt-loaded SHRs. The beneficial effects of nebivolol may be attributed, at least in part, to the decreased ACE/ACE2 ratio and consequent reduction of cardiac angiotensin II levels.
Hypertension and Vascular Research Center, Wake Forest University, Winston-Salem, North Carolina 27157, USA. jvaragic@wakehealth.edu
Jasmina
J
Varagic
Sarfaraz
S
Ahmad
Jessica L
JL
Voncannon
Norihito
N
Moniwa
Stephen W
SW
Simington
Bridget K
BK
Brosnihan
Patricia E
PE
Gallagher
Javad
J
Habibi
James R
JR
Sowers
Carlos M
CM
Ferrario
D000804:Angiotensin II / Q000378:metabolism*; D000818:Animals; D062186:Arterial Pressure; D001578:Benzopyrans / Q000494:pharmacology*; D004983:Ethanolamines / Q000494:pharmacology*; D005355:Fibrosis; D020869:Gene Expression Profiling; D006321:Heart / Q000187:drug effects*; D008297:Male; D000068577:Nebivolol; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D011918:Rats, Inbred SHR; D012965:Sodium Chloride / Q000008:administration & dosage*
D001578:Benzopyrans; D004983:Ethanolamines; D000068577:Nebivolol; D000804:Angiotensin II; D012965:Sodium Chloride